ATG7 Promotes Bladder Cancer Invasion via Autophagy‐Mediated Increased ARHGDIB mRNA Stability

Zhu, Junlan; Tian, Zhongxian; Li, Yang; Hua, Xiaohui; Zhang, Dongyun; Li, Jingxia; Jin, Honglei; Xu, Jiheng; Chen, Wei; Niu, Beifang; Wu, Xue-Ru; Comincini, Sergio; Huang, Haishan; Huang, Chuanshu

doi:10.1002/advs.201801927

Cited by 70 publications

(47 citation statements)

References 47 publications

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“…The results from the present study discovered that MIR516A targeted 3ʹ-UTR of PHLPP2 mRNA, which downregulates its protein translation in human BC; therefore, we defined the novel mechanism of MIR516A regulating PHLPP2 protein translation. Due to the complexity of autophagy, it has been shown to function as a double-edged sword that either protect or suppress human bladder cancer, depending on the stimuli of autophagy, the stage of cancer, and the downstream mediators or effectors [47,48]. Our recent studies have shown that autophagic responses mediated by SESN2/Sestrin 2 mainly result in autophagic inhibition of human bladder cancer cells [48], whereas ATG7-mediated autophagic responses promote growth and invasion of human bladder cancer cells [47].…”

Section: Discussionmentioning

confidence: 99%

Oncogenic role of MIR516A in human bladder cancer was mediated by its attenuating PHLPP2 expression and BECN1-dependent autophagy

Jin

et al. 2020

Autophagy

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Although MIR516A has been reported to be downregulated and act as a tumor suppressor in multiple cancers, its expression and potential contribution to human bladder cancer (BC) remain unexplored. Unexpectedly, we showed here that MIR516A was markedly upregulated in human BC tissues and cell lines, while inhibition of MIR516A expression attenuated BC cell monolayer growth in vitro and xenograft tumor growth in vivo, accompanied with increased expression of PHLPP2. Further studies showed that MIR516A was able to directly bind to the 3′-untranslated region of PHLPP2 mRNA, which was essential for its attenuating PHLPP2 expression. The knockdown of PHLPP2 expression in MIR516A-inhibited cells could reverse BC cell growth, suggesting that PHLPP2 is a MIR516A downstream mediator responsible for MIR516A oncogenic effect. PHLPP2 was able to mediate BECN1/Beclin1 stabilization indirectly, therefore promoting BECN1-dependent macroautophagy/autophagy, and inhibiting BC tumor cell growth. In addition, our results indicated that the increased autophagy by attenuating MIR516A resulted in a dramatic inhibition of xenograft tumor formation in vivo. Collectively, our results reveal that MIR516A has a novel oncogenic function in BC growth by directing binding to PHLPP2 3′-UTR and inhibiting PHLPP2 expression, in turn at least partly promoting CUL4A-mediated BECN1 protein degradation, thereby attenuating autophagy and promoting BC growth, which is a distinct function of MIR516A identified in other cancers.

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Section: Discussionmentioning

confidence: 99%

Oncogenic role of MIR516A in human bladder cancer was mediated by its attenuating PHLPP2 expression and BECN1-dependent autophagy

Jin

et al. 2020

Autophagy

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“…Increasing evidence has shown that autophagy is an important mechanism of tumorigenesis and that interfering with autophagy signaling by targeting key ARGs may be a novel therapeutic strategy for cancer treatment. Previously, researchers have confirmed that four ARGs, including hypoxia inducible factor-1 (HIF-1α), autophagy-related 7 (ATG7), sestrin 2 (SENS2), and beclin 1 (BECN1), were associated with the cell proliferation, apoptosis and invasion of BUC cells (28)(29)(30)(31). However, the potential clinical value of ARGs for the prognosis of patients with BUC remains unclarified.…”

