WSB1 promotes tumor metastasis by inducing pVHL degradation

Kim, Jung Jin; Lee, Seung Baek; Jang, Jiseon; Yi, Sang Yeop; Kim, Sun Hyun; Han, Seok Joo; Lee, Jong Min; Tong, Seo Yun; Vincelette, Nicole D.; Gao, Bowen; Yin, Ping; Evans, Debra L.; Choi, Dong Wook; Qin, Bo; Liu, Tongzheng; Zhang, Haoxing; Deng, Min; Jen, Jin; Zhang, Jun; Wang, Liewei; Lou, Zhenkun

doi:10.1101/gad.268128.115

Cited by 59 publications

(70 citation statements)

References 63 publications

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“…MiRNAs regulate many cellular functions such as cell proliferation, differentiation, and migration, and are implicated in pathologic conditions including cancer [13, 14]. MicroRNA-145 (miR-145) is a tumor suppressor that inhibits tumor cell growth and metastasis in many cancers [15-18]. Interestingly, a number of recent studies have shown that miR-145 directly downregulates SMAD3 by binding to its three prime untranslated region (3'-UTR) [19-22].…”

Section: Introductionmentioning

confidence: 99%

MALAT1 Modulates TGF-β1-Induced Endothelial-to-Mesenchymal Transition through Downregulation of miR-145

Yin¹,

Zhang²,

Tang³

et al. 2017

Cell Physiol Biochem

120

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Background/Aims: Endothelial-to-mesenchymal transition (EndMT) plays significant roles under various pathological conditions including cardiovascular diseases, fibrosis, and cancer. EndMT of endothelial progenitor cells (EPCs) contributes to neointimal hyperplasia following cell therapy Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a long non-coding RNA (lncRNA) that promotes metastasis and cancer. MicroRNA-145 (miR-145) is a tumor suppressor that has been reported to inhibit SMAD3-mediated epithelial-to-mesenchymal transition (EMT) of cancer cells. In the present study, we investigated the role of MALAT1 and miR-145 in EndMT of human circulating EPCs induced by transforming growth factor beta1 (TGF-β1). Methods: Human circulating EPCs were isolated and characterized by fluorescence-activated cell sorting (FACS). Expression levels of EndMT markers were assessed by qRT-PCR and western blotting. Alpha-smooth muscle actin (α-SMA) expression was measured by cell immunofluorescence staining. The regulatory relationship between MALAT1 and miR-145 and its target genes, TGFBR2 (TGFβ receptortype II) and SMAD3 (mothers against decapentaplegic homolog 3) was analyzed using the luciferase reporter assay. Results: We found that EndMT of EPCs induced by TGF-β1 is accompanied by increased MALAT1 expression and decreased miR-145 expression, and MALAT1 and miR-145 directly bind and reciprocally repress each other in these cells. Dual-Luciferase Reporter assay indicated that miR-145 inhibits TGF-β1-induced EndMT by directly targeting TGFBR2 and SMAD3. Conclusions: MALAT1 modulates TGF-β1-induced EndMT of EPCs through regulation of TGFBR2 and SMAD3 via miR-145. Thus, the MALAT1-miR-145-TGFBR2/SMAD3 signaling pathway plays a key role in TGF-β1-induced EndMT.

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Section: Introductionmentioning

confidence: 99%

MALAT1 Modulates TGF-β1-Induced Endothelial-to-Mesenchymal Transition through Downregulation of miR-145

Yin¹,

Zhang²,

Tang³

et al. 2017

Cell Physiol Biochem

120

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“…These findings open new areas of research aimed at understanding how epigenetic changes at prometastatic loci are altered during tumor progression. Recent studies have also indicated that VHL activity in tumors can be regulated by WSB1, an E3 ligase that targets pVHL for ubiquitination and proteasomal degradation ( 27 ). WSB1 expression in tumor cells leads to HIF stabilization under normoxic and hypoxic conditions and correlates with metastasis in cancer patients (Fig.…”

