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Microbiota-associated molecular genotoxicity
Irene Maier
doi : 10.18632/aging.203446
Volume 13, Issue 16 pp 19948—19949
The role of KRT17 in colorectal cancer
Daisuke Ujiie, Hirokazu Okayama, Koji Kono
doi : 10.18632/aging.203471
Volume 13, Issue 16 pp 19950—19951
Challenges in targeting the tryptophan metabolism in cancer immunotherapy
Julia Schollbach, Stefan Löb
doi : 10.18632/aging.203492
Volume 13, Issue 16 pp 19952—19953
COVID-19 mortality rate in children is U-shaped
Nina Khera1,3 , Didac Santesmasses2 , Csaba Kerepesi2 , Vadim N. Gladyshev2
doi : 10.18632/aging.203442
Volume 13, Issue 16 pp 19954—19962
Children are known to be better protected from COVID-19 than adults, but their susceptibility patterns and the risk relative to other diseases are insufficiently defined. Here, we found that the COVID-19 mortality rate is U-shaped in childhood: it initially decreases, reaching the minimum at the ages 3-10 years, and then increases throughout life. All-cause mortality and mortality from other diseases, such as pneumonia and influenza, show a similar pattern; however, childhood mortality rates from COVID-19 are considerably lower than from other diseases, with the best relative protection achieved at the youngest ages. Consistent with this, the fraction of COVID-19 deaths among all deaths increases as a function of age throughout childhood and the entire life. We discuss implications of the elevated postnatal COVID-19 risk and lower childhood COVID-19 mortality compared to other diseases.
The interplay between gray matter and white matter neurodegeneration in subjective cognitive decline
Nira Cedres1,2 , Patricia Diaz-Galvan1,3 , Lucio Diaz-Flores4 , J-Sebastian Muehlboeck1 , Yaiza Molina5 , José Barroso6 , Eric Westman1,7, * , Daniel Ferreira1,3,6, *
doi : 10.18632/aging.203467
Volume 13, Issue 16 pp 19963—19977
To investigate the interplay between gray matter (GM) and white matter (WM) neurodegeneration in subjective cognitive decline (SCD), including thickness across the whole cortical mantle, hippocampal volume, and integrity across the whole WM.
TGF-?2 and collagen play pivotal roles in the spheroid formation and anti-aging of human dermal papilla cells
Hyunju Kim1 , Nahyun Choi1 , Doo Yeong Kim2 , So Yoon Kim1 , Seung Yong Song3 , Jong-Hyuk Sung1,2
doi : 10.18632/aging.203419
Volume 13, Issue 16 pp 19978—19995
Dermal papilla cells (DPCs) tend to aggregate both in vitro and in vivo, which increases the hair inductivity of DPCs. However, the underlying mechanism of spheroid formation is unknown. We investigated whether collagen expression in human DPCs (hDPCs) is involved in the spheroid formation and hair inductivity of hDPCs and further examined the underlying molecular mechanism of collagen upregulation. The expression of diverse collagens, such as COL13A1 and COL15A1, was upregulated in three dimensional (3D)-cultured or intact DPCs, compared to 2D-cultured hDPCs. This collagen expression was a downregulated in aged hair follicle, and aged DPCs were difficult to aggregate. Blocking of COL13A1 and COL15A1 by small interfering RNA reduced aggregation, while induced senescence of hDPCs in vitro. Further, transforming growth factor-?2 (TGF-?2) expression decreases with aging, and is involved in regulating the expression of COL13A1 and COL15A1. Addition of recombinant TGF-?2 delayed cellular senescence, and recovered spheroid formation in aged hDPCs by upregulating collagen levels. On the contrary, knock-out of TGF-?2 induced the aging of DPCs, and inhibited spheroid formation. These results suggested that COL13A1 and COL15A1 expression is downregulated with aging in DPCs, and upregulation of collagen by TGF-?2 induces the spheroid formation of DPCs. Therefore, TGF-?2 supplement in DPC culture medium could enhance the maintenance and hair inductivity of DPCs.
Stress-induced aberrations in sensory processing predict worse cognitive outcomes in healthy aging adults
Rachel K. Spooner1,2 , Brittany K. Taylor1 , Emma L’Heureux2 , Mikki Schantell1,2 , Yasra Arif1,2 , Pamela E. May3 , Brenda Morsey3 , Tina Wang4 , Trey Ideker4 , Howard S. Fox3 , Tony W. Wilson1,2
doi : 10.18632/aging.203433
Volume 13, Issue 16 pp 19996—20015
It is well recognized that not all individuals age equivalently, with functional dependence attributable, at least in part, to stress accumulated across the lifespan. Amongst these dependencies are age-related declines in cognitive function, which may be the result of impaired inhibitory processing (e.g., sensory gating). Herein, we examined the unique roles of life and biological stress on somatosensory gating dynamics in 74 adults (22-72 years old). Participants completed a sensory gating paired-pulse electrical stimulation paradigm of the right median nerve during magnetoencephalography (MEG) and data were subjected to advanced oscillatory and time-domain analysis methods. We observed separable mechanisms by which increasing levels of life and biological stress predicted higher oscillatory gating ratios, indicative of age-related impairments in inhibitory function. Specifically, elevations in life stress significantly modulated the neural response to the first stimulation in the pair, while elevations in biological stress significantly modulated the neural response to the second stimulation in the pair. In contrast, neither elevations in life nor biological stress significantly predicted the gating of time-domain neural activity in the somatosensory cortex. Finally, our study is the first to link stress-induced decline in sensory gating to cognitive dysfunction, suggesting that gating paradigms may hold promise for detecting discrepant functional trajectories in age-related pathologies in the future.
Oral administration of berberine represses macrophage activation-associated benign prostatic hyperplasia: a pivotal involvement of the NF-?B
Bo-Ram Jin1 , Hyo-Jin An1
doi : 10.18632/aging.203434
Volume 13, Issue 16 pp 20016—20028
Benign prostatic hyperplasia (BPH) is one of the most common chronic diseases in men over the age of 50. Clinical studies have suggested that chronic inflammation is associated with BPH pathoprogression. Berberine (BB) is a natural compound found in Berberis vulgaris, Coptis chinensis and Phellodendron amurense. Although several studies have documented that BB may be effective for inflammation, the effects of the oral administration of BB on BPH are not fully understood. The effects of BB on chronic prostatic inflammation were evaluated in a testosterone-induced BPH animal model. Orally administered BB alleviated the pathological alterations induced by BPH and significantly suppressed the expression of inflammatory markers while enhancing the expression of antioxidant factors. Furthermore, BB regulated the activation of macrophages via NF-?B signaling pathway inhibition in the BPH rat model. The effects and underlying signaling pathway of BB in RWPE-1 cells exposed to macrophage conditioned medium (CM) were also demonstrated in vitro. While CM stimulation induced prostatic cell proliferation and upregulated the expression of inflammatory factors, BB exerted anti-proliferation and anti-inflammatory effects in RWPE-1 cells. These findings propose that BB suppresses androgen-dependent BPH development by targeting NF-?B-mediated pro-inflammatory signaling.
Association between housing type and accelerated biological aging in different sexes: moderating effects of health behaviors
Ted Kheng Siang Ng1,10, * , David Bruce Matchar2,3 , Timothy V. Pyrkov4 , Peter O. Fedichev4,5 , Angelique Wei-Ming Chan2,6,7 , Brian Kennedy8,9
doi : 10.18632/aging.203447
Volume 13, Issue 16 pp 20029—20049
Despite associated with multiple geriatric disorders, whether housing type, an indicator of socioeconomic status (SES) and environmental factors, is associated with accelerated biological aging is unknown. Furthermore, although individuals with low-SES have higher body mass index (BMI) and are more likely to smoke, whether BMI and smoking status moderate the association between SES and biological aging is unclear. We examined these questions in urbanized low-SES older community-dwelling adults.
Effects of Siberian fir terpenes extract Abisil on antioxidant activity, autophagy, transcriptome and proteome of human fibroblasts
Anastasiya Lipatova1 , George Krasnov1,2 , Pavel Vorobyov1 , Pavel Melnikov3 , Olga Alekseeva1 , Yulia Vershinina1 , Alexander Brzhozovskiy4 , Daria Goliusova5 , Faniya Maganova6 , Natalia Zakirova1,2 , Anna Kudryavtseva1,2 , Alexey Moskalev1,7,8
doi : 10.18632/aging.203448
Volume 13, Issue 16 pp 20050—20080
Abisil is an extract of Siberian fir terpenes with antimicrobial and wound healing activities. Previous studies revealed that Abisil has geroprotective, anti-tumorigenic, and anti-angiogenic effects. Abisil decreased the expression of cyclin D1, E1, A2, and increased the phosphorylation rate of AMPK.
Effect of diabetic kidney disease on therapeutic strategies for coronary artery disease: ten year follow-up
Daniel Valente Batista1 , Whady Hueb1 , Eduardo Gomes Lima1 , Paulo Cury Rezende1 , Cibele Larrosa Garzillo1 , Rosa Maria Rahmi Garcia1 , Jaime Paula Pessoa Linhares Filho1 , Eduardo Bello Martins1 , Carlos Vicente Serrano Junior1 , Jose Antonio Franchini Ramires1 , Roberto Kalil Filho1
doi : 10.18632/aging.203476
Volume 13, Issue 16 pp 20081—20093
The best treatment for coronary artery disease (CAD) in patients with type 2 diabetes (DM2) and chronic kidney disease is unknown.
