MiR-200a inhibits epithelial-mesenchymal transition of pancreatic cancer stem cell

Lu, Yao; Lu, Jingjing; Li, Xiaohong; Zhu, Hui; Fan, Xiangjun; Zhu, Shajun; Wang, Yao; Guo, Qingsong; Wang, Lei; Huang, Yan; Zhu, Mingyan; Wang, Zhiwei

doi:10.1186/1471-2407-14-85

Cited by 80 publications

(69 citation statements)

References 42 publications

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“…Down-regulation of miR-200a has been shown to be linked with EMT phenotype. For example, Xia [47]. Consistently, our data showed that miR-200a expression was significantly decreased in LCSCs and reexpression of miR-200a reversed EMT to MET phenotype.…”

Section: Discussionsupporting

confidence: 89%

“…It has been emerged that EMT was associated with cancer invasion and metastasis, drug resistance, and can generate cells with properties of stem cells. According to recent reports, CSCs often exhibits EMT phenotype in several human malignancies, such as breast cancer [23], pancreatic cancer [47], and prostate cancer [48]. Here, we found that EMT phenotype was also occurred in LCSCs.…”

Section: Discussionsupporting

confidence: 52%

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Overexpression of miR-200a suppresses epithelial-mesenchymal transition of liver cancer stem cells

et al. 2014

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Due to high incidence of invasion and intrahepatic metastasis, hepatocellular carcinoma (HCC) is one of the most aggressive tumors in the world, which is also associated with the acquisition of epithelial-mesenchymal transition (EMT). Increasing evidence suggests that cancer cells with EMT traits share many biological characteristics with cancer stem cells. And miR-200a has been known as a powerful regulator of EMT. Here, we sought to investigate the role of miR-200a in regulation of EMT phenotype of liver cancer stem cells (LCSCs). We used side population (SP) sorting to obtain cancer stem-like cells from HCC cell lines and identified that the SP fraction could be enriched with LCSCs. Then, we detected the expression of miR-200a and EMT makers in SP and non-SP cells. Our results suggested that miR-200a was down-regulated in SP cells, along with relatively low epithelial marker and high mesenchymal marker. In order to find the role of miR-200a in the manipulation of EMT, we transfected miR-200a mimic into LCSCs and found that overexpression of miR-200a resulted in down-regulation of N-cadherin, ZEB2, and vimentin, but up-regulation of E-cadherin. Moreover, overexpression of miR-200a resulted in decreased migration and invasion ability in LCSCs. In conclusion, our study revealed that miR-200a played an important role in linking the characteristics of cancer stem cells with EMT phenotype in HCC, and targeting miR-200a might be an effective strategy to weaken the invasive behavior of LCSCs.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 52%

Overexpression of miR-200a suppresses epithelial-mesenchymal transition of liver cancer stem cells

et al. 2014

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“…Therefore, further investigations into the mechanisms by which DCLK1 regulates Bmi-1 in human cancers are necessary to increase our knowledge of the way cancer progression is regulated. Moreover, we found the high DCLK1 subtype to be strongly enriched for EMT pathway genes as well as miR-200 and let-7 targets, both of which have been reported to be EMT inhibitors [35,48,49]. Therefore, the study presented here provides strong evidence that DCLK1 silencing could inhibit Bmi-1 expression and EMT, which may be one of the molecular mechanisms by which DCLK1 facilitates cancer metastasis.…”

Section: Discussionmentioning

confidence: 51%

Doublecortin-Like Kinase 1 (DCLK1) Regulates B Cell-Specific Moloney Murine Leukemia Virus Insertion Site 1 (Bmi-1) and is Associated with Metastasis and Prognosis in Pancreatic Cancer

