SESN2/sestrin 2 induction-mediated autophagy and inhibitory effect of isorhapontigenin (ISO) on human bladder cancers

Liang, Yumei; Zhu, Junlan; Huang, Haishan; Xiang, Di; Yang, Li; Zhang, Dongyun; Li, Jingxia; Wang, Yulei; Jin, Honglei; Jiang, Guosong; Liu, Zeyuan; Huang, Chuanshu

doi:10.1080/15548627.2016.1179403

Cited by 85 publications

(90 citation statements)

References 40 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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“…Human BC cell lines, UMUC3 and T24, were used and are described in our previous studies 49, 50, 51, 52. These cells were maintained in DMEM-F12 (1:1) (Invitrogen) supplemented with 5% heat-inactivated fetal bovine serum (FBS), 2 μM L-glutamine, and 25 μg/mL gentamycin.…”

Section: Methodsmentioning

confidence: 99%

ATG7 Overexpression Is Crucial for Tumorigenic Growth of Bladder Cancer In Vitro and In Vivo by Targeting the ETS2/miRNA196b/FOXO1/p27 Axis

Zhu

Yang

Tian

et al. 2017

Molecular Therapy - Nucleic Acids

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Human bladder cancer (BC) is the fourth most common cancer in the United States. Investigation of the strategies aiming to elucidate the tumor growth and metastatic pathways in BC is critical for the management of this disease. Here we found that ATG7 expression was remarkably elevated in human bladder urothelial carcinoma and N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN)-induced mouse invasive BC. Knockdown of ATG7 resulted in a significant inhibitory effect on tumorigenic growth of human BC cells both in vitro and in vivo by promoting p27 expression and inducing cell cycle arrest at G2/M phase. We further demonstrated that knockdown of ATG7 upregulated FOXO1 (forkhead box protein O 1) expression, which specifically promoted p27 transcription. Moreover, mechanistic studies revealed that inhibition of ATG7 stabilized ETS2 mRNA and, in turn, reduced miR-196b transcription and expression of miR-196b, which was able to bind to the 3′ UTR of FOXO1 mRNA, consequently stabilizing FOXO1 mRNA and finally promoting p27 transcription and attenuating BC tumorigenic growth. The identification of the ATG7/FOXO1/p27 mechanism for promoting BC cell growth provides significant insights into understanding the nature of BC tumorigenesis. Together with our most recent discovery of the crucial role of ATG7 in promoting BC invasion, it raises the potential for developing an ATG7-based specific therapeutic strategy for treatment of human BC patients.

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“…The normal bladder cell line UROtsa and human BC cell lines T24T, UMUC3 were described in previous studies [51][52][53][54]. For the details of reagents, cell lines, and cell culture, see the Supplement of "Materials and Methods".…”

Section: Reagents Cell Lines and Cell Culturementioning

confidence: 99%

Overexpressed miR-200a promotes bladder cancer invasion through direct regulating Dicer/miR-16/JNK2/MMP-2 axis

Yang

Hua

et al. 2019

Oncogene

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Invasive bladder cancer (BC) is one of the most lethal malignant urological tumors. Although miR-200a has been reported as an onco-miRNA that targets the PTEN gene in endometrioid carcinoma, its biological significance in BC invasion has been poorly explored. In the current study, we found that miR-200a was markedly overexpressed in both human BC tissues and BBN-induced muscle-invasive BC tissues. We further showed that miR-200a overexpression specifically promoted human BC cell invasion, but not migration, via transcriptional upregulation of matrix metalloproteinase (MMP)-2. Mechanistic studies indicated that the increased phosphorylation of c-Jun mediated the increasing levels of MMP-2 mRNA transcription. Further investigation revealed that Dicer was decreased in miR-200a overexpressed BC cells; this resulted in inhibition of miR-16 maturation and consequently led to increased JNK2 protein translation and c-Jun activation. Taken together, the studies here showed that miR-200a overexpression inhibited Dicer expression, in turn, resulted in inhibition of miR-16 maturation, leading to upregulation of JNK2 expression, c-Jun phosphorylation, MMP-2 transcription and, ultimately, BC invasion. Collectively, these results demonstrate that miR-200a is an onco-miRNA that is a positive regulator for BC invasion. This finding could be very useful in the ongoing development of new strategies to treat invasive BC patients.

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SESN2/sestrin 2 induction-mediated autophagy and inhibitory effect of isorhapontigenin (ISO) on human bladder cancers

Cited by 85 publications

References 40 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

ATG7 Overexpression Is Crucial for Tumorigenic Growth of Bladder Cancer In Vitro and In Vivo by Targeting the ETS2/miRNA196b/FOXO1/p27 Axis

Overexpressed miR-200a promotes bladder cancer invasion through direct regulating Dicer/miR-16/JNK2/MMP-2 axis

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