Overexpressed DEPDC1B contributes to the progression of hepatocellular carcinoma by CDK1
Xiao-Wei Dang1, * , Qi Pan2, * , Zhen-Hai Lin2, * , Hao-Hao Wang1 , Lu-Hao Li1 , Lin Li1 , Dong-Qi Shen1 , Pei-Ju Wang1
doi : 10.18632/aging.203016
Volume 13, Issue 16 pp 20094—20115
Hepatocellular carcinoma (HCC) is the main type of primary liver cancer and shows a heavy burden worldwide. Its recurrence and mortality rate are still uncontrolled by the usage of present treatments. More attention has been focused on exploring specific genes that play important roles in HCC procession, and the function of DEP domain containing 1B (DEPDC1B) in HCC has not been researched.
LncRNA RUSC1-AS1 promotes osteosarcoma progression through regulating the miR-340-5p and PI3K/AKT pathway
Chang-Jun Tong1, * , Qing-Chun Deng2, * , Di-Jun Ou1 , Xia Long3 , He Liu1 , Kang Huang1
doi : 10.18632/aging.203047
Volume 13, Issue 16 pp 20116—20130
Dysregulation of long noncoding RNA (lncRNA) is frequently involved in the progression and development of osteosarcoma. LncRNA RUSC1-AS1 is reported to be upregulated and acts as an oncogene in hepatocellular carcinoma, cervical cancer and breast cancer. However, its role in osteosarcoma has not been studied yet. In the present study, we investigated the role of RUSC1-AS1 in osteosarcoma both in vitro and in vivo. The results showed that the expression of RUSC1-AS1 was significantly upregulated in osteosarcoma cell line U2OS and HOS compared to that in human osteoblast cell line hFOB1.19. Similar results were found in human samples. Silencing RUSC1-AS1 by siRNA significantly inhibited U2OS and HOS cell proliferation and invasion, measured by CCK-8 and transwell assay. Besides, knockdown of RUSC1-AS1 increased cell apoptosis in osteosarcoma cell lines. In addition, RUSC1-AS1 promoted the epithelial-mesenchymal transition (EMT) process of osteosarcoma cells. In vivo experiments confirmed that RUSC1-AS1 knockdown had an inhibitory effect on osteosarcoma tumor growth. Mechanically, we showed that RUSC1-AS1 directly binds to and inhibits miR-340-5p and activates the PI3K/AKT signaling pathway. In conclusion, our study demonstrated that RUSC1-AS1 promoted osteosarcoma development both in vitro and in vivo through sponging to miR-340-5p and activating the PI3K/AKT signaling pathway. Therefore, RUSC1-AS1 becomes a potential therapeutic target for osteosarcoma.
Immune normalization strategy against suboptimal health status: safe and efficacious therapy using mixed-natural killer cells
Ying Li1,2 , ODA Harunori1,3 , Shihu Fu1 , Fuyuan Xing1 , Huawan Wu1 , Juan Wang1 , Aihua Chen1 , Xinhua Ren1 , Dawei Peng1 , Xia Ling1,3, & , Ming Shi2 , Hongjin Wu1
doi : 10.18632/aging.203279
Volume 13, Issue 16 pp 20131—20148
“Immune normalization” has emerged as a new paradigm in immunotherapy, which is proposed in cancer patients instead of conventional “immune-enhancement” therapy. Immune normalization may also be implemented in cancer prevention of “sub-healthy” individuals. We established in vitro cultured mixed-natural killer (NKM) cells to achieve immune normalization. The in vitro cytotoxicity of NKM cells was tenfold higher than that of peripheral blood mononuclear cells (PBMCs). The cytotoxicity of NKM cells was negatively correlated with the proportion of T-helper cells (cluster of differentiation: CD3+CD4+ T), and positively correlated with the proportion of NK cells (especially CD56brightCD16bright NK cells). Then, we defined “sub-healthy individuals” after measuring Programmed cell death protein-1 (PD-1) expression in PBMCs from 95 donors aged > 50 years. Furthermore, we evaluated the potential clinical application of NKM-cell therapy in 11 patients with malignant lymphoma, one patient with pancreatic cancer, and four sub-healthy individuals. NKM-cell therapy elicited good tolerance and side-effects were not found. In sub-healthy individuals, the proportion of CD3+PD-1+ T cells and CD3+CD8+PD-1+ T cells was reduced significantly after NKM-cell treatment. We demonstrated that a new method using NKM cells was safe and efficacious as adjuvant treatment for cancer patients as well as therapy for sub-healthy individuals. Normalization of the peripheral immune system through NKM-cell therapy could expand its scope of application in different disorders.
25-Hydroxycholesterol protecting from cerebral ischemia-reperfusion injury through the inhibition of STING activity
Feihong Lin1, * , Xinyu Yao1, * , Chang Kong1 , Xia Liu1 , Zhangfan Zhao1 , Suhuan Rao1 , Lu Wang1 , Shan Li1 , Junlu Wang1 , Qinxue Dai1
doi : 10.18632/aging.203337
Volume 13, Issue 16 pp 20149—20163
Middle cerebral artery occlusion (MCAO) injury refers to impaired blood supply to the brain that is caused by a cerebrovascular disease, resulting in local brain tissue ischemia, hypoxic necrosis, and rapid neurological impairment. Nevertheless, the mechanisms involved are unclear, and pharmacological interventions are lacking. 25-Hydroxycholesterol (25-HC) was reported to be involved in cholesterol and lipid metabolism as an oxysterol molecule. This study aimed to determine whether 25-HC exerts a cerebral protective effect on MCAO injury and investigate its potential mechanism. 25-HC was administered prior to reperfusion in a mouse model of MCAO injury. 25-HC evidently decreased infarct size induced by MCAO and enhanced brain function. It reduced stimulator of interferon gene (STING) activity and regulated mTOR to inhibit autophagy and induce cerebral ischemia tolerance. Thus, 25-HC improved MCAO injury through the STING channel. As indicated in this preliminary study, 25-HC improved MCAO injury by inhibiting STING activity and autophagy as well as by reducing brain nerve cell apoptosis. Thus, it is a potential treatment drug for brain injury.
Identification of 4-methylation driven genes based prognostic signature in thyroid cancer: an integrative analysis based on the methylmix algorithm
Zhiwei Chen5 , Xiaoli Liu5 , Fangfang Liu5 , Guolie Zhang2 , Haijian Tu3 , Wei Lin4 , Haifeng Lin1
doi : 10.18632/aging.203338
Volume 13, Issue 16 pp 20164—20178
Thyroid cancer (TC) is known with a high rate of persistence and recurrence. We aimed to develop a prognostic signature to monitor and assess the survival of TC patients. mRNA expression and methylation data were downloaded from the TCGA database. Then, R package methylmix was applied to construct a mixed model was used to identify methylation-driven genes (MDGs) according to the methylation levels. Furthermore, an MDGs based prognostic signature and predictive nomogram were constructed according to the analysis of univariate and multivariate Cox regression. Totally 62 methylation-driven genes that were mainly enriched in substrate-dependent cell migration, cellular response to mechanical stimulus, et al. were found in TC tissues. aldolase C (AldoC), C14orf62, dishevelled 1 (DVL1), and protein tyrosine phosphatase receptor type C (PTPRC) were identified to be significantly related to patients' survival, and may serve as independent prognostic biomarkers for TC. Additionally, the prognostic methylation signature and a novel prognostic, predictive nomogram was established based on the methylation level of 4 MDGs. In this study, we developed a 4-MDGs based prognostic model, which might be the potential predictors for the survival rate of TC patients, and this findings might provide a novel sight for accurate monitoring and prognosis assessment.
Long non-coding RNA ABHD11-AS1 promotes colorectal cancer progression and invasion through targeting the integrin subunit alpha 5/focal adhesion kinase/phosphoinositide 3 kinase/Akt signaling pathway
Jia Luo1, * , Yigui Jiang1, * , Lianhui Wu2, * , Dexiang Zhuo3 , Shengjun Zhang1 , Xiang Jiang4 , Yingming Sun5 , Yue Huang1,2
doi : 10.18632/aging.203342
Volume 13, Issue 16 pp 20179—20191
Long non-coding (lnc)RNA ABHD11-AS1 participates in the development and progress of various cancers, but its role in colorectal cancer (CRC) remains poorly known. In the present study, public database analysis and quantitative reverse transcription PCR of CRC and normal tissues showed that ABHD11-AS1 was overexpressed in CRC and associated with poor prognosis in CRC patients. Both in vitro and in vivo experiments demonstrated that loss-of-function of ABHD11-AS1 attenuated the proliferation, migration, and invasion of CRC cells and induced their apoptosis. Transcriptome sequencing and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis indicated that the phosphoinositide 3 kinase (PI3K)/Akt signaling pathway is a potential target of ABHD11-AS1. Additionally, we noted that ABHD11-AS1 deficiency reduced integrin subunit alpha (ITGA)5 expression, and impaired the phosphorylation of P85, focal adhesion kinase (FAK), and Akt1 in CRC cell lines and tumor tissues of nude mice. Furthermore, we observed that ITGA5 overexpression abrogated the effect of ABHD11-AS1 knockdown on the proliferation and invasion abilities of CRC cells. Taken together, our studies suggest that lncRNA ABHD11-AS1 promotes proliferation, migration, and invasion in CRC by activating the ITGA5/Fak/PI3K/Akt signaling pathway, and that the ITGA5/Fak/PI3K/Akt axis is a promising target for CRC therapy.
