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Exploring aging interventions in human brain organoids
Julio Aguado, Ernst J. Wolvetang
doi : 10.18632/aging.203925
pp 1592—1593
Enhancing CISD2 expression to retard liver aging
Yi-Long Huang, Zhao-Qing Shen, Ting-Fen Tsai
doi : 10.18632/aging.203929
pp 1594—1596
Elevated levels of serum CDCP1 in individuals recovering from severe COVID-19 disease
Jose-Ramon Blanco1,2, * , MarÃa-Jesús Cobos-Ceballos3,4 , Francisco Navarro5 , Isabel Sanjoaquin6 , Carlos Armiñanzas7 , Enrique Bernal8 , Luis Buzon-Martin9 , Miguel Viribay10 , Laura Pérez-MartÃnez2 , Simona Espejo-Pérez3,11 , Borja Valencia12 , Jesus Guzman-Aguilar13 , Juan-Jose Ruiz-Cubillan14 , Consuelo Alcalde15 , Fernando Gustavo Gutierrez-Herrero16 , Julian Olalla5 , Eva-Maria Andres-Esteban17,18 , Bernabe Jurado-Gamez3,4, * , Javier Ugedo19
doi : 10.18632/aging.203898
Volume 14, Issue 4 pp 1597—1610
Background: COVID-19 survivors report residual lung abnormalities after discharge from the hospital. The aim of this study was to identify biomarkers in serum and induced sputum samples from patients after hospitalization for COVID-19.
Physiological health indexes predict deterioration and mortality in patients with COVID-19: a comparative study
Irina Strazhesko1 , Olga Tkacheva1 , Daria Kashtanova1 , Mikhail Ivanov1 , Vladislav Kljashtorny1 , Antonina Esakova1 , Maria Karnaushkina2 , Cassandra Guillemette3 , Amber Hewett3 , Véronique Legault3 , Lilit Maytesian1 , Maria Litvinova4,8 , Alan Cohen3,5,6 , Alexey Moskalev1,7
doi : 10.18632/aging.203915
Volume 14, Issue 4 pp 1611—1626
Old age is a crucial risk factor for severe coronavirus disease 2019 (COVID-19), with serious or fatal outcomes disproportionately affecting older adults compared with the rest of the population. We proposed that the physiological health status and biological age, beyond the chronological age itself, could be the driving trends affecting COVID-19 severity and mortality. A total of 155 participants hospitalized with confirmed COVID-19 aged 26–94 years were recruited for the study. Four different physiological summary indices were calculated: Klemera and Doubal’s biological age, PhenoAge, physiological dysregulation (PD; globally and in specific systems), and integrated albunemia. All of these indices significantly predicted the risk of death (p < 0.01) after adjusting for chronological age and sex. In all models, men were 2.4–4.4-times more likely to die than women. The global PD was shown to be a good predictor of deterioration, with the odds of deterioration increasing by 41.7% per 0.5-unit increase in the global PD. As for death, the odds also increased by 68.3% per 0.5-unit increase in the global PD. Our results are partly attributed to common chronic diseases that aggravate COVID-19, but they also suggest that the underlying physiological state could capture vulnerability to severe COVID-19 and serve as a tool for prognosis that would, in turn, help inpatient management.
The telomere-mitochondrial axis of aging in newborns
Charlotte Van Der Stukken1 , Tim S. Nawrot1,2 , Rossella Alfano1 , Congrong Wang1 , Sabine A.S. Langie1 , Michelle Plusquin1 , Bram G. Janssen1 , Dries S. Martens1
doi : 10.18632/aging.203897
Volume 14, Issue 4 pp 1627—1650
Aging starts at the beginning of life as evidenced by high variability in telomere length (TL) and mitochondrial DNA content (mtDNAc) at birth. Whether p53 and PGC-1α are connected to these age-related markers in early life is unclear. In this study, we hypothesized that these hallmarks of aging are associated at birth.
Mitochondrial dysfunction in mandibular hypoplasia, deafness and progeroid features with concomitant lipodystrophy (MDPL) patients
Michela Murdocca1 , Paola Spitalieri1 , Angela Cappello2,3 , Fiorella Colasuonno4 , Sandra Moreno4,5 , Eleonora Candi2,3 , Maria Rosaria D'Apice1 , Giuseppe Novelli1 , Federica Sangiuolo1
doi : 10.18632/aging.203910
Volume 14, Issue 4 pp 1651—1664
Mandibular hypoplasia, Deafness and Progeroid features with concomitant Lipodystrophy is a rare, genetic, premature aging disease named MDPL Syndrome, due to almost always a de novo variant in POLD1 gene, encoding the DNA polymerase δ. In previous in vitro studies, we have already described several hallmarks of aging, including genetic damage, telomere shortening, cell senescence and proliferation defects. Since a clear connection has been reported between telomere shortening and mitochondria malfunction to initiate the aging process, we explored the role that mitochondrial metabolism and activity play in pathogenesis of MDPL Syndrome, an aspect that has not been addressed yet. We thus evaluated mtDNA copy number, assessing a significant decrease in mutated cells.
