Loss of NDRG2 promotes epithelial-mesenchymal transition of gallbladder carcinoma cells through MMP-19-mediated Slug expression

Lee, Dong Gwang; Lee, Sang Hyun; Kim, Jang Seong; Park, Jong Jin; Cho, Young Lai; Kim, Koon Soon; Jo, Deog Yeon; Song, Ik Chan; Kim, Nayoung; Yun, Hwan Jung; Park, Young Jun; Lee, Seon-Jin; Lee, Hee Gu; Bae, Kwang‐Hee; Lee, Sang Chul; Shim, Sungbo; Kim, Young Myeong; Kwon, Young Guen; Kim, Jin Man; Lee, Hyo Jin; Kim, Jung Min

doi:10.1016/j.jhep.2015.08.007

Cited by 40 publications

(42 citation statements)

References 37 publications

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“…Hong and collaborators found that epigenetic silencing of NDRG2 induced proliferation and invasion of primary colorectal cancer cells, and that this could be associated with advanced stages of the disease (49). Similarly, Lee and collaborators found that in patients with gallbladder carcinoma loss of NDRG2 expression was an independent predictor of decreased patient survival and was significantly associated with a more advanced tumor stage (32). In addition, loss of NDRG2 expression in gallbladder carcinoma cells resulted in enhanced proliferation, migration and invasiveness in vitro , and enhanced tumor growth and metastasis in mice (32).…”

Section: Discussionmentioning

confidence: 94%

A 22q11.2 amplification in the region encoding microRNA-650 correlates with the epithelial to mesenchymal transition in breast cancer primary cultures of Mexican patients

Lango-Chavarría

Chimal-Ramírez

Ruiz‐Tachiquín

et al. 2017

International Journal of Oncology

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Breast cancer ranks first in incidence and mortality in working age women. Cancer initiation and progression relies on accumulation of genetic and epigenetic aberrations that alter cellular processes, among them, epithelial to mesenchymal transition (EMT) denotes particularly aggressive neoplasias given its capacity to invade and metastasize. Several microRNAs (miRNA) have been found able to regulate gene expression at the core of EMT. In this study, the Affymetrix CytoScan HD array was used to analyze three different primary tumor cell isolates from Mexican breast cancer patients. We found an amplification in band 22q11.2 shared by the three samples, in the region that encodes miRNA-650. Overexpression of this miRNA has been associated with downregulation of tumor suppressors ING4 and NDRG2, which have been implicated in cancer progression. Using the Pathway Linker platform the ING4 and NDRG2 interaction networks showed a significant association with signaling pathways commonly deregulated in cancer. Also, several studies support their participation in the EMT. Supporting the latter, we found that the three primary isolates were E-cadherin negative, vimentin positive, presented a cancer stem cell-like phenotype CD44+CD24−/low and were invasive in Transwell invasion assays. This evidence suggests that the gain of region 22q11.2 contributes to trigger EMT. This is the first evidence linking miR-650 and breast cancer.

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Section: Discussionmentioning

confidence: 94%

A 22q11.2 amplification in the region encoding microRNA-650 correlates with the epithelial to mesenchymal transition in breast cancer primary cultures of Mexican patients

Lango-Chavarría

Chimal-Ramírez

Ruiz‐Tachiquín

et al. 2017

International Journal of Oncology

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“…To explore the mechanisms underlying Slug-mediated AP-1 activation, we tested the possible involvement of Axl in this process because several previous reports revealed the induction of Axl by Slug [26–28]. PC3 cells were transiently transfected with a Slug expression vector or siRNA specific to Slug for 48 h. Axl expression was induced by Slug at both the mRNA and protein levels, while Axl expression was reduced by suppression of Slug by siRNA at both the mRNA and protein levels (Supplementary Figure S3C), suggesting that Slug upregulates Axl expression in PC3 cells.…”

Section: Resultsmentioning

confidence: 99%

“…Consistently, several groups reported induction of Axl by Slug. For example, Axl is upregulated by Slug and Snail in MCF10A immortalized breast epithelial cells and plays a critical role in breast cancer cell invasion [26], and Slug induces the expression of Axl among 49 receptor tyrosine kinases at the transcriptional level to activate Axl, which maintains Slug expression through a positive feedback loop [28]. In addition, the Gas6/Axl pathway upregulates Slug expression through MAPK [29, 51], suggesting a positive feedback loop between Slug and Axl during cancer progression.…”

Section: Discussionmentioning

confidence: 99%

TMPRSS4 induces invasion and proliferation of prostate cancer cells through induction of Slug and cyclin D1