Hsa-circ-0007292 promotes the osteogenic differentiation of posterior longitudinal ligament cells via regulating SATB2 by sponging miR-508-3p
Anlong Jiang1,2, * , Nanxiang Wang1, * , Xinxing Yan1 , Yunheng Jiang1 , Chengchao Song1 , Hui Chi1 , Guanghua Chen1 , Feng Wu1 , Ye Ji1 , Jinglong Yan1
doi : 10.18632/aging.203381
Volume 13, Issue 16 pp 20192—20217
Ossification of the posterior longitudinal ligament (OPLL) is a disorder with multiple pathogenic mechanisms and leads to different degrees of neurological symptoms. Recent studies have revealed that non-coding RNA (ncRNA), including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), could influence the development of OPLL. Nevertheless, the molecular mechanisms linking circular RNAs (circRNAs) and the progression of OPLL is still unknown. The current research explored the expression profiles of OPLL-related circRNAs by microarray analysis, and applied qRT-PCR to validate the results. Subsequently, we confirmed the upregulation of hsa_circ_0007292 in OPLL cells by qRT-PCR and validated the circular characteristic of hsa_circ_0007292 by Sanger sequencing. Fluorescence in situ hybridization (FISH) unveiled that hsa_circ_0007292 was predominantly located in the cytoplasm. Functionally, gain-of-function and loss-of-function experiments showed that hsa_circ_0007292 promoted the osteogenic differentiation of OPLL cells. Mechanistically, the interaction of hsa_circ_0007292 and miR-508-3p was predicted and validated by bioinformatics analysis, dual-luciferase reporter assays, and Ago2 RNA immunoprecipitation (RIP). Similarly, we validated the correlation between miR-508-3p and SATB2. Furthermore, rescue experiments were performed to prove that hsa_circ_0007292 acted as a sponge for miR-508-3p, and SATB2 was revealed to be the target gene of miR-508-3p. In conclusion, our research shows that hsa_circ_0007292 regulates OPLL progression by the miR-508-3p/SATB2 pathway. Our results indicate that hsa_circ_0007292 can be used as a promising therapeutic target for patients with OPLL.
ERCC6L promotes cell growth and metastasis in gastric cancer through activating NF-?B signaling
Dehu Chen1 , Qinghong Liu1 , Gan Cao1
doi : 10.18632/aging.203387
Volume 13, Issue 16 pp 20218—20228
ERCC6L has been reported to act as a potential oncogenic protein in various cancers. However, the role of ERCC6L in the progression of gastric cancer (GC) remains to be elucidated. Herein, we aimed to assess the clinical significance, the role, and the underlying mechanism of ERCC6L in GC progression. In this study, the mRNA and protein expression levels of ERCC6L were measured in GC specimens by quantitative real-time PCR (qRT-PCR), Western blot, and immunohistochemistry, and its clinical significance was assessed. The effect of ERCC6L overexpression or knockdown on GC cell growth, migration, and invasion was explored by functional experiments. Notably, the possible mechanisms underlying the action of ERCC6L were also investigated. We found that ERCC6L was upregulated in GC tissues, and its expression was associated with tumor size, clinical stage, and poor prognosis in GC patients. Besides, ERCC6L facilitated GC cell proliferation and metastasis in vitro and in vivo. Mechanically, ERCC6L modulated GC cell behavior via activation of NF-?B signaling. Our results indicated that ERCC6L played a critical role in GC progression and metastasis. In addition, ERCC6L promoted GC cell growth and metastasis via activation of NF-?B signaling, thus possibly providing a target for GC.
Autophagic flux in cancer cells at the invasive front in the tumor-stroma border
Fei Yan1, * , Xuexi Zhang1, * , Rongying Tan1 , Mingchen Li1 , Zengtuan Xiao2 , Hao Wang1 , Zhenfa Zhang2 , Zhenyi Ma1 , Zhe Liu1
doi : 10.18632/aging.203406
Volume 13, Issue 16 pp 20229—20245
Cancer cells at the invasive front directly interact with stromal tissue that provides a microenvironment with mechanical, nutrient, and oxygen supply characteristics distinct from those of intratumoral tissues. It has long been known that cancer cells at the invasive front and cancer cells inside the tumor body exhibit highly differentiated functions and behaviors. However, it is unknown whether cancer cells at different locations exhibit a variety of autophagic flux, an important catabolic process to maintain cellular homeostasis in response to environmental changes. Here, using transmission electron microscopy (TEM), we found that invading cancer cells at the invasive front, which show mesenchymal transcriptomic traits, exhibit higher autophagic flux than cancer cells inside the tumor body in human primary non-small cell lung cancer (NSCLC) tissues. This autophagic feature was further confirmed by a live cell autophagic flux monitoring system combined with a 3D organotypic invasion coculture system. Additionally, the increased autophagic flux endows cancer cells with invasive behavior and positively correlates with the advanced tumor stages and the reduced survival period of lung cancer patients. These findings expand the understanding of autophagic dynamics during cancer invasion.
Identification of effective natural PIK3CA H1047R inhibitors by computational study
Naimeng Liu1 , Xinhui Wang2 , Xuan Li3 , Xiaye Lv4 , Haoqun Xie5 , Zhen Guo5 , Jing Wang5 , Gaojing Dou1,5 , Ye Du1 , Dong Song1
doi : 10.18632/aging.203409
Volume 13, Issue 16 pp 20246—20257
Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer with a poor prognosis and a high recurrence rate. PIK3CA gene is frequently mutated in breast cancer, with PIK3CA H1047R as the hotspot mutation reported in TNBC. We used the ZINC database to screen natural compounds that could be structurally modified to develop drugs targeting the PIK3CA H1047R mutant protein in the PI3K pathway. The LibDock module showed that 2,749 compounds could strongly bind to the PIK3CA H1047R protein. Ultimately, the top 20 natural ligands with high LibDock scores were used for further analyses including assessment of ADME (absorption, distribution, metabolism, and excretion), toxicity, stability, and binding affinity. ZINC000004098448 and ZINC000014715656 were selected as the safest drug candidates with strong binding affinity to PIK3CA H1047R, no hepatotoxicity, less carcinogenicity, better plasma protein binding (PPB) properties, and enhanced intestinal permeability and absorption than the two reference drugs, PKI-402 and wortmannin. Moreover, their lower potential energies than those of PIK3CA H1047R confirmed the stability of the ligand-receptor complex under physiological conditions. ZINC000004098448 and ZINC000014715656 are thus safe and stable leads for designing drugs against PIK3CA H1047R as part of a targeted therapeutic approach for patients with TNBC.
DNMT3B decreases extracellular matrix degradation and alleviates intervertebral disc degeneration through TRPA1 methylation to inhibit the COX2/YAP axis
Zhiqiang Luo1 , Yanchao Ma1 , Tianning Di1 , Bing Ma1 , Hongwei Li1 , Jiangdong An1 , Yonggang Wang1 , Haihong Zhang1, &
doi : 10.18632/aging.203410
Volume 13, Issue 16 pp 20258—20276
Intervertebral disc degeneration (IVDD) is a main cause of low back pain that is associated with extracellular matrix (ECM) degradation and inflammation. This study aims to investigate the role of DNMT3B and its regulatory mechanisms in IVDD. IVDD rat models were constructed followed by transfections with oe-DNMT3B or oe-YAP in order to explore the role of DNMT3B in the development of IVDD. After that transfection, nucleus pulposus (NP) cells were isolated and transfected with oe-DNMT3B, oe-TRPA1, si-YAP, oe-YAP or oe-COX2 in order to investigate the functions of DNMT3B in NP cells. DNMT3B was poorly expressed in IVDD tissues and NP cells whereas TRPA1, COX2, and YAP were highly expressed. The proliferation or apoptosis of NP cells was detected through CCK-8 assay or flow cytometry, respectively. Overexpression of DNMT3B promoted the proliferation of NP cells, inhibited their apoptosis, as well as increasing the expression of collagen II and aggrecan and decreasing expression of MMP3 and MMP9. Besides, DNMT3B suppressed inflammation and alleviated IVDD. Mechanistically, DNMT3B modified the TRPA1 promoter by methylation to inhibit the expression of COX2. Overexpression of COX2 promoted the apoptosis of NP cells and decreased the expression of YAP, which was reversed by upregulating DNMT3B. DNMT3B may promote the proliferation of NP cells and prevent their ECM degradation through the TRPA1/COX2/YAP axis, thereby alleviating IVDD in rats.
Comprehensive analysis of ubiquitin-proteasome system genes related to prognosis and immunosuppression in head and neck squamous cell carcinoma
Juncheng Wang1,5, * , Jianing Li2 , Luan Zhang2 , Yuexiang Qin3 , Fengyu Zhang1,5 , Rulong Hu1,5 , Huihong Chen1,5 , Yongquan Tian1,5 , Zhifeng Liu1,4,5, * , Yuxi Tian6 , Xin Zhang1,4
doi : 10.18632/aging.203411
Volume 13, Issue 16 pp 20277—20301
The ubiquitin-proteasome system (UPS) with a capacity of degrading multiple intracellular proteins is an essential regulator in tumor immunosurveillance. Tumor cells that escape from recognition and destruction of immune system have been consistently characterized an important hallmark in the setting of tumor progression. Little know about the exact functions of UPS-related genes (UPSGs) and their relationships with antitumor immunity in head and neck squamous cell carcinoma (HNSCC) patients. In this study, for the first time, we comprehensively identified 114 differentially expressed UPSGs (DEUPSGs) and constructed a prognostic risk model based on the eight DEUPSGs (BRCA1, OSTM1, PCGF2, PSMD2, SOCS1, UCHL1, UHRF1, and USP54) in the TCGA-HNSCC database. This risk model was validated using multiple data sets (all P < 0.05). The high-risk score was found to be an independently prognostic factor in HNSCC patients and was significantly correlated with T cells suppression. Accordingly, our risk model can act as a prognostic signature and provide a novel concept for improving the precise immunotherapy for patients with HNSCC.
