USP20 positively regulates tumorigenesis and chemoresistance through β-catenin stabilization

Wu, Chenming; Luo, Kuntian; Zhao, Fei; Yin, Ping; Song, Ying; Deng, Min; Huang, Jinzhou; Chen, Yuping; Li, Lei; Lee, Seung Baek; Kim, Jung Jin; Zhou, Qin; Tu, Xinyi; Nowsheen, Somaira; Luo, Qifeng; Gao, Xiumei; Lou, Zhenkun; Liu, Zhongmin; Yuan, Jian

doi:10.1038/s41418-018-0138-z

Cited by 71 publications

(49 citation statements)

References 76 publications

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“…β-catenin, a major transcriptional activator of the canonical Wnt/β-catenin signaling pathway, is important for a series of biological processes, including tissue homeostasis and embryonic development, and is involved in various human diseases. USP20 was reported to positively regulate tumorigenesis and chemoresistance through β-catenin stabilization [ 45 ]. Moreover, lncRNAs, such as the lncRNA CRNDE, were also found to regulate cancer chemo-resistance by influencing Wnt/β-catenin signaling [ 46 ].…”

Section: Discussionmentioning

confidence: 99%

LncRNA PVT1 promotes gemcitabine resistance of pancreatic cancer via activating Wnt/β-catenin and autophagy pathway through modulating the miR-619-5p/Pygo2 and miR-619-5p/ATG14 axes

et al. 2020

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Background Pancreatic cancer is one of the most lethal malignancies and has an extremely poor diagnosis and prognosis. The development of resistance to gemcitabine is still a major challenge. The long noncoding RNA PVT1 was reported to be involved in carcinogenesis and chemoresistance; however, the mechanism by which PVT1 regulates the sensitivity of pancreatic cancer to gemcitabine remains poorly understood. Methods The viability of pancreatic cancer cells was assessed by MTT assay in vitro and xenograft tumor formation assay in vivo. The expression levels of PVT1 and miR-619-5p were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Western blotting analysis and qRT-PCR were performed to assess the protein and mRNA levels of Pygo2 and ATG14, respectively. Autophagy was explored via autophagic flux detection under confocal microscopy and autophagic vacuole investigation under transmission electron microscopy (TEM). The functional role and mechanism of PVT1 were further investigated by gain- and loss-of-function assays in vitro. Results In the present study, we demonstrated that PVT1 was up-regulated in gemcitabine-resistant pancreatic cancer cell lines. Gain- and loss-of-function assays revealed that PVT1 impaired sensitivity to gemcitabine in vitro and in vivo. We further found that PVT1 up-regulated the expression of both Pygo2 and ATG14 and thus regulated Wnt/β-catenin signaling and autophagic activity to overcome gemcitabine resistance through sponging miR-619-5p. Moreover, we discovered three TCF/LEF binding elements (TBEs) in the promoter region of PVT1, and activation of Wnt/β-catenin signaling mediated by the up-regulation of Pygo2 increased PVT1 expression by direct binding to the TBE region. Furthermore, PVT1 was discovered to interact with ATG14, thus promoting assembly of the autophagy specific complex I (PtdIns3K-C1) and ATG14-dependent class III PtdIns3K activity. Conclusions These data indicate that PVT1 plays a critical role in the sensitivity of pancreatic cancer to gemcitabine and highlight its potential as a valuable target for pancreatic cancer therapy.

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Section: Discussionmentioning

confidence: 99%

LncRNA PVT1 promotes gemcitabine resistance of pancreatic cancer via activating Wnt/β-catenin and autophagy pathway through modulating the miR-619-5p/Pygo2 and miR-619-5p/ATG14 axes

et al. 2020

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“…Furthermore, we determined a promoting effect of miR-532-3p in CRC chemosensitivity via its inhibition of β-catenin and activation of p53. Multiple chemotherapies were verified to induce cell cycle arrest and early apoptosis by both inhibition of Wnt responsiveness and stabilization and activation of p53 32,33 . Moreover, the activation of Wnt/ β-catenin and mutation or depletion of p53 were regarded as a fundamental process of adaptive resistance in CRC 34,35 .…”