A tandem segmentation-classification approach for the localization of morphological predictors of C. elegans lifespan and motility
Evgeniy Galimov1, * , Artur Yakimovich1,2,3, *
doi : 10.18632/aging.203916
Volume 14, Issue 4 pp 1665—1677
C. elegans is an established model organism for studying genetic and drug effects on aging, many of which are conserved in humans. It is also an important model for basic research, and C. elegans pathologies is a new emerging field. Here we develop a proof-of-principal convolutional neural network-based platform to segment C. elegans and extract features that might be useful for lifespan prediction. We use a dataset of 734 worms tracked throughout their lifespan and classify worms into long-lived and short-lived. We designed WormNet - a convolutional neural network (CNN) to predict the worm lifespan class based on young adult images (day 1 – day 3 old adults) and showed that WormNet, as well as, InceptionV3 CNN can successfully classify lifespan. Based on U-Net architecture we develop HydraNet CNNs which allow segmenting worms accurately into anterior, mid-body and posterior parts. We combine HydraNet segmentation, WormNet prediction and the class activation map approach to determine the segments most important for lifespan classification. Such a tandem segmentation-classification approach shows the posterior part of the worm might be more important for classifying long-lived worms. Our approach can be useful for the acceleration of anti-aging drug discovery and for studying C. elegans pathologies.
PKC is an indispensable factor in promoting environmental toxin chromium-mediated transformation and drug resistance
Suthakar Ganapathy1, * , Jian Liu2, * , Tianqi Yu1 , Rui Xiong2 , Qiang Zhang2 , Alexandros Makriyannis1 , Changyan Chen1
doi : 10.18632/aging.203917
Volume 14, Issue 4 pp 1678—1690
Hexavalent chromium [Cr(VI)] pollution is a serious environmental problem, due to not only its toxicity but also carcinogenesis. Although studies reveal several features of Cr(VI)-induced carcinogenesis, the underlying mechanisms of how Cr(VI) orchestrates multiple mitogenic pathways to promote tumor initiation and progression remain not fully understood. Src/Ras and other growth-related pathways are shown to be key players in Cr(VI)-initiated tumor prone actions. The role of protein kinase C (PKC, an important signal transducer) in Cr(VI)-mediated carcinogenesis has not been thoroughly investigated. In this study, using human bronchial/lung epithelial cells and keratinocytes, we demonstrate that PKC activity is increased by transient or chronic Cr(VI) exposure, which plays no role in the activation of Src/Ras signaling and ROS upregulation by this metal toxin. PKC in chronic Cr(VI)-treated cells stabilizes Bcl-2 to mitigate doxorubicin (an anti-cancer drug)-mediated apoptosis. After the suppression of this kinase by GO6976 (a PKC inhibitor), the cells chronically exposed to Cr(VI) partially regain the sensitivity to doxorubicin. However, when co-suppressed PKC and Ras, the chronic Cr(VI)-treated cells become fully responsive to doxorubicin and are unable to be transformed. Taken together, our study provides a new insight into the mechanisms, in which PKC is an indispensable player and cooperates with other mitogenic pathways to achieve Cr(VI)-induced carcinogenesis as well as to establish drug resistance. The data also suggest that active PKC can serve as a potential biomarker for early detection of health damages by Cr(VI) and therapeutic target for developing new treatments for diseases caused by Cr(VI).
Mid-life epigenetic age, neuroimaging brain age, and cognitive function: coronary artery risk development in young adults (CARDIA) study
Yinan Zheng1, * , Mohamad Habes2,3, * , Mitzi Gonzales2 , Raymond Pomponio3 , Ilya Nasrallah3 , Sadiya Khan1,4 , Douglas E. Vaughan5 , Christos Davatzikos3 , Sudha Seshadri2,6 , Lenore Launer7 , Farzaneh Sorond8 , Sanaz Sedaghat9 , Derek Wainwright10 , Andrea Baccarelli11 , Stephen Sidney12 , Nick Bryan13 , Philip Greenland1 , Donald Lloyd-Jones1 , Kristine Yaffe14,15,16,17, # , Lifang Hou1, #
doi : 10.18632/aging.203918
Volume 14, Issue 4 pp 1691—1712
The proportion of aging populations affected by dementia is increasing. There is an urgent need to identify biological aging markers in mid-life before symptoms of age-related dementia present for early intervention to delay the cognitive decline and the onset of dementia. In this cohort study involving 1,676 healthy participants (mean age 40) with up to 15 years of follow up, we evaluated the associations between cognitive function and two classes of novel biological aging markers: blood-based epigenetic aging and neuroimaging-based brain aging. Both accelerated epigenetic aging and brain aging were prospectively associated with worse cognitive outcomes. Specifically, every year faster epigenetic or brain aging was on average associated with 0.19-0.28 higher (worse) Stroop score, 0.04-0.05 lower (worse) RAVLT score, and 0.23-0.45 lower (worse) DSST (all false-discovery-rate-adjusted p <0.05). While epigenetic aging is a more stable biomarker with strong long-term predictive performance for cognitive function, brain aging biomarker may change more dynamically in temporal association with cognitive decline. The combined model using epigenetic and brain aging markers achieved the highest accuracy (AUC: 0.68, p<0.001) in predicting global cognitive function status. Accelerated epigenetic age and brain age at midlife may aid timely identification of individuals at risk for accelerated cognitive decline and promote the development of interventions to preserve optimal functioning across the lifespan.