Regulation of follistatin-like 3 expression by miR-486-5p modulates gastric cancer cell proliferation, migration and tumor progression
Zhou-Tong Dai1, * , Yuan Xiang1,2, * , Xiao-Yu Zhang1, * , Qi-Bei Zong1 , Qi-Fang Wu1 , You Huang1 , Chao Shen1 , Jia-Peng Li1 , Sreenivasan Ponnambalam3 , Xing-Hua Liao1
doi : 10.18632/aging.203412
Volume 13, Issue 16 pp 20302—20318
Cancer development and progression can be regulated by the levels of endogenous factors. Gastric cancer is an aggressive disease state with poor patient prognosis, needing the development of new diagnostics and therapeutic strategies. We investigated the close association between follistatin-like 3 (FSTL3) and different cancers, and focused on its role in gastric cancer cell function. Using cancer bioinformatics, we found that FSTL3 expression is elevated in a large majority of the 33 cancers we analyzed in publicly available cancer databases. Elevated levels of FSTL3 is associated with poor patient prognosis in gastric cancer. In a comparison of normal gastric epithelial cells and gastric cancer cell lines, FSTL3 expression was consistently elevated in gastric cancer cells. Overexpression of FSTL3 promoted gastric cancer cell viability, proliferation and migration. Conversely, FSTL3 knockdown inhibits these cellular processes. Using bioinformatics, we found that the FSTL3 mRNA has a potential binding site in the 3’-UTR for a small microRNA, miR-486-5p. Further bioinformatics revealed significant negative correlation between FSTL3 and miR-486-5p levels. Using luciferase reporter constructs, we provide evidence that the 3’UTR from the FSTL3 mRNA can confer downregulation in the presence of miR-486-5p. These studies lead us to conclude that FSTL3 has oncogenic properties and increased expression of this gene product promotes gastric cancer development and progression.
Inhibition of endoplasmic reticulum stress reverses synaptic plasticity deficits in striatum of DYT1 dystonia mice
Huaying Cai1 , Linhui Ni1 , Xingyue Hu1 , Xianjun Ding2
doi : 10.18632/aging.203413
Volume 13, Issue 16 pp 20319—20334
Striatal plasticity alterations caused by endoplasmic reticulum (ER) stress is supposed to be critically involved in the mechanism of DYT1 dystonia. In the current study, we expanded this research field by investigating the critical role of ER stress underlying synaptic plasticity impairment imposed by mutant heterozygous Tor1a+/- in a DYT1 dystonia mouse model.
Proteomic characterization of secretory granules in dopaminergic neurons indicates chromogranin/secretogranin-mediated protein processing impairment in Parkinson’s disease
Gehua Wen1 , Hao Pang1 , Xu Wu1 , Enzhu Jiang1 , Xique Zhang2 , Xiaoni Zhan1
doi : 10.18632/aging.203415
Volume 13, Issue 16 pp 20335—20358
Parkinson’s disease (PD) is an aging disorder related to vesicle transport dysfunctions and neurotransmitter secretion. Secretory granules (SGs) are large dense-core vesicles for the biosynthesis of neuropeptides and hormones. At present, the involvement of SGs impairment in PD remains unclear. In the current study, we found that the number of SGs in tyrosine hydroxylase-positive neurons and the marker proteins secretogranin III (Scg3) significantly decreased in the substantia nigra and striatum regions of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) exposed mice. Proteomic study of SGs purified from the dopaminergic SH-sy5Y cells under 1-methyl-4-phenylpyridinium (MPP+) treatments (ProteomeXchange PXD023937) identified 536 significantly differentially expressed proteins. The result indicated that disabled lysosome and peroxisome, lipid and energy metabolism disorders are three characteristic features. Protein-protein interaction analysis of 56 secretory proteins and 140 secreted proteins suggested that the peptide processing mediated by chromogranin/secretogranin in SGs was remarkably compromised, accompanied by decreased candidate proteins and peptides neurosecretory protein (VGF), neuropeptide Y, apolipoprotein E, and an increased level of proenkephalin. The current study provided an extensive proteinogram of SGs in PD. It is helpful to understand the molecular mechanisms in the disease.
LncRNA GACAT1 targeting miRNA-149 regulates the molecular mechanism of proliferation, apoptosis and autophagy of oral squamous cell carcinoma cells
Jingxin Chen1, * , Xubin Chen1, * , Liangbin Fu1 , Jimin Chen2 , Yang Chen1 , Feng Liu3
doi : 10.18632/aging.203416
Volume 13, Issue 16 pp 20359—20371
To explore the effects of lncRNA GACAT1/miR-149 molecular axis on the proliferation, apoptosis, migration and autophagy of oral squamous cell carcinoma (OSCC) cells, and to explore its molecular mechanism. The expressions of lncRNA GACAT1 and miR-149 in tissues and cell lines of patients with OSCC were detected by qRT-PCR. Si-control, GACAT1-siRNA, inhibitor NC and miR-149 inhibitors were transfected into OSCC cells separately or in combination with Lipofectamine 2000. The binding sites between lncRNA GACAT1 and miR-149 were predicted using the miRanda website, and the targeting relationship was verified by dual-luciferase assay. The expression of lncRNA XIST and miR-149 was detected by qRT-PCR. CCK-8 assay was used to detect cell activity. Cell cycle distribution and apoptosis were detected by flow cytometry. Cell migration ability was detected by Transwell assay. The expression of migration and autophagy-related proteins was detected by western blot. LncRNA GACAT1 was highly expressed in cancer tissues and cell lines of OSCC patients (P < 0.01), while miR-149 was low expressed (P < 0.01). LncRNA GACAT1 binds to miR-149 targeting. The down-regulation of lncRNA GACAT1 inhibited the proliferation and migration of OSCC cells and promoted apoptosis and autophagy (P < 0.01). The transfection of miR-149 inhibitor had the opposite effect. Knockdown of lncRNA GACAT1 and transfection with miR-149 inhibitor reversed the effect of GACAT1 silencing on OSCC cells. Inhibition of lncRNA GACAT1 can inhibit the proliferation and migration of OSCC cells, promote apoptosis and autophagy, and the mechanism may be related to the targeting of miR-149.
Circular RNA circRHOT1 contributes to pathogenesis of non-small cell lung cancer by epigenetically enhancing C-MYC expression through recruiting KAT5
Xiaoyan Ren1 , Jiangang Yu1 , Lili Guo1 , Hong Ma1
doi : 10.18632/aging.203417
Volume 13, Issue 16 pp 20372—20382
Non-small cell lung cancer (NSCLC) one of the most prevalent and severe malignancies globally and the molecular mechanisms of NSCLC are poor understood, limiting the development of diagnostic biomarkers and targeted therapies. Circular RNAs (circRNAs) have been identified as a sort of critical regulator in cancer progression. In this study, we identities the epigenetic regulation function of circular RNA circRHOT1 in promoting NSCLC cell proliferation. We found that circRHOT1 were elevated in the clinical tumor tissues relative to that in the peritumor tissues from NSCLC patients. circRHOT1 was up-regulated in human lung cancer cell lines compared with normal human lung epithelial cell line. MTT assays revealed that the silencing of circRHOT1 by siRNA suppressed cell viabilities of NSCLC cells. Colony formation and Edu assays confirmed that circRHOT1 knockdown attenuated NSCLC cell proliferation in vitro. Meanwhile, the depletion of circRHOT1 induced NSCLC cell apoptosis and cell cycle arrest in vitro. Mechanically, the depletion of circRHOT1 remarkably reduced c-MYC mRNA and protein expression in NSCLC cells. Inhibition of circRHOT1 reduced the enrichment of transcription active marker histone H3 lysine 27 acetylation (H3K27ac) and RNA polymerase II on the promoter of c-MYC. RNA pull down analysis showed that circRHOT1 was able to directly interact with acetyltransferase KAT5 in NSCLC cells. In summary, we concluded that circRHOT1 contributed to pathogenesis of NSCLC by epigenetically enhancing c-MYC expression through recruiting KAT5. CircRHOT1 and KAT5 may be used as the potential targets for NSCLC therapy.
Hsa_circ_0134111 promotes osteoarthritis progression by regulating miR-224-5p/CCL1 interaction
Yongbao Liu1 , Yanxiu Zhang1
doi : 10.18632/aging.203420
Volume 13, Issue 16 pp 20383—20394
Mechanical, metabolic, inflammatory, and immune factors contribute to the development of osteoarthritis (OA), a joint disease characterized by cartilage destruction. The circular RNA (circRNA) hsa_circ_0134111 is upregulated in the cartilage of OA patients; however, its potential role in OA pathogenesis and progression remains unexplored. In this study, the effects of hsa_circ_0134111 knockdown were evaluated in primary human chondrocytes treated with IL-1? to simulate OA, as well as in a rat model of OA. Hsa_circ_0134111 expression was upregulated in IL-1?-stimulated chondrocytes. CCK-8 and flow cytometry assays showed that hsa_circ_0134111 knockdown reversed IL-1?-induced cell decline by inhibiting apoptosis. Following prediction analysis of circRNA and miRNA targets, dual-luciferase reporter and silencing/overexpression assays suggested that a regulatory network composed of hsa_circ_0134111, miR-224-5p, and CCL1 modulates IL-1?-mediated OA-like effects in chondrocytes. Accordingly, CCL1 overexpression abrogated the prosurvival effects of hsa_circ_0134111 knockdown in vitro. Moreover, hsa_circ_0134111 silencing in vivo alleviated cartilage destruction in an OA rat model, decreased IL-6 and TNF-? levels in synovial fluid, and downregulated CCL1 expression in the affected joints. These results suggest that hsa_circ_0134111 contributes to OA development by binding to miR-224-5p, thereby releasing the inhibition that miR-224-5p exerts over CCL1.