Section: Discussionmentioning

confidence: 99%

MiR-532-3p suppresses colorectal cancer progression by disrupting the ETS1/TGM2 axis-mediated Wnt/β-catenin signaling

Cai

et al. 2019

Cell Death Dis

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The expression panel of plasma microRNA defined miR-532-3p as a valuable biomarker for colorectal adenoma (CRA). However, its expression pattern and function in colorectal cancer (CRC) have remained unclear. The present study investigated the expression levels of miR-532-3p and found that it was in situ downregulated both in CRA and CRC. Moreover, it functioned as a sensitizer for chemotherapy in CRC by inducing cell cycle arrest and early apoptosis via its activating effects on p53 and apoptotic signaling pathways. In addition, miR-532-3p was found to restrain cell growth, metastasis, and epithelial–mesenchymal transition (EMT) phenotype of CRC. A study on the mechanism behind these effects revealed that miR-532-3p directly binds to 3′UTR regions of ETS1 and TGM2, ultimately repressing the canonical Wnt/β-catenin signaling. Further investigation showed that TGM2 was transcriptionally regulated by ETS1 and ETS1/TGM2 axis served as a vital functional target of miR-532-3p in suppressing CRC progression. To conclude, miR-532-3p mimics could act as potential candidate for molecular therapy in CRC through inactivation of the canonical Wnt/β-catenin signaling and enhancement of chemosensitivity.

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“…For instance, p0071 interacts with E-cadherin in the cytoplasm and promotes invasion and metastasis in nonsmall cell lung cancer [45]. Furthermore, ubiquitin speci c peptidase 20 (USP20) regulates the deubiquitination of β-catenin to control the invasion and migration of cancer cells [46]. Our results showed that the overexpression of mir-335-5p decreases the expression of vimentin and β-catenin and increases E-cadherin in MKN-28 and SGC-7901 cells.…”

Section: Discussionmentioning

confidence: 76%

miR-335-5p suppresses gastric cancer progression by targeting MAPK10

Gao

Wang

et al. 2020

Preprint

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Background: Recent studies have established the roles of microRNAs (miRNAs) in cancer progression. The aberrant expression of miR-335-5p has been reported in many cancers, including gastric cancer (GC). In this study, the precise roles of miR-335-5p in GC as well as the molecular mechanisms underlying its effects, including the role of its target MAPK10, were evaluated.Methods: Quantitative real-time PCR was used to evaluate miR-335-5p levels in GC cell lines and tissues. MTT and colony formation assays were used to detect cell proliferation, and Transwell and wound-healing assays were used to evaluate the invasion and migration of GC cells. The correlation between levels of miR-335-5p and the cell cycle-related target gene mitogen-activated protein kinase 10 (MAPK10) in GC was analyzed. In addition, the candidate target was evaluated by a luciferase reporter assay, qRT-PCR, and western blotting.Results: The levels of miR-335-5p were downregulated in GC tissues and cell lines. Furthermore, miR-335-5p inhibited the proliferation and migration of GC cells and induced apoptosis. Additionally, miR-335-5p arrested the cell cycle at the G1/S phase in GC cells in vitro. Levels of miR-335-5p and the cell cycle-related target gene MAPK10 in GC were correlated, and MAPK10 was directly targeted by miR-335-5p.Conclusions: These data suggest that miR-335-5p is a tumor suppressor and acts via MAPK10 to inhibit GC progression.

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USP20 positively regulates tumorigenesis and chemoresistance through β-catenin stabilization

Cited by 71 publications

References 76 publications

LncRNA PVT1 promotes gemcitabine resistance of pancreatic cancer via activating Wnt/β-catenin and autophagy pathway through modulating the miR-619-5p/Pygo2 and miR-619-5p/ATG14 axes

LncRNA PVT1 promotes gemcitabine resistance of pancreatic cancer via activating Wnt/β-catenin and autophagy pathway through modulating the miR-619-5p/Pygo2 and miR-619-5p/ATG14 axes

MiR-532-3p suppresses colorectal cancer progression by disrupting the ETS1/TGM2 axis-mediated Wnt/β-catenin signaling

miR-335-5p suppresses gastric cancer progression by targeting MAPK10

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