Telomere length in leucocytes and solid tissues of young and aged rats
M. Donatella Semeraro1 , Gunter Almer1 , Wilfried Renner1 , Hans-Jürgen Gruber1 , Markus Herrmann1
doi : 10.18632/aging.203922
Volume 14, Issue 4 pp 1713—1728
Background: Telomeres are protective nucleoprotein structures at the end of chromosomes that shorten with age. Telomere length (TL) in peripheral blood mononuclear cells (PBMCs) has been proposed as surrogate marker for TL in the entire organism. Solid evidence that supports this concept is lacking.
The elevation of miR-185-5p alleviates high-fat diet-induced atherosclerosis and lipid accumulation in vivo and in vitro via SREBP2 activation
Wenyun Tan1, * , Gang Wang2, * , Gang Liu1 , Daofeng You1 , Mei Wei1 , Xiaojing Jin3 , Wei Zhao4 , Mingqi Zheng1
doi : 10.18632/aging.203896
Volume 14, Issue 4 pp 1729—1742
Objective: SREBP2, a member of the SREBP family, is a primary regulator of lipid metabolism. In recent years, an increasing number of studies have suggested that miRNAs regulate lipid metabolism-related genes. It was speculated in this study that miRNAs may be implicated in the regulation of lipid accumulation in macrophages by SREBP2 protein.
THRSP identified as a potential hepatocellular carcinoma marker by integrated bioinformatics analysis and experimental validation
Yuxi Ding1,2,3, * , Xiaoling Liu1,2,3, * , Yue Yuan1,2,3 , Yunjian Sheng1,2,3 , Decheng Li1,2,3 , Suvash Chandra Ojha1,2,3 , Changfeng Sun1,2,3 , Cunliang Deng1,2,3
doi : 10.18632/aging.203900
Volume 14, Issue 4 pp 1743—1766
Hepatocellular carcinoma (HCC) is the most common malignant liver tumor with high mortality and poor prognosis worldwide. This study aimed to identify hub genes and investigate the underlying molecular mechanisms in HCC progression by integrated bioinformatics analysis and experimental validation. Based on the Gene Expression Omnibus (GEO) databases and The Cancer Genome Atlas (TCGA), 12 critical differential co-expression genes were identified between tumor and normal tissues. Via survival analysis, we found higher expression of LCAT, ACSM3, IGF1, SRD5A2, THRSP and ACADS was associated with better prognoses in HCC patients. Among which, THRSP was selected for the next investigations. We found that THRSP mRNA expression was negatively correlated with its methylation and closely associated with clinical characteristics in HCC patients. Moreover, THRSP expression had a negative correlation with the infiltration levels of several immune cells (e.g., B cells and CD4+ T cells). qRT-PCR verified that THRSP was lower expressed in HCC tissues and cell lines compared with control. Silencing of THRSP promoted the migration, invasion, proliferation, and inhibited cell apoptosis of HCCLM and Huh7 cell lines. Decreased expression of THRSP promoted HCC progression by NF-κB, ERK1/2, and p38 MAPK signaling pathways. In conclusion, THRSP might serve as a novel biomarker and therapeutic target of HCC.