ADAM15 correlates with prognosis, immune infiltration and apoptosis in hepatocellular carcinoma
Jun Hui Xu1,2,3 , Yong Jun Guan1 , Yi Chao Zhang1 , Zhen Dong Qiu1 , Yu Zhou1 , Chen Chen1 , Jia Yu1 , Wei Xing Wang1
doi : 10.18632/aging.203425
Volume 13, Issue 16 pp 20395—20417
ADAM15 is highly expressed in malignant tumors and is correlated with tumor progression. However, the role of ADAM15 in hepatocellular carcinoma (HCC) remains unclear. In the study, our results indicated that ADAM15 was highly expressed in HCC tissues and cells compared with corresponding tissues and liver cells. Overexpression of ADAM15 was linked to poor prognosis, and was an independent risk factor for HCC prognosis. Besides, analysis of immune infiltration indicated that ADAM15 expression was related to tumor infiltrating lymphocytes based on the TIMER, TISIDB and GEPIA databases. Many immune checkpoint gene expression was associated with ADAM15 expression. Functional enrichment analyses indicated that apoptosis, cell adhesion was enriched. ADAM15 knockdown promoted apoptosis and suppressed proliferation, migration and invasion of liver cancer cells. The findings of western blot showed that ADAM15 knockdown reduced the expression of Bcl-2, Vimentin, N-Cadherin and Snail, and elevated the expression of Bax, E-cadherin and ZO-1. However, overexpression of ADAM15 had the opposite results. Collectively, our findings demonstrated that ADAM15 was connected with poor prognosis of HCC patients, and could be considered as a potential biomarker for the diagnosis and treatment of HCC.
Bu-Shen-Zhu-Yun decoction induces PRLR deubiquitination and JAK2/STAT5 activation via CSN5 in vitro
Hua Feng1,2 , Huifang Zhou3, & , Jianxia Lu1 , Qing Zhang4 , Xingran Tang5 , Yujie Shang5
doi : 10.18632/aging.203426
Volume 13, Issue 16 pp 20418—20437
To determine the effect of Bu-Shen-Zhu-Yun Decoction (BSZY-D) on the kisspeptin through JAK2/STAT5 signaling pathway in hyperprolactinemia (HPRL) infertility.
Ceruloplasmin correlates with immune infiltration and serves as a prognostic biomarker in breast cancer
Fei Chen1, * , Bihui Han1, * , Yanxiu Meng1, * , Yu Han1 , Bing Liu1 , Bo Zhang1 , Yanzhong Chang1 , Pengxiu Cao1 , Yumei Fan1 , Ke Tan1
doi : 10.18632/aging.203427
Volume 13, Issue 16 pp 20438—20467
Breast-invasive carcinoma (BRCA) is the most frequent and malignant tumor in females. Ceruloplasmin (CP) is a multifunctional molecule involved in iron metabolism, but its expression profile, prognostic potential and relationship with immune cell infiltration in BRCA are unknown. Ceruloplasmin mRNA and protein expression was significantly decreased in BRCA patients according to the Oncomine, UALCAN, GEPIA and TCGA databases. Ceruloplasmin expression was strongly correlated with various clinicopathological features of BRCA patients. BRCA patients with high ceruloplasmin expression exhibited shorter survival times than those with low ceruloplasmin expression based on the Kaplan-Meier plotter and PrognoScan databases. GO and KEGG analyses and GSEA revealed a strong correlation between ceruloplasmin and various immune-related pathways. Ceruloplasmin expression was significantly associated with the infiltration of immune cells into tumor sites by analyzing the TIMER and CIBERSORT. Additionally, ceruloplasmin was positively correlated with immune checkpoints in BRCA. These findings suggest that low ceruloplasmin expression correlates with a favorable prognosis and tumor immune cell infiltration in BRCA patients. Ceruloplasmin may serve as a therapeutic target and predict the efficacy of immunotherapy for BRCA.
The efficacy and safety of PD-1/PD-L1 immune checkpoint inhibitors in treating advanced urothelial cancer: a meta-analysis of clinical trials
Fei Li1, * , Yu Wang1, * , Kunfeng Xie1 , Yunze Fang1 , Yuejun Du1 , Lina Hou2, *,& , Wanlong Tan1, *
doi : 10.18632/aging.203429
Volume 13, Issue 16 pp 20468—20480
Survival outcomes in advanced urothelial cancer (UC) are dismal. Over the past years, immunotherapy remains an evolving treatment modality for these patients. This meta-analysis was performed to comprehensively evaluate the efficacy and safety of immune checkpoint inhibitors. For this purpose, 18 clinical trials comprising a total of 3,144 patients were identified from the PubMed database up to September 2020. Overall, the objective response rate (ORR) to PD-1/PD-L1 inhibitors was 0.20 [95% confidence intervals (CI) 0.17–0.23]. Furthermore, the pooled 1-year overall survival (OS) and 1-year progression-free survival (PFS) rates were 0.43 (95% CI 0.33–0.53) and 0.19 (95% CI 0.17–0.21), respectively. The summary rates of any-grade and grade ?3 adverse events (AEs) were 0.66 (95% CI 0.58–0.74) and 0.13 (95% CI 0.09–0.18), respectively. Among the different subgroups, PD-1/PD-L1 inhibitors elicited a promising ORR in patients with lymph node-only metastasis compared to those with visceral metastasis (0.41 VS. 0.17). Additionally, patients with primary tumor in the lower tract had higher ORR compared to those with primary tumor in the upper tract (0.24 VS. 0.15). Briefly speaking, this immunotherapy protocol showed an encouraging efficacy and acceptable safety profile in the treatment of advanced UC. Moreover, our findings provided potential clinical significance for patients with lymph node-only metastasis or primary tumor in the lower tract. However, these exciting findings need further confirmation.
miR-33a-5p inhibits the progression of esophageal cancer through the DKK1-mediated Wnt/?-catenin pathway
Qingping Song1, * , Hui Liu2, * , Chengyan Li2 , Haifeng Liang1
doi : 10.18632/aging.203430
Volume 13, Issue 16 pp 20481—20494
Esophageal cancer (EC) is one of the most lethal malignancies in humans, and multiple miRNAs have been identified to modulate EC progression by targeting different targets. However, the effect and related mechanism of microRNA-33a-5p (miR-33a-5p) on EC development remain elusive. In this study, we explored the clinical value, function, and possible mechanism of miR-33a-5p in EC. We uncovered that miR-33a-5p and DKK1 are involved in the progression of EC. Significantly, the expression levels of miR-33a-5p were reduced and DKK1 levels were elevated in serum and tissues of clinical EC samples and in EC cell lines. The downregulation of miR-33a-5p and DKK1 upregulation were related to high TNM staging and poor differentiation of patients. The area under the curves (AUCs) of miR-33a-5p and DKK1 for the occurrence of EC were 0.914 and 0.900, respectively. Down-regulation of miR-33a-5p or overexpression of DKK1 indicated a worse prognosis. The miR-33a-5p overexpression or DKK1 depletion induced apoptosis and repressed proliferation, migration, and invasion of EC cells. The repression of miR-33a-5p by inhibitor or DKK1 overexpression presented the conversed effects on EC cells. Mechanically, miR-33a-5p suppressed DKK1 expression, and miR-33a-5p targeted DKK1 to affect the biological behavior of EC through the Wnt/?-catenin pathway. Meanwhile, miR-33a-5p inhibited the tumor growth of EC in vivo. Thus, we concluded that miR-33a-5p inhibited the progression of EC through the DKK1-mediated Wnt/?-catenin pathway. MiR-33a-5p and DKK1 can be used as potential therapeutic targets of EC.
Anti-apoptotic and pro-survival effect of exercise training on early aged hypertensive rat cerebral cortex
Yi-Jie Liu1,2, * , Zhen-Yang Cui3, * , Ai-Lun Yang4 , Amadou W. Jallow5 , Hai-Liang Huang6 , Chun-Lei Shan1,2 , Shin-Da Lee1,3,5,7,8
doi : 10.18632/aging.203431
Volume 13, Issue 16 pp 20495—20510
The anti-apoptotic and pro-survival effects of exercise training were evaluated on the early aged hypertensive rat cerebral cortex. The brain tissues were analysed from ten sedentary male Wistar Kyoto normotensive rats (WKY), ten sedentary spontaneously 12 month early aged hypertensive rats (SHR), and ten hypertensive rats undergoing treadmill exercise training (60 min/day, 5 days/week) for 12 weeks (SHR-EX). TUNEL-positive apoptotic cells, the expression levels of endonuclease G (EndoG) and apoptosis-inducing factor (AIF) (caspase-independent apoptotic pathway), Fas ligand, Fas death receptor, tumor necrosis factor (TNF)-?, TNF receptor 1, Fas-associated death domain, active caspase-8 and active caspase-3 (Fas-mediated apoptotic pathways) as well as t-Bid, Bax, Bak, Bad, cytochrome c, active caspase 9 and active caspase-3 (mitochondria-mediated apoptotic pathways) were reduced in SHR-EX compared with SHR. Pro-survival Bcl2, Bcl-xL, p-Bad, 14-3-3, insulin-like growth factor (IGF)-1, pPI3K/PI3K, and pAKT/AKT were significantly increased in SHR-EX compared to those in SHR. Exercise training suppressed neural EndoG/AIF-related caspase-independent, Fas/FasL-mediated caspase-dependent, mitochondria-mediated caspase-dependent apoptotic pathways as well as enhanced Bcl-2 family-related and IGF-1-related pro-survival pathways in the early aged hypertensive cerebral cortex. These findings indicated new therapeutic effects of exercise training on preventing early aged hypertension-induced neural apoptosis in cerebral cortex.