Wang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Cancer stem cells (CSCs) are largely responsible for tumor relapse and metastatic behavior. Doublecortin-like kinase 1 (DCLK1) was recently reported to be a biomarker for gastrointestinal CSCs and involved in the epithelial-mesenchymal transition (EMT) and tumor progression. B cell-specific Moloney murine leukemia virus insertion site 1 (Bmi-1) is a crucial regulator of CSC self-renewal, malignant transformation and EMT, and a previous study from our group showed that Bmi-1 is upregulated in pancreatic cancer progression and participates in EMT. However, it remains unclear whether DCLK1 is involved in pancreatic cancer or whether DCLK1 is associated with the altered level of Bmi-1 expression. Methods: The correlation of DCLK1 expression and clinical features of pancreatic cancer was analyzed in 210 paraffin-embedded archived pancreatic cancer specimens by immunohistochemical analysis. The biological effects of DCLK1 siRNA on cells were investigated by examining cell proliferation using a cell counting kit and cell colony assays, cell migration by wound healing assay and cell invasion by Transwell invasion assay. We further investigated the effect of therapeutic siRNA targeting DCLK1 on pancreatic cancer cell growth in vivo. Moreover, the molecular mechanism by which DCLK1 upregulates Bmi-1 expression was explored using real-time PCR, western blotting and Co-immunoprecipitation assay. Results: DCLK1 is overexpressed in pancreatic cancer and is related to metastasis and prognosis. Knockdown of DCLK1 markedly suppressed cell growth in vitro and in vivo and also inhibited the migration and invasion of pancreatic cancer cells. Furthermore, we found that DCLK1 silencing could inhibit EMT in cancer cells via downregulation of Bmi-1 and the mesenchymal markers Snail and Vimentin and upregulation of the epithelial marker E-cadherin. Moreover, high DCLK1 expression in human pancreatic cancer samples was associated with a mesenchymal phenotype and increased cell proliferation. Further co-immunoprecipitation indicated that DCLK1 did not interact with Bmi-1 directly. Conclusion: Our data suggest that upregulation of DCLK1 may contribute to pancreatic cancer metastasis and poor prognosis by increasing Bmi-1 expression indirectly. The findings indicate that inhibiting DCLK1 expression might be a novel strategy for pancreatic cancer therapy.

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“…It has also been associated with worse survival in prostate carcinomas [26]. Conversely, in pancreatic cancer, miR-200a has been reported to suppress EMT, proliferation, and invasion in vitro, by down-regulating DEK protein at least [27-29]. The results of a small study with 11 patients suggested that miR-200a may be overexpressed in cancer tissue when compared with samples from benign pancreas [30].…”

Section: Discussionmentioning

confidence: 99%

Expression Levels of microRNAs miR-93 and miR-200a in Pancreatic Adenocarcinoma with Special Reference to Differentiation and Relapse-Free Survival

et al. 2018

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Objectives: Protein levels of the transcription factor nuclear factor erythroid-derived 2-like 2 (Nrf2) and its inhibitor Kelch-like ECH-associated protein 1 (Keap1) have been proposed as prognostic factors in pancreatic ductal adenocarcinomas (PDACs). These cellular redox-state-regulating enzymes are targeted by several microRNAs, including miR-93 and miR-200a. Methods: We assessed mRNA levels of Nrf2 and Keap1 and tissue expression of miR-93 and miR-200a in 51 patients with surgically treated PDAC. Expression levels were separately measured in malignant cells and adjacent benign cells. Results: Keap1 and Nrf2 mRNA expression levels in cancer cells were lower than in adjacent benign tissue (Wilcoxon’s test; p = 0.0015 and p = 0.000032, respectively). Conversely, miR-93 expression was higher in cancer cells than in adjacent benign tissue (p = 0.00082). Low levels of miR-93 and miR-200a in cancer cells were associated with poorer differentiation (p = 0.004 and p = 0.002, respectively). In univariate survival analysis, benign-tissue levels of miR-200a above the median predicted better relapse-free survival (RFS) (p = 0.045). Conclusions: High miR-93 and miR-200a levels in cancer cells of PDAC were associated with better differentiation, and miR-200a expression in benign tissue with excellent RFS. Keap1 and Nrf2 mRNA levels showed prominent down-regulation in cancerous versus benign tissue, but they were not associated with disease aggressiveness or outcome.

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MiR-200a inhibits epithelial-mesenchymal transition of pancreatic cancer stem cell

Cited by 80 