The novel lncRNA GPC5-AS1 stabilizes GPC5 mRNA by competitively binding with miR-93/106a to suppress gastric cancer cell proliferation
Guo Bo1,2 , Yijie Liu1,2 , Wen Li1,2 , Lumin Wang3 , Lingyu Zhao1,2 , Dongdong Tong1,2 , Lei Ni1 , Liying Liu4 , Yannan Qin1 , Wenjing Wang1,5 , Chen Huang1,2,4,6
doi : 10.18632/aging.203901
Volume 14, Issue 4 pp 1767—1781
Long non-coding RNAs (lncRNAs) are of importance in the genesis and progression of gastric cancer (GC). GPC5-AS1 is a novel lncRNA associated with methyl-CpG-binding protein 2 (MeCP2), identified in our previous microarray analysis; however, the role of GPC5-AS1 in GC remains unknown. In the present study, we demonstrate that GPC5-AS1 is downregulated in GC cells and tissues, and this aberrant expression is regulated by MeCP2 through CpG site binding in the promoter region. Importantly, we also demonstrate that GPC5-AS1 overexpression suppresses cell proliferation, colony formation, and cell cycle transition; induces apoptosis in vitro; and inhibits tumorigenicity in vivo. The expression of the controversial gene GPC5 was downregulated in GC tissues, and elevated GPC5 level could inhibit GC cell growth. Mechanistically, we demonstrated that GPC5-AS1 stabilizes GPC5 mRNA by acting as a molecular sponge for miR-93 and miR-106a, thereby reducing GC tumor progression. In conclusion, our results suggest that GPC5-AS1 may play a pivotal role in GC and serve as a potential diagnostic biomarker and a powerful therapeutic target for GC.
Long non-coding RNA Linc00205 promotes hepatoblastoma progression through regulating microRNA-154-3p/Rho-associated coiled-coil Kinase 1 axis via mitogen-activated protein kinase signaling
Guoqing Liu1 , Qiang Zhu1 , Hao Wang1 , Jianfeng Zhou1 , Bin Jiang1
doi : 10.18632/aging.203902
Volume 14, Issue 4 pp 1782—1796
Hepatoblastoma (HB) is the most common pediatric liver tumor. The significant tumor heterogeneity of HB leads to varied prognoses among children with the disease. Recent studies have suggested that long non-coding RNAs (lncRNAs) can serve as novel therapies for HB treatment. Thus, in this study, we aimed to reveal the function and mechanism of the lncRNA Linc00205 in HB. Our results exhibited that, in both HB tissues and cell lines, levels of Linc00205 were significantly increased. In addition, knockdown of Linc00205 led to suppression of HB development. Moreover, we identified that Linc00205 was able to directly bind to miR-154-3p, thus isolating miR-154-3p from its target Rho-associated coiled-coil Kinase 1 (ROCK1). Further cellular behavioral experiments elucidated that the miR-154-3p inhibitor and ROCK1 overexpression were able to reverse the effect of downregulated Linc00205 on proliferation, migration, invasion, and apoptosis of HB cells by rescue assays via mitogen-activated protein kinase (MAPK) signaling. Our results demonstrated that Linc00205 enhanced HB progression by regulating ROCK1 expression via sponging miR-154-3p through MAPK signaling, which suggests a novel potential therapeutic target for HB.
LncRNA HULC as a potential predictor of prognosis and clinicopathological features in patients with digestive system tumors: a meta-analysis
Duo Li1 , Rui Wang1 , Na Wu1 , Yongqiang Yu1
doi : 10.18632/aging.203903
Volume 14, Issue 4 pp 1797—1811
Objective: This meta-analysis aimed to evaluate the correlation between lncRNA HULC, prognosis and clinicopathological characteristics in patients with digestive system tumors.
Qi Ling decreases paclitaxel resistance in the human prostate cancer by reversing tumor-associated macrophages function
Hongwen Cao1, * , Dan Wang1, * , Renjie Gao1, * , Yigeng Feng1 , Lei Chen1
doi : 10.18632/aging.203904
Volume 14, Issue 4 pp 1812—1821
Tumor-associated macrophages (TAMs) are critical immune cells infiltrated into tumor. In present study, we evaluated the effects of Qi Ling (QL), a traditional Chinese medicine on paclitaxel resistance in prostate cancer cells and explored the underlying mechanisms. We administrated QL to rats and collected the serum from QL-treated rats (QL-serum). We established the co-culture system of TAMs/paclitaxel resistant prostate cancer cells. We treated the TAMs with QL-serum and measured the viability of paclitaxel resistant prostate cancer cells after exposing to paclitaxel. We monitored the expression of M1 and M2 markers, the expression and activation of IL-6/STAT3 signaling pathways in TAMs after QL treatment. We treated TAMs with QL-serum together with interleukin (IL)-6, measured the expression of M1 and M2 markers, and the viability of paclitaxel resistant prostate cancer cells. In co-culture system, QL-serum-treated TAMs decreased the paclitaxel resistance in the human prostate cancer cells. QL-serum treatment significantly up-regulated the expression of M1 markers inducible nitric oxide synthase and tumor necrosis factor α while decreased the expression of M2 markers IL-10 and chemokine (C-C motif) ligand 22. QL-serum suppressed the activation of IL-6/ signal transducer and activator of transcription 3 signaling pathway. All these effects of QL-serum were abolished in the presence of IL-6. Qi Ling re-programmed TAMs and decreases paclitaxel resistance in prostate cancer cells.