A comprehensive transcriptomic analysis of alternate interferon signaling pathways in peripheral blood mononuclear cells in rheumatoid arthritis
Liang Han1, * , Shenghao Tu1, * , Pan Shen1 , Jiahui Yan1 , Yao Huang1 , Xin Ba1 , Tingting Li1 , Weiji Lin1 , Huihui Li2 , Kun Yu2 , Jing Guo3 , Ying Huang1 , Kai Qin1 , Yu Wang1 , Zhe Chen1
doi : 10.18632/aging.203432
Volume 13, Issue 16 pp 20511—20533
Interferon (IFN) signaling pathways play crucial roles in the pathogenesis of rheumatoid arthritis (RA). Prior studies have mainly studied mixed alterations in the IFN signaling pathway in RA, but these studies have not been sufficient to elucidate how imbalanced IFN signaling subtly influences immune cells. Single-cell RNA (scRNA) sequencing makes it possible to better understand the alternations in the interferon signaling pathways in RA. In the present study, we found that IFN signaling pathways were activated in natural killer (NK) cells, monocytes, T cells, B cells, and most immune cell subclasses in RA. We then explored and analyzed the connections between abnormal IFN signaling pathways and cellular functional changes in RA. Single-Cell rEgulatory Network Inference and Clustering (SCENIC) analysis and gene regulatory network (GRN) construction were also performed to identify key transcription factors in RA. Finally, we also investigated altered IFN signaling pathways in multiple RA peripheral blood samples, which indicated that abnormal IFN signaling pathways were universally observed in RA. Our study contributes to a better understanding of the delicate and precise regulation of IFN signaling in the immune system in RA. Furthermore, common alternations in IFN signaling pathway-related transcription factors could help to identify novel therapeutic targets for RA treatment.
NLRP3 inflammasome activation contributes to the pathogenesis of cardiocytes aging
Li-Zhen Liao1,2, * , Zhi-Chong Chen3, * , Sui-Sui Wang1,2 , Wen-Bin Liu1,2 , Chang-Lin Zhao1,2 , Xiao-Dong Zhuang4
doi : 10.18632/aging.203435
Volume 13, Issue 16 pp 20534—20551
The NOD-like receptor protein 3 (NOD-like receptor protein 3, NLRP3) inflammasome is associated with many physiological processes related to aging. We investigated whether NLRP3 inflammasome activation contributes to the pathogenesis of cardiocytes aging dissected the underlying mechanism.
Mediation of circ_RPPH1 on miR-146b-3p/E2F2 pathway to hinder the growth and metastasis of breast carcinoma cells
Hai Feng1 , Shou-Zhan Sun2 , Fang Cheng3 , Nian-Qu Zhang4
doi : 10.18632/aging.203439
Volume 13, Issue 16 pp 20552—20568
Nova Circular RNA (circRNA) of non-coding RNA has gradually become an important regulatory factor, and it has made people attach great concern over the occurrence and development of many diseases, particularly carcinomas. circ_RPPH1 is a newly discovered circRNA. Gene Expression Omnibus (GEO) analysis showed that there are high contents of circ_RPPH1 in breast cancer (BC), but the mechanism of circRNA in BC remains unclear.
NPAS2 ameliorates myocardial ischaemia/reperfusion injury in rats via CX3CL1 pathways and regulating autophagy
Jing Huang1 , Wan Qing1 , Yesheng Pan1
doi : 10.18632/aging.203445
Volume 13, Issue 16 pp 20569—20584
Myocardial ischemia/reperfusion (I/R) injury is common during the treatment of cardiovascular diseases. Neuronal PAS Domain Protein 2 (NPAS2) is one of the core genes that control the rhythm of the biological clock. NPAS2 also regulates the biological rhythm.
Prognostic and clinicopathological significance of systemic immune-inflammation index in pancreatic cancer: a meta-analysis of 2,365 patients
Yifang Shui1,2,3,4,5 , Mengquan Li5 , Jing Su5 , Mingxun Chen6 , Xiaobin Gu7 , Wenzhi Guo1,2,3,4
doi : 10.18632/aging.203449
Volume 13, Issue 16 pp 20585—20597
The prognostic value of the systemic immune-inflammation index (SII) in patients with pancreatic cancer is conflicting according to previous investigations. Therefore, we performed a meta-analysis to explore the association between SII and pancreatic cancer prognosis. Electronic databases were searched for studies exploring the association of SII with prognostic outcomes in pancreatic cancer. The endpoints were overall survival (OS), disease-free survival (DFS), recurrence-free survival (RFS), progression-free survival (PFS), cancer-specific survival (CSS), and clinicopathological parameters. The prognostic value of SII was estimated by hazard ratio (HR) or odds ratio (OR) with a 95% confidence interval (CI). Nine studies containing 11 cohorts with 2,365 subjects in total were included in this meta-analysis. Elevated SII was associated with poor OS (HR=1.50, 95% CI=1.15–1.96, p=0.002), RFS/PFS/DFS (HR=1.52, 95% CI=1.01–2.28, p=0.045), and CSS (HR=2.60, 95% CI=1.65–4.09, p < 0.001) in patients with pancreatic cancer. Additionally, there was no significant association between SII and other parameters in pancreatic cancer such as sex, tumor location, lymph node metastasis, tumor-node-metastasis stage, vascular invasion, and grade. This meta-analysis suggested that elevated SII was a significant prognostic marker for short-term and long-term survival outcomes in patients with pancreatic cancer.
Knockdown of hsa_circ_0091994 constrains gastric cancer progression by suppressing the miR-324-5p/HMGA1 axis
Yi Xie1 , Zhao Liu1 , Hanfang Zhu1
doi : 10.18632/aging.203450
Volume 13, Issue 16 pp 20598—20608
CircRNAs have emerged as potential therapeutic targets for diseases such as gastric cancer (GC). We identified highly dysregulated circRNAs in GC tissue and further explored their potential mechanisms in the progression of GC. Hsa_circ_0091994 (cicrRNA_105040) was identified as a highly upregulated circRNA in GC tissues, whose host gene is negatively associated with the overall survival of patients. Using cell counting kit-8 and Annexin V assays, we observed that hsa_circ_0091994 knockdown inhibited the viability of AGS and HGC-27 cells by inducing apoptosis. Scratch wound healing assays showed that hsa_circ_0091994 knockdown also inhibited GC cell healing. Bioinformatics analysis and a luciferase assays revealed that hsa_circ_0091994 knockdown inhibits GC progression by suppressing miR-324-5p and HMGA1 expression. The antitumor effect of hsa_circ_0091994 knockdown was confirmed in vivo using a mouse xenograft model. Hsa_circ_0091994 knockdown inhibited the progression of GC by inhibiting the miR-324-5p/HMGA1 axis.
Intravascular emboli relates to immunosuppressive tumor microenvironment and predicts prognosis in stage III colorectal cancer
Xiangping Song1,2 , Di Xie3 , Fengbo Tan1 , Yuan Zhou1 , Yuqiang Li1 , Zhongyi Zhou1 , Qian Pei1 , Haiping Pei1,4
doi : 10.18632/aging.203451
Volume 13, Issue 16 pp 20609—20628
Stage III colorectal cancer (CRC) patients experience varying degrees of prognosis even if receiving standard therapeutic regimes. Intravascular emboli (IVE), a type of vascular invasion, impacts the clinical outcome in CRC. In this study, we confirmed the role of IVE in predicting the prognosis of stage III CRC patients and characterized the tumor microenvironment (TME) of CRC with IVE.
A systematic dissection of human primary osteoblasts in vivo at single-cell resolution
Yun Gong1, * , Junxiao Yang2, * , Xiaohua Li3 , Cui Zhou3 , Yu Chen3 , Zun Wang6 , Xiang Qiu5 , Ying Liu3 , Huixi Zhang3 , Jonathan Greenbaum1 , Liang Cheng7 , Yihe Hu2 , Jie Xie2 , Xuecheng Yang2 , Yusheng Li2 , Yuntong Bai8 , Yu-Ping Wang8 , Yiping Chen9 , Li-Jun Tan3 , Hui Shen1 , Hong-Mei Xiao4,5 , Hong-Wen Deng1,5
doi : 10.18632/aging.203452
Volume 13, Issue 16 pp 20629—20650
Human osteoblasts are multifunctional bone cells, which play essential roles in bone formation, angiogenesis regulation, as well as maintenance of hematopoiesis. However, the categorization of primary osteoblast subtypes in vivo in humans has not yet been achieved. Here, we used single-cell RNA sequencing (scRNA-seq) to perform a systematic cellular taxonomy dissection of freshly isolated human osteoblasts from one 31-year-old male with osteoarthritis and osteopenia after hip replacement. Based on the gene expression patterns and cell lineage reconstruction, we identified three distinct cell clusters including preosteoblasts, mature osteoblasts, and an undetermined rare osteoblast subpopulation. This novel subtype was found to be the major source of the nuclear receptor subfamily 4 group A member 1 and 2 (NR4A1 and NR4A2) in primary osteoblasts, and the expression of NR4A1 was confirmed by immunofluorescence staining on mouse osteoblasts in vivo. Trajectory inference analysis suggested that the undetermined cluster, together with the preosteoblasts, are involved in the regulation of osteoblastogenesis and also give rise to mature osteoblasts. Investigation of the biological processes and signaling pathways enriched in each subpopulation revealed that in addition to bone formation, preosteoblasts and undetermined osteoblasts may also regulate both angiogenesis and hemopoiesis. Finally, we demonstrated that there are systematic differences between the transcriptional profiles of human and mouse osteoblasts, highlighting the necessity for studying bone physiological processes in humans rather than solely relying on mouse models. Our findings provide novel insights into the cellular heterogeneity and potential biological functions of human primary osteoblasts at the single-cell level.