Section: Hypoxic Signalingmentioning

confidence: 99%

“…WSB1 expression in tumor cells leads to HIF stabilization under normoxic and hypoxic conditions and correlates with metastasis in cancer patients (Fig. 1) ( 27 ).…”

Section: Hypoxic Signalingmentioning

confidence: 99%

Hypoxic control of metastasis

Rankin

Giaccia

2016

Science

1,038

870

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Metastatic disease is the leading cause of cancer-related deaths and involves critical interactions between tumor cells and the microenvironment. Hypoxia is a potent microenvironmental factor promoting metastatic progression. Clinically, hypoxia and the expression of the hypoxia-inducible transcription factors HIF-1 and HIF-2 are associated with increased distant metastasis and poor survival in a variety of tumor types. Moreover, HIF signaling in malignant cells influences multiple steps within the metastatic cascade. Here we review research focused on elucidating the mechanisms by which the hypoxic tumor microenvironment promotes metastatic progression. These studies have identified potential biomarkers and therapeutic targets regulated by hypoxia that could be incorporated into strategies aimed at preventing and treating metastatic disease.

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“…Given that WSB1 increases one of the most important glycolytic proteins-HIF-1α and contributes to human malignancy [10], thus WSB1 was predicted as a potentially functional target gene of miR-592. As shown in Figure 3A, one predicted binding site in the WSB1 3′-UTR with a perfect complementarity to the seed region of the miR-592 was identified.…”

Section: Resultsmentioning

confidence: 99%

“…More recent evidence suggested that WSB1 is a direct target of HIF-1α in a human HCC model [9]. Interestingly, WSB1 can in turn stabilize HIF-1α by protecting it from VHL-induced degradation [10]. Thus it is possible that WSB1 may promote HCC progression through altering cancer cell metabolism.…”

Section: Introductionmentioning

confidence: 99%

miR-592/WSB1/HIF-1α axis inhibits glycolytic metabolism to decrease hepatocellular carcinoma growth

Jia

Zhao

et al. 2016

Oncotarget

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Hepatocellular carcinoma (HCC) cells rapidly switch their energy source from oxidative phosphorylation to glycolytic metabolism in order to efficiently proliferate. However, the molecular mechanisms responsible for this switch remain unclear. In this study, we found that miR-592 was frequently downregulated in human HCC tissues and cell lines, and its downregulation was closely correlated with aggressive clinicopathological features and poor prognosis of HCC patients. Overexpression of miR-592 inhibited aerobic glycolysis and proliferation in HCC cells in vitro. Conversely, knockdown of miR-592 promoted HCC growth in both subcutaneous injection and orthotopic liver tumor implantation models in vivo. Mechanistically, miR-592 downregulation in human HCCs was correlated with an upregulation of WD repeat and SOCS box containing 1 (WSB1). We further showed that miR-592 directly binds to the 3'-UTR of the WSB1 gene, thus disrupting hypoxia inducible factor-1α (HIF-1α) protein stabilization. In turn, overexpression of WSB1 in HCC cells rescued decreased HIF-1α expression, glucose uptake, and HCC growth induced by miR-592. Collectively, our clinical data and functional studies suggest that miR-592 is a new robust inhibitor of the Warburg effect and a promising therapeutic target for HCC treatment.

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WSB1 promotes tumor metastasis by inducing pVHL degradation

Cited by 59 publications

References 63 publications

MALAT1 Modulates TGF-β1-Induced Endothelial-to-Mesenchymal Transition through Downregulation of miR-145

MALAT1 Modulates TGF-β1-Induced Endothelial-to-Mesenchymal Transition through Downregulation of miR-145

Hypoxic control of metastasis

miR-592/WSB1/HIF-1α axis inhibits glycolytic metabolism to decrease hepatocellular carcinoma growth

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