Downregulated exosome-associated gene FGF9 as a novel diagnostic and prognostic target for ovarian cancer and its underlying roles in immune regulation
Zhijie Xu1,2,3, * , Yuan Cai1, * , Wei Liu4 , Fanhua Kang2 , Qingchun He5,6 , Qianhui Hong2 , Wenqin Zhang2 , Jianbo Li2 , Yuanliang Yan7 , Jinwu Peng1,2
doi : 10.18632/aging.203905
Volume 14, Issue 4 pp 1822—1835
Exosome has been demonstrated to be secreted from cells and seized by targeted cells. Exosome could transmit signals and exert biological functions in cancer progression. Nevertheless, the underlying mechanisms of exosome in ovarian cancer (OC) have not been fully explored. In this study, we wanted to explore whether Fibroblast growth factor 9 (FGF9), as an exosome-associated gene, was importantly essential in OC progression and prognosis. Firstly, comprehensive bioinformatics platforms were applied to find that FGF9 expression was lower in OC tissues compared to normal ovarian tissues. Meanwhile, downregulated FGF9 displayed favorable prognostic values in OC patients. The gene enrichment of biological functions indicated that abnormally expressed FGF9 could be involved in the OC-related immune signatures, such as immunoinhibitors and chemokine receptors. Taken together, these findings could provide a novel insight into the significance of FGF9 in OC progress and supply a new destination of FGF9-related immunotherapy in clinical treatment.
KCNQ1OT1 polymorphism rs35622507 and methylation status of KCNQ1OT1 promoter influence the drug resistance to L-OHP
Caihong Zhang1 , Yonglin Wang2, &
doi : 10.18632/aging.203906
Volume 14, Issue 4 pp 1836—1847
Background: LncRNA potassium voltage-gated channel subfamily Q member 1 opposite strand/antisense transcript 1 (KCNQ1OT1) has been reported to promote resistance to chemotherapy in colon cancer by inhibiting the expression of miR-34a. And the methylation of KCNQ1OT1 was also reported in the pathogenesis of various diseases. In this study, we aimed to study the combined effect of allele variation of KCNQ1OT1 polymorphism rs35622507 and methylation status of KCNQ1OT1 promoter in the treatment of colon cancer.
Computational research of Belnacasan and new Caspase-1 inhibitor on cerebral ischemia reperfusion injury
Hui Li2, * , Zhen Guo3, * , Jun Chen3 , Zhishan Du3 , Han Lu3 , Zhenhua Wang3 , Jianxin Xi3 , Yang Bai1
doi : 10.18632/aging.203907
Volume 14, Issue 4 pp 1848—1864
Cerebral ischemia-reperfusion injury is one of the most severe diseases in terms of mortality and disability, which seriously threatens human life and health. In clinical treatment, drug thrombolysis or mechanical interventional thrombolysis are used to quickly restore the blood supply of ischemic brain tissue. But with the rapid recovery of blood flow, complex pathophysiological processes such as oxidative stress and inflammation will further aggravate brain tissue damage, namely cerebral ischemia-reperfusion injury, for which there is no effective treatment. Recent studies have shown that the medical community has paid the role of inflammation and pyroptosis in cerebral ischemia-reperfusion injury more and more attention. And Caspase-1 was found to play a vital role in regulating inflammation pathways and pyroptosis in many inflammation-associated diseases, especially in cerebral ischemia-reperfusion injury. Not only that, Caspase-1 inhibitors have been shown to reduce the damage of cerebral ischemia-reperfusion injury by inhibiting inflammation and pyroptosis. And the Caspase-1 inhibitor, Belnacasan, has been proved to modify the active site of Caspase-1 and lead to the blocking of Caspase-1, thus correlating with tissue protection of inflammatory diseases in animal models. Therefore, it’s essential to screen and design potential Caspase-1 inhibitors to reduce cerebral ischemia-reperfusion injury and protect brain function by reducing inflammation and pyroptosis, which provides a new idea for clinical treatment of the cerebral ischemia-reperfusion injury. This study applied a group of computer-aided technology, such as Discovery Studio 4.5, Schrodinger, and PyMol, to screen and assess potential Caspase-1 inhibitors. Moreover, the ADME (absorption, distribution, metabolism, excretion) and TOPKAT (Toxicity Prediction by Computer Assisted Technology) molecules of Discovery Studio 4.5 were conducted to evaluate molecules' pharmacological and toxicological features. Then, precise molecular docking was applied to assess the binding mechanism and affinity between Caspase-1 and selected compounds. Besides, molecular dynamics simulations were performed to determine the stability of ligand-receptor complexes in the natural environment. In summary, this study lists promising drug candidates and their pharmacological properties, promoting the development of Caspase-1 inhibitors and deepening the understanding of the interaction between inhibitors and Caspase-1.