NLRC5 attenuates inflammatory response in IL-1?-stimulated human osteoarthritis chondrocytes through the NF-?B signaling pathway
Yiping Mu1 , Yang Zhang1 , Jie Wu1 , Qi Li1, &
doi : 10.18632/aging.203453
Volume 13, Issue 16 pp 20651—20660
NOD-like receptor family caspase recruitment domain family domain containing 5 (NLRC5) has been found to be a critical mediator of inflammatory response. However, the role of NLRC5 in osteoarthritis (OA) has not been reported. Our results showed that NLRC5 was down-regulated by IL-1? induction in chondrocytes. Overexpression of NLRC5 in chondrocytes significantly suppressed IL-1?-induced inflammatory response through inhibiting the production of multiple inflammatory mediators including inducible nitric oxide synthases (iNOS), and cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), NO, TNF-? and IL-6, as well matrix metalloproteinase 3 (MMP-3) and MMP-13. Consistently, NLRC5 knockdown exhibited opposite effects on the production of these inflammatory mediators in IL-1?-induced chondrocytes. Furthermore, overexpression of NLRC5 increased the I?B? expression, while decreased the p-p65 expression, indicating that NLRC5 inhibited the activation of NF-?B signaling. Additionally, inhibition of NF-?B by PDTC mitigated the si-NLRC5-mediated promotion of IL-1?-induced inflammatory injury in chondrocytes. Finally, NLRC5 treatment ameliorated cartilage degeneration in an OA model in rats. Taken together, these findings revealed that NLRC5 attenuated IL-1?-induced inflammatory injury in chondrocytes through regulating the NF-?B signaling.
METTL21B is a prognostic biomarker and potential therapeutic target in low-grade gliomas
Xin Shu1 , Xinquan Li1 , Xiaochen Xiang1 , Qiang Wang1 , Qingming Wu1, &
doi : 10.18632/aging.203454
Volume 13, Issue 16 pp 20661—20683
A considerable amount of literature has demonstrated that eukaryotic translation elongation factor 1A (eEF1A) is closely related to tumors. As a newly identified lysine specific methyltransferase targeting eEF1A at Lys-165, too little attention has been paid to the function of METTL21B. To determine the potential significance and prognostic value of METTL21B in low grade glioma (LGG), we analyzed the expression, methylation level and copy number variations (CNV) of METTL21B and its effect on prognosis in patients with LGG by 4 public databases in conjunction with experimental examination of LGG patient samples. As a result, we found that high expression, hypomethylation and gain/amplification of CNV of METTL21B were associated with poor prognosis in LGG. The potential functions of METTL21B in LGG may be involved in cell adhesion, angiogenesis and cell proliferation of tumor by enrichment analysis. In addition, METTL21B may facilitate immune evasion of tumor and affect prognosis by mediating macrophage polarization from M1 to M2 and regulating expression of immune checkpoints. Nevertheless, patients with high METTL21B level are likely to have better response to immune checkpoints blockage therapy. Because of its substrate specificity, METTL21B is expected to be a promising target for the treatment of glioma.
Construction of an immune-related lncRNA signature as a novel prognosis biomarker for LUAD
Hang Chen1, * , Wei Shen2, * , Saiqi Ni3, * , Menglu Sang4, * , Shibo Wu4 , Yinyu Mu4 , Kaitai Liu4 , Ni Li4 , Linwen Zhu4 , Guodong Xu4
doi : 10.18632/aging.203455
Volume 13, Issue 16 pp 20684—20697
The tumor immune microenvironment of lung cancer is associated with prognosis and immunotherapy efficacy. Long noncoding RNAs are identified as prognostic biomarkers associated with immune functions. We constructed a signature comprising differentially expressed immune-related lncRNAs to predict the prognosis of patients with lung adenocarcinoma. We established the immune-related lncRNA signature by pairing immune-related lncRNAs regardless of expression level and lung adenocarcinoma patients were divided into high- and low-risk groups. The prognosis of patients in the two groups was significantly different; The immune-related lncRNA signature could serve as an independent lung adenocarcinoma prognostic indicator. The signature correlated negatively with B cell, CD4+ T cell, M2 macrophage, neutrophil, and monocyte immune infiltration. Patients with low risk scores had a higher abundance of immune cells and stromal cells around the tumor. Gene set enrichment analysis showed that samples from low-risk group were more active in the IgA production in intestinal immune network and the T and B cell receptor signaling pathway. High-risk groups had significant involvement of the cell cycle, DNA replication, adherens junction, actin cytoskeleton regulation, pathways in cancer, and TGF-? signaling pathways. High risk scores correlated significantly negatively with high CTLA-4 and HAVCR2 expression and higher median inhibitory concentration of common anti-tumor chemotherapeutics (e.g., cisplatin, paclitaxel, gemcitabine) and targeted therapy (e.g., erlotinib and gefitinib). We identified a reliable immune-related lncRNA lung adenocarcinoma prognosis model, and the immune-related lncRNA signature showed promising clinical prediction value.
m6A regulator-mediated methylation modification patterns and tumor microenvironment infiltration characterization in hepatocellular carcinoma
Xiongpei Huang2 , Zecheng Qiu2 , Liusheng Li2 , Bin Chen2 , Peiyuan Huang1
doi : 10.18632/aging.203456
Volume 13, Issue 16 pp 20698—20715
There is increasing evidence of the epigenetic regulation of the immune response in cancer. However, the specific functions and mechanisms of RNA N6-methyladenosine (m6A) modification in the cell infiltration in the hepatocellular carcinoma (HCC) tumor microenvironment (TME) is unknown.
N6-methyladenosine (m6A) modification and its clinical relevance in cognitive dysfunctions
Bingying Du1, * , Yanbo Zhang2, * , Meng Liang1 , Zengkan Du3 , Haibo Li4 , Cunxiu Fan1 , Hailing Zhang1 , Yan Jiang5 , Xiaoying Bi1
doi : 10.18632/aging.203457
Volume 13, Issue 16 pp 20716—20737
N6 adenosine methylation (m6A) is the most abundant internal RNA modification in eukaryotic cells. Dysregulation of m6A has been associated with the perturbations of cell proliferation and cell death in different diseases. However, the roles of m6A in the neurodegenerative process and cognitive dysfunction are unclear.
Apatinib inhibits the proliferation of gastric cancer cells via the AKT/GSK signaling pathway in vivo
Yi Chen1, * , Nan Chen2, * , Jin Xu3, * , Xindong Wang4 , Xiaowei Wei5 , Cuiju Tang5 , Zhong Duanmu5 , Junfeng Shi5
doi : 10.18632/aging.203458
Volume 13, Issue 16 pp 20738—20747
Gastric cancer (GC) is the third leading cause of cancer-associated mortality globally. Although the diagnosis and therapeutic strategies for GC have improved, the prognosis for advanced gastric cancer (AGC) remains poor. Hence, the present study sought to design a zebrafish model established by microinjecting human MGC-803 GC cell line for studying personalized molecular-targeted cancer therapy. Apatinib, a novel molecular-targeted agent, was evaluated for its in vivo efficacy through a comparison among the control groups (no treatment) and subject groups (treatment). Newly formed vessel length and tumor volume were measured in all of the groups for further study. The length of newly formed vessels was obviously shortened after apatinib treatment in the zebrafish model established in this study. Meanwhile, apatinib exhibited the best antitumor growth effect with dose and time dependence by suppressing AKT/GSK3?/? signaling, which may be the mechanism underlying the profound antitumor clinical effect of apatinib. The data indicated that apatinib therapy exerts an anti-angiogenesis effect and it can be recommended as a proper antitumor growth therapy for GC patients. Additionally, zebrafish models could be designed as a potential practical tool to explore new anti-GC cancer drugs.
Enriched environment remedies cognitive dysfunctions and synaptic plasticity through NMDAR-Ca2+-Activin A circuit in chronic cerebral hypoperfusion rats
Xin Zhang1 , Xiaohua Shi1 , Jiaoqi Wang1 , Zhongxin Xu1 , Jinting He1
doi : 10.18632/aging.203462
Volume 13, Issue 16 pp 20748—20761
Chronic cerebral ischemia (CCI) is one of the critical factors in the occurrence and development of vascular cognitive impairment (VCI). Apoptosis of nerve cells and changes in synaptic activity after CCI are the key factors to induce VCI. Synaptic stimulation up-regulates intraneuronal Ca2+ level through N-methyl-D-aspartic acid receptor (NMDAR) via induction of the activity-regulated inhibitor of death (AID) expression to produce active-dependent neuroprotection. Moreover, the regulation of synaptic plasticity could improve cognition and learning ability. Activin A (ActA), an exocrine protein of AID, can promote NMDAR phosphorylation and participate in the regulation of synaptic plasticity. We previously found that exogenous ActA can improve the cognitive function of rats with chronic cerebral ischemia and enhance the oxygenated glucose deprivation of intracellular Ca2+ level. In addition to NMDAR, the Wnt pathway is critical in the positive regulation of LTP through activation or inhibition. It plays an essential role in synaptic transmission and activity-dependent synaptic plasticity. The enriched environment can increase ActA expression during CCI injury. We speculated that the NMDAR-Ca2+-ActA signal pathway has a loop-acting mode, and the environmental enrichment could improve chronic cerebral ischemia cognitive impairment via NMDAR-Ca2+-ActA, Wnt/?-catenin pathway is involved in this process. For the hypothesis verification, this study intends to establish chronic cerebral hypoperfusion (CCH) rat model, explore the improvement effect of enriched environment on VCI, detect the changes in plasticity of synaptic morphology and investigate the regulatory mechanism NMDAR-Ca2+-ActA-Wnt/?-catenin signaling loop, providing a therapeutic method for the treatment of CCH.