Lee

Min

et al. 2016

Oncotarget

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TMPRSS4 is a novel type II transmembrane serine protease found at the cell surface that is highly expressed in pancreatic, colon, and other cancer tissues. Previously, we demonstrated that TMPRSS4 mediates tumor cell invasion, migration, and metastasis. We also found that TMPRSS4 activates the transcription factor activating protein-1 (AP-1) to induce cancer cell invasion. Here, we explored TMPRSS4-mediated cellular functions and the underlying mechanisms. TMPRSS4 induced Slug, an epithelial-mesenchymal transition (EMT)-inducing transcription factor, and cyclin D1 through activation of AP-1, composed of c-Jun and activating transcription factor (ATF)-2, which resulted in enhanced invasion and proliferation of PC3 prostate cancer cells. In PC3 cells, not only c-Jun but also Slug was required for TMPRSS4-mediated proliferation and invasion. Interestingly, Slug induced phosphorylation of c-Jun and ATF-2 to activate AP-1 through upregulation of Axl, establishing a positive feedback loop between Slug and AP-1, and thus induced cyclin D1, leading to enhanced proliferation. Using data from The Cancer Genome Atlas, we found that Slug expression positively correlated with that of c-Jun and cyclin D1 in human prostate cancers. Expression of Slug was positively correlated with that of cyclin D1 in various cancer cell lines, whereas expression of other EMT-inducing transcription factors was not. This study demonstrates that TMPRSS4 modulates both invasion and proliferation via Slug and cyclin D1, which is a previously unrecognized pathway that may regulate metastasis and cancer progression.

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“…Of note, the ability of miR-122 and miR-200c to target RhoA and ZEB1/2, respectively, though well recognized in many cancer types, is not yet documented in CCA 178,179 . Among target genes of up-regulated miRNAs, tissue inhibitor of metalloproteinases (TIMP)3 is a broad-spectrum inhibitor of MMPs, reversion-inducing-cysteine-rich protein with Kazal motif (RECK) is a membrane-anchored protein inhibiting MMP-2, MMP-9, MMP-14, and ADAM10 180 , and N-myc downstream regulated gene (NDRG)2 is a recently identified tumor suppressor of unknown function inhibiting metastasis in several human cancers, including HCC 181 , gallbladder cancer 182 , and CCA 173 .…”

Section: Regulation Of Cholangiocarcinoma Invasiveness By Micrornasmentioning

confidence: 99%

Molecular Mechanisms Driving Cholangiocarcinoma Invasiveness: An Overview

et al. 2018

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The acquisition of invasive functions by tumor cells is a first and crucial step towards the development of metastasis, which nowadays represents the main cause of cancer-related death. Cholangiocarcinoma (CCA), a primary liver cancer originating from the biliary epithelium, typically develops intrahepatic or lymph node metastases at early stages, thus preventing the majority of patients from undergoing curative treatments, consistent with their very poor prognosis. As in most carcinomas, CCA cells gradually adopt a motile, mesenchymal-like phenotype, enabling them to cross the basement membrane, detach from the primary tumor, and invade the surrounding stroma. Unfortunately, little is known about the molecular mechanisms that synergistically orchestrate this pro-invasive phenotypic switch. Autocrine and paracrine signals (cyto/chemokines, growth factors, morphogens) permeating the tumor microenvironment undoubtedly play a prominent role in this context. Moreover, a number of recently identified signaling systems are currently drawing attention as putative mechanistic determinants of CCA cell invasion. They encompass transcription factors, protein kinases and phosphatases, ubiquitin ligases, adaptor proteins, and miRNAs, whose aberrant expression may result from either stochastic mutations or the abnormal activation of upstream pro-oncogenic pathways. Herein, we sought to summarize the most relevant molecules in this field, and to discuss their mechanism of action and potential prognostic relevance in CCA. Hopefully, a deeper knowledge of the molecular determinants of CCA invasiveness will help to identify clinically useful biomarkers and novel druggable targets, with the ultimate goal to develop innovative approaches to the management of this devastating malignancy.

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Loss of NDRG2 promotes epithelial-mesenchymal transition of gallbladder carcinoma cells through MMP-19-mediated Slug expression

Cited by 40 publications

References 37 publications

A 22q11.2 amplification in the region encoding microRNA-650 correlates with the epithelial to mesenchymal transition in breast cancer primary cultures of Mexican patients

A 22q11.2 amplification in the region encoding microRNA-650 correlates with the epithelial to mesenchymal transition in breast cancer primary cultures of Mexican patients

TMPRSS4 induces invasion and proliferation of prostate cancer cells through induction of Slug and cyclin D1

Molecular Mechanisms Driving Cholangiocarcinoma Invasiveness: An Overview

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