miR-223-3p inhibits the progression of atherosclerosis via down-regulating the activation of MEK1/ERK1/2 in macrophages
Daofeng You1 , Qiuge Qiao2 , Katsushige Ono3 , Mei Wei1 , Wenyun Tan1 , Cuihua Wang1 , Yangong Liu1 , Gang Liu1 , Mingqi Zheng1
doi : 10.18632/aging.203908
Volume 14, Issue 4 pp 1865—1878
Background: microRNAs (miRNAs) have drawn more attention to the progression of atherosclerosis (AS), due to their noticeable inflammation function in cardiovascular disease. Macrophages play a crucial role in disrupting atherosclerotic plaque, thereby we explored the involvement of miR-223-3p in the inflammatory response in macrophages.
Galectin-9 expression predicts poor prognosis in hepatitis B virus-associated hepatocellular carcinoma
Jianhua Jiao1, * , Dian Jiao2, * , Fa Yang1, * , Jingliang Zhang1,3 , Yu Li1 , Donghui Han1 , Keying Zhang1 , Yingmei Wang4 , Rui Zhang5 , An-Gang Yang5 , Anhui Wang6 , Weihong Wen7 , Weijun Qin1
doi : 10.18632/aging.203909
Volume 14, Issue 4 pp 1879—1890
Objectives: The aim of this study was to explore the expression of Galectin-9 in hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC), evaluate its clinicopathological significance, and investigate whether Galecin-9 expression has prognostic value in HBV-associated HCC.
Circular RNA circSHPRH inhibits the malignant behaviors of bladder cancer by regulating the miR-942/BARX2 pathway
Ling Zuo1, * , Yi Zhu2, * , Jinli Han3, * , Hongwei Liu2
doi : 10.18632/aging.203911
Volume 14, Issue 4 pp 1891—1909
Bladder cancer (BCa) is one of the most common tumors of the genitourinary system. However, the detailed molecular mechanism of BCa progression is still unclear. Recently, an increasing number of studies have demonstrated that circular RNAs (circRNAs) play a critical role in the tumorigenesis and progression of BCa. In this article, we showed that circSHPRH expression was obviously decreased in BCa tissues, compared with adjacent normal tissues. Moreover, a low circSHPRH level was positively correlated with a high grade, a high pathological stage, lymphatic metastasis and an unfavorable prognosis for BCa patients. Cell function studies indicated that silencing circSHPRH dramatically increased the proliferation, migration and invasion of BCa cells. Animal experiments revealed that circSHPRH overexpression repressed tumor growth. Mechanistic studies demonstrated that circSHPRH could combine with miR-942 and serve as a sponge of miR-942, which targets BARX2 in BCa cells. Rescue experiments showed that suppression of miR-942 or BARX2 overexpression could significantly abrogate the promoting effects of circSHPRH silencing on BCa cell proliferation and invasion. Furthermore, circSHPRH overexpression partly eliminated the suppressive effects of miR-942 on BARX2 expression. In addition, circSHPRH knockdown promoted activation of the Wnt/β-catenin signaling pathway by regulating BARX2. Taken together, our findings indicate that circSHPRH serves as a sponge of miR-942 to inhibit BCa progression by upregulating BARX2 expression, thereby inhibiting the Wnt/β-catenin signaling pathway.
Expression profile and prognostic values of Chromobox family members in human glioblastoma
Juanni Li1,2, * , Zhijie Xu1, * , Lei Zhou3 , Kuan Hu4
doi : 10.18632/aging.203912
Volume 14, Issue 4 pp 1910—1931
Glioblastoma (GBM) is the most common and deadly malignant primary brain tumor. Chromobox (CBX) family proteins are essential components of the epigenetic regulatory complex and are involved in the occurrence and development of various cancers. However, the roles of CBX members in GBM is little known. In this analysis, we synthesized several mainstream bioinformatics databases to comprehensively explore the expression profiles, prognostic implications, genetic alterations, immune infiltration, and potential biological functions of the CBXs in GBM, and cell experiments were also conducted to investigate the role of CBX8 in GBM. We found that the elevated mRNA expression of CBX2/3/5/8 and reduced mRNA expression of CBX6/7 were found in GBM. The protein levels of CBX2/3/5/8 were elevated in GBM tissues, whereas the protein levels of CBX6/7 showed no significant difference. The upregulated expression of CBX2/3/8 was found to be both correlated with the tumor grade and recurrent status. The overexpression of CBX3/8 and underexpression of CBX6 mRNA were associated with the poor prognosis. These findings suggested that CBX3 and CBX8 might be useful diagnostic and prognostic biomarkers in GBM. Further cell experiment results supported that CBX8 promoted the proliferation of glioma cells. Moreover, a high genetic alteration rate of CBXs (37%) was found in GBM and to varying degrees. The expression of CBXs was significantly related to the immune cells infiltration. CBX7 methylation level was significantly increased in GBM tissues. Our results may provide novel ideas to find potential prognostic markers and new therapeutic targets among CBX family members in glioblastoma.