High red blood cell distribution width levels could increase the risk of hemorrhagic transformation after intravenous thrombolysis in acute ischemic stroke patients
Hongyang Fan1,2, * , Xiaojie Liu2, * , Sai Li2, * , Peipei Liu2 , Yuxia Song3 , Haili Wang3 , Xiaojia Tang3 , Yuhan Luo3 , Jun Li2 , Yan Zhu2, & , Yingzhu Chen2
doi : 10.18632/aging.203465
Volume 13, Issue 16 pp 20762—20773
The association between the red blood cell distribution width (RDW) and hemorrhagic transformation (HT) after thrombolysis in acute ischemic stroke patients remains inconclusive. Our study aimed to assess whether high RDW levels are associated with the occurrence of HT after thrombolysis. Data were consecutively collected and retrospectively analyzed for stroke patients treated with thrombolysis between 1 January 2017 and 31 December 2019. The primary outcomes were the occurrence of HT and symptomatic HT. Among the 286 patients enrolled, 36 (12.6%) developed HT and15 (5.2%) were classified as symptomatic HT. Patients with high RDW levels were associated with a higher percentage of HT and symptomatic HT (P<0.05). The RDW levels in the HT and symptomatic HT groups were also greater compared with the no-HT group (P<0.001). Multivariable logistic regression analysis revealed that high RDW levels were independently associated with an increased risk of HT (adjusted odds ratio 2.5, 95 % CI, 1.74–3.83 P < 0.001). In conclusion, we found that high RDW levels may be an independent predictor of HT in stroke patients after thrombolysis.
NF-?B inducible miR-30b-5p aggravates joint pain and loss of articular cartilage via targeting SIRT1-FoxO3a-mediated NLRP3 inflammasome
Haiting Xu1 , Jie Zhang2 , Xiaoming Shi2 , Xiaoyang Li1, & , Chao Zheng3
doi : 10.18632/aging.203466
Volume 13, Issue 16 pp 20774—20792
MicroRNAs (miRNAs) contribute to osteoarthritis (OA) development. Nevertheless, the function and mechanism of miR-30b-5p in OA are unclear. In the present article, we gauged the miR-30b-5p level in OA patients and analyzed its correlation with OA stages. Then, we conducted in-vivo and in-vitro gain-of-function assays to determine the function of miR-30b-5p, silent information regulator 2 homolog 1 (SIRT1) and Fox. Cell counting Kit-8 (CCK-8) assay, BrdU assay and flow cytometry were utilized to gauge cell viability and apoptosis of human chondrocyte (HC-A). The targeting association between miR-30b-5p and SIRT1 was validated through the dual-luciferase reporter assay and RNA immunoprecipitation (RIP) experiment. The results signified that miR-30b-5p was up-regulated in OA patients, OA rats and interleukin-1? (IL-1?)-induced chondrocytes. The higher miR-30b-5p expression brought about progressive stages of OA patients and enhanced levels of pro-inflammatory mediators in the synovial fluid. Functionally, overexpressing miR-30b-5p hampered cell viability, aggravated chondrocyte apoptosis and NLRP3 inflammasome activation induced by IL-1?, while down-regulating miR-30b-5p exerted the reverse effects. The in-vivo experiment exhibited that down-regulating miR-30b-5p improved joint pain and loss of articular cartilage in the rats with restrained inflammation and NLRP3 inflammasome activation. Mechanistically, miR-30b-5p targeted the 3’-non-translated region (3’UTR) of SIRT1, and miR-30b-5p was inducible with NF-?B phosphorylation enhancement. Overexpressing SIRT1 or inhibiting NF-?B relieved miR-30b-5p-induced apoptosis and NLRP3 inflammasome activation by promoting FoxO3a, while down-regulating SIRT1 or FoxO3a reversed miR-30b-5p-in-induced anti-inflammatory and apoptosis-suppressive effects. Collectively, NF-?B-induced miR-30b-5p modulates chondrocyte apoptosis and OA progression by regulating the SIRT1-FoxO3a-mediated NLRP3 inflammasome.
Stimulator of interferon response cGAMP interactor overcomes ERBB2-mediated apatinib resistance in head and neck squamous cell carcinoma
Guo Ye1,2 , Junbin Zhang1,2 , Chengyao Zhang1,2
doi : 10.18632/aging.203475
Volume 13, Issue 16 pp 20793—20807
Apatinib resistance is the main obstacle to the effective treatment of advanced head and neck squamous cell carcinoma (HNSCC). This study aimed to evaluate the function of Erb-B2 receptor tyrosine kinase 2 (ERBB2) and stimulator of interferon response cGAMP interactor (STING) in apatinib resistance in HNSCC.
LINC01087 inhibits glioma cell proliferation and migration, and increases cell apoptosis via miR-384/Bcl-2 axis
Yao-Hui Tian1 , Lin-Wei Jia1 , Zhi-Feng Liu1 , Yong-Han Chen1
doi : 10.18632/aging.203478
Volume 13, Issue 16 pp 20808—20819
Long non-coding RNA (LncRNA) is associated with disease progression. It is reported that LINC01087 is highly expressed in cancer and participates in tumorigenesis. However, whether it regulates the development of glioma has not been studied. So, the goal of this research is to determine the role of LINC01087 in gliomas and to provide potential targets for clinical treatment.
Long non-coding RNA KTN1-AS1 promotes progression in pancreatic cancer through regulating microRNA-23b-3p/high-mobility group box 2 axis
Zhong-Bo Zhang1 , Ning Liu1, &
doi : 10.18632/aging.203481
Volume 13, Issue 16 pp 20820—20835
To explore the inhibitory effect of long non-coding RNA (LncRNA) antisense of KTN1 (KTN1-AS1) on the growth of pancreatic cancer (PC) cells by regulating the microRNA-23b-3p (miR-23b-3p)/high-mobility group box 2 (HMGB2) axis. The expression of KTN1-AS1 in tissues and cells was detected by qRT-PCR, and the relationship between KTN1-AS1 and clinicopathological data of patients with PC was analyzed. In addition, stable and transient overexpression and inhibition vectors were established and transfected into PC cells PANC-1, BxPC-3. CCK-8, transwell, and flow cytometry were responsible for the detection of proliferation, invasion, and apoptosis of transfected cells, respectively. The correlation of miR-23b-3p between KTN1-AS1 and HMGB2 was determined by dual luciferase reports, and the relationship between KTN1-AS1 and miR-23b-3p was further verified by RNA immunoprecipitation (RIP). The highly expressed KTN1-AS1 in PC patients was indicative of its high diagnostic value in this disease. Besides, it was found that KTN1-AS1 was linked with the pathological stage, differentiation degree and lymph node metastasis (LNM) of PC patients. Underexpressed KTN1-AS1 led to decreased proliferation and invasion ability of cells and increased apoptosis rate, while the effect of further overexpression of KTN1-AS1 on cells was the opposite. Dual luciferase reporter (DLR) assay confirmed that KTN1-AS1 could target miR-23b-3p, while miR-23b-3p could target HMGB2. Functional analysis showed that the overexpression of miR-23b-3p inhibited the expression of HMGB2 in PC cells and affected cell proliferation, invasion and apoptosis. Co-transfection of Sh-KTN1-AS1 and miR-23b-3p-mimics exhibited that up-regulation of KTN1-AS1 expression could reverse the effect of miR-23b-3p-mimics on PC cells.
Heparanase is a novel biomarker for immune infiltration and prognosis in breast cancer
Wen-Jing Yang1 , Lin Shi1 , Xiao-Min Wang1 , Guo-Wang Yang1
doi : 10.18632/aging.203489
Volume 13, Issue 16 pp 20836—20852
Heparanase (HPSE), an endoglycosidase that cleaves heparan sulfate, regulates a variety of biological processes that promote tumor progression. In this study, we analyzed the correlation between HPSE expression and prognosis in cancer patients, using multiple databases (Oncomine, TIMER, PrognoScan, GEPIA, Kaplan–Meier plotter, miner v4.1, DAVID). HPSE expression was significantly increased in bladder, breast, lung, and stomach cancer compared to matched normal tissues. The increased HPSE expression correlated with poor prognosis and increased immune infiltration levels of B cells, CD8+ and CD4+ T cells, macrophages, neutrophils and dendritic cells in bladder and breast cancer. In breast cancer, the high HPSE expression was associated with basal-like subtypes, younger age (0-40), advanced Scarff-Bloom-Richardson grade, Nottingham Prognostic Index and p53 mutation status. In addition, using a mouse model of breast cancer, our data showed that HPSE upregulated IL-10 expression and promoted macrophage M2 polarization and T cell exhaustion. Together, our data provide a novel immunological perspective on the mechanisms underlying breast cancer progression, and indicate that HPSE may serve as a biomarker for immune infiltration and prognosis in breast cancer.
Correction for: TGF-? and NF-?B signaling pathway crosstalk potentiates corneal epithelial senescence through an RNA stress response
Zhi-Yuan Li1 , Zhao-Li Chen1 , Ting Zhang1,2 , Chao Wei1 , Wei-Yun Shi1
doi : 10.18632/aging.203516
Volume 13, Issue 16 pp 20853