Section: Discussionmentioning

confidence: 99%

Significant Prognostic Value of the Autophagy-Related Gene P4HB in Bladder Urothelial Carcinoma

et al. 2020

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While hundreds of consistently altered autophagy-related genes (ARGs) have been identified in cancers, their prognostic value in bladder urothelial carcinoma (BUC) remains unclear. In the present study, we collected 232 ARGs from the Human Autophagy Database (HADb), and identified 37 differentially expressed ARGs in BUC based on The Cancer Genome Atlas (TCGA) database. Kaplan-Meier survival analysis based on the Gene Expression Profiling Interactive Analysis (GEPIA) database revealed that among the 37 differentially expressed ARGs, prolyl 4-hydroxylase, beta polypeptide (P4HB), and regulator of G protein signaling 19 (RGS19) were significantly negatively correlated with overall survival (OS) and disease-free survival (DFS). Overexpression of P4HB and RGS19 in BUC was further validated using independent data sets, including those from the Oncomine and Gene Expression Omnibus (GEO) databases. cBioPortal and UALCAN analyses indicated that altered P4HB and RGS19 mRNA expression was significantly associated with mutations and clinical characteristics (nodal metastasis and cancer stage). Moreover, co-expression network analysis and gene set enrichment analysis (GSEA) predicted that the potential functions of P4HB and RGS19 are involved in the endoplasmic reticulum (ER) stress response, cytokine-mediated signaling pathway and inflammatory response. More importantly, multivariate Cox proportional hazards regression analysis demonstrated that P4HB, but not RGS19, is an independent and unfavorable BUC biomarker based on clinical characteristics (age, gender, cancer stage, and pathological TNM stage). Finally, we validated that the mRNA and protein expression levels of P4HB were upregulated in four bladder cancer cell lines (T24, J82, EJ, and SW780) and found that knockdown of P4HB dramatically inhibited the invasion and proliferation of bladder cancer cells. In summary, our study screened ARGs and identified P4HB as a biomarker that can predict the progression and prognosis of BUC and may provide a better understanding of the autophagy regulatory mechanisms involved in BUC.

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“…BECN1 affects the drug sensitivity of OS cells by mediating the autophagy process [43]. ATG12 is involved in osteosarcoma cell metastasis [44], and ATG7 is associated with the invasiveness of bladder cancer cells [45]. The expression level of PIK3C3 in breast cancer gradually increases with disease progression [46], and low expression of GABARAPL1 is associated with poor prognosis in patients with breast cancer and hepatocellular carcinoma [47,48].…”

Section: Discussionmentioning

confidence: 99%

Identification of a novel autophagy-related gene signature for predicting metastasis and survival in patients with osteosarcoma

Zhang

Deng

et al. 2020

Preprint

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Background: Osteosarcoma (OS) is a bone malignant tumor that occurs in children and adolescents. Due to a lack of reliable prognostic biomarkers, the prognosis of OS patients is often uncertain. This study aimed to construct an autophagy-related gene signature to predict the prognosis of OS patients.Methods: The gene expression profile data of OS and normal muscle tissue samples were downloaded separately from the Therapeutically Applied Research To Generate Effective Treatments (TARGET) and Genotype-Tissue Expression (GTEx) databases . The differentially expressed autophagy-related genes (DEARGs) in OS and normal muscle tissue samples were screened using R software, before being subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. A protein-protein interaction (PPI) network was constructed and hub autophagy-related genes were screened. Finally, the screened autophagy-related genes were subjected to univariate Cox regression, Lasso Cox regression, survival analysis, and clinical correlation analysis.Results: A total of 120 DEARGs and 10 hub autophagy-related genes were obtained. A prognostic autophagy-related gene signature consisting of 9 genes ( BNIP3 , MYC , BAG1 , CALCOCO2 , ATF4 , AMBRA1 , EGFR , MAPK1 , and PEX ) was constructed. This signature was significantly correlated to the prognosis ( P <0.0001) and distant metastasis of OS patients ( P = 0.013).Conclusion: This signature based on 9 autophagy-related genes could predict metastasis and survival in patients with OS.

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ATG7 Promotes Bladder Cancer Invasion via Autophagy‐Mediated Increased ARHGDIB mRNA Stability

Cited by 70 publications

References 47 publications

Oncogenic role of MIR516A in human bladder cancer was mediated by its attenuating PHLPP2 expression and BECN1-dependent autophagy

Oncogenic role of MIR516A in human bladder cancer was mediated by its attenuating PHLPP2 expression and BECN1-dependent autophagy

Significant Prognostic Value of the Autophagy-Related Gene P4HB in Bladder Urothelial Carcinoma

Identification of a novel autophagy-related gene signature for predicting metastasis and survival in patients with osteosarcoma

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