Different tumorigenicity and distinct metastasis and gene signature between orthotopic and subcutaneous neuroblastoma xenografted mice
Rui Han1,2 , Wenjie Zhao1,2 , Xu Gu1,2 , Xue Gao1,2 , Yong-Guang Yang1,2,3 , Xiaoling Zhang1,2
doi : 10.18632/aging.203913
Volume 14, Issue 4 pp 1932—1940
Patient-derived (PDX) and cell-derived (CDX) xenograft models are widely used in preclinical studies of human neuroblastoma. In this study, we constructed orthotopic and subcutaneous neuroblastoma CDX models by injecting human neuroblastoma cells into the adrenal gland and the flanks of immunodeficient mice, respectively. The tumorigenesis, metastasis and response to chemotherapy for the two models were also compared. Our results indicated that orthotopic tumor mice showed significantly faster tumor growth than that of subcutaneous mice. Importantly, the expression of PHOX2B and GAB2 was dramatically increased in the tumors of orthotopic CDX mice. Furthermore, orthotopic CDX mice developed multiple organ metastasis resembling that of neuroblastoma patients, while metastasis occurred predominantly in lung in subcutaneous CDX mice. Moreover, the two CDX models showed comparable response to cyclophosphamide treatment. Our results suggest that orthotopic CDX mice are superior to subcutaneous CDX mice as a preclinical model to study human neuroblastoma.
Fusobacterium nucleatum promotes liver metastasis in colorectal cancer by regulating the hepatic immune niche and altering gut microbiota
Han Yin1 , Zhuangzhuang Miao2 , Lu Wang1 , Beibei Su1 , Chaofan Liu1 , Yu Jin1 , Bili Wu1 , Hu Han1 , Xianglin Yuan1
doi : 10.18632/aging.203914
Volume 14, Issue 4 pp 1941—1958
Liver metastasis is the major cause of death in colorectal cancer (CRC) patients. Nevertheless, the underlying mechanisms remain unknown. Gut microbiota intricately affect the initiation and progression of CRC by instigating immune response through the secretion of pro-inflammatory cytokines. In this study, we investigated the contribution of Fusobacterium nucleatum (F.nucleatum) to the microbiota-liver axis of CRC in mice, focusing on the correlation between liver immunity and gut microbiota alterations. When F. nucleatum was orally administered to mice, CRC liver metastasis was evidently exaggerated and accompanied by noticeable deleterious effects on body weight, cecum weight, and overall survival time. Further evaluation of the immune response and cytokine profiles revealed a substantial increase in the levels of pro-inflammatory cytokines such as IL6, IL12, IL9, IL17A, CXCL1, MCP-1, TNF-α, and IFN-γ in the plasma of mice treated with F. nucleatum as compared to that in the untreated control mice. Besides, hepatic immune response was also modulated by recruitment of myeloid-derived suppressor cells, reduction in the infiltration of natural killer (NK) and T helper-17 (Th17) cells, as well as increase in regulatory T cell accumulation in the liver. Additionally, sustained F. nucleatum exposure abridged the murine gut microbiota diversity, inducing an imbalanced and restructured intestinal microflora. In particular, the abundance of CRC-promoting bacteria such as Enterococcus and Escherichia/Shigella was evidently elevated post F. nucleatum treatment. Thus, our findings suggest that F. nucleatum might be an important factor involved in promoting CRC liver metastasis by triggering of liver immunity through the regulation of gut microbiota structure and composition.
Comparison of one-week versus three-week paclitaxel for advanced pan-carcinomas: systematic review and meta-analysis
Shitong Lin1,2, * , Ting Peng1,2, * , Yifan Meng3 , Canhui Cao4 , Peipei Gao1,2 , Ping Wu1,2 , Wenhua Zhi1,2 , Ye Wei1,2 , Tian Chu1,2 , Binghan Liu1,2 , Juncheng Wei1,2 , Xiaoyuan Huang1,2 , Wencheng Ding1,2 , Cai Cheng5, &
doi : 10.18632/aging.203919
Volume 14, Issue 4 pp 1959—1982
Paclitaxel remains the first-line chemotherapy regimen for many malignant tumors. However, prognosis and adverse events under different dosing regimens (one-week versus three-week treatment) remain contradictory in many randomized controlled trials (RCTs). Here, we performed a comprehensive meta-analysis to measure the efficacy and toxicities of these two dosing regimens. Four databases were systematically retrieved. RCTs comparing two paclitaxel dosing regimens for advanced malignant tumors with assessable outcomes (e.g., overall survival (OS), progression-free survival (PFS), toxicities, response rates) were included. In total, 19 eligible RCTs involving 9 674 patients were included. Meta-analysis of pan-cancers revealed that weekly paclitaxel treatment was more beneficial regarding PFS compared to three-week paclitaxel treatment (hazard ratio (HR) = 0.90, 95% confidence interval (CI) = 0.82–0.99, P = 0.02). Nevertheless, there was no significant difference in terms of OS between the two dosing regimens (HR = 0.98, 95%CI = 0.91–1.06, P = 0.62) or other tested subgroups. In terms of serious adverse events, grade 3 or 4 (G3/4) neutropenia, G3/4 febrile neutropenia, G3/4 arthritis, and G3/4 alopecia occurred less often under weekly paclitaxel treatment. In summary, Weekly paclitaxel treatment demonstrates better PFS and fewer chemotherapy-induced hematological and non-hematological toxicities compared to the three-week paclitaxel regimen.
Pseudogene AK4P1 promotes pancreatic ductal adenocarcinoma progression through relieving miR-375-mediated YAP1 degradation
Lang Jia1,5, * , Yun Zhang1,4, * , Feng Pu1,4, * , Chong Yang1,4 , Shula Yang1,4 , Jinze Yu1,4 , Zihan Xu1,4 , Hongji Yang1,2,4 , Yu Zhou3,4 , Shikai Zhu1,2,4
doi : 10.18632/aging.203921
Volume 14, Issue 4 pp 1983—2003
Pseudogenes have been reported to play oncogenic or tumor-suppressive roles in cancer progression. However, the molecular mechanism of most pseudogenes in pancreatic ductal adenocarcinoma (PDAC) remains unknown. Herein, we characterized a novel pseudogene-miRNA-mRNA network associated with PDAC progression using bioinformatics analysis. After screening by dreamBase and GEPIA, 12 up-regulated and 7 down-regulated differentially expressed pseudogenes (DEPs) were identified. According to survival analysis, only elevated AK4P1 indicated a poor prognosis for PDAC patients. Moreover, we found that AK4 acts as a cognate gene of AK4P1 and also predicts worse survival for PDAC patients. Furthermore, 32 miRNAs were predicted to bind to AK4P1 by starBase, among which miR-375 was identified as the most potential binding miRNA of AK4P1. A total of 477 potential target genes of miR-375 were obtained by miRNet, in which 49 hub genes with node degree ≥ 20 were identified by STRING. Subsequent analysis for hub genes demonstrated that YAP1 may be a functional downstream target of AK4P1. To confirmed the above findings, microarray, and qRT-PCR assay revealed that YAP1 was dramatically upregulated in both PDAC cells and tissues. Functional experiments showed that knockdown of YAP1 significantly suppressed PDAC cells growth, increased apoptosis, and decreased the ability of invasion. In conclusion, amplification of AK4P1 may fuel the onset and development of PDAC by targeting YAP1 through competitively binding to miR-375, and serve as a promising biomarker and therapeutic target for PDAC.
MKRN2 inhibits the proliferation of gastric cancer by downregulating PKM2
Zheng Liu1, * , Shuyao Xiang2, * , Xingchen Guo1, * , Jinghuan Zhou1 , Lixin Liao1 , Jiaxin Kou1 , Jun Zhang3
doi : 10.18632/aging.203643
Volume 14, Issue 4 pp 2004—2013
Cumulative evidence suggests that dysfunction of ubiquitinating enzymes is responsible for multiple types of diseases including cancer. However, what role the ubiquitinating enzyme plays in gastric cancer remains unknown. In this study, using bioinformatics analysis and a series of experimental analyses, we found that an E3 ubiquitin-protein, MKRN2 was down-regulated in gastric cancer tissues. Kaplan–Meier survival analysis showed the low MKRN2 expression significantly indicated poor prognosis. Overexpression of MKRN2 notably inhibited cell proliferation in vitro and in vivo. Conversely, knockdown of MKRN2 had the opposite effects in vitro. Additionally, the mechanical analysis indicated that MKRN2 promoted ubiquitination-mediated degradation of PKM2 and attenuated its effect on ERK. Overall, the present study suggests that MKRN2 may be a potential therapeutic target for gastric cancer.
Correction for: Identification of colorectal cancer associated biomarkers: an integrated analysis of miRNA expression
André Fonseca1 , Sara Ventura Ramalhete1,2 , André Mestre1,2 , Ricardo Pires das Neves3,4 , Ana Marreiros1,2 , Pedro Castelo-Branco1,2,5, * , Vânia Palma Roberto1,2,6, *
doi : 10.18632/aging.203866
Volume 14, Issue 4 pp 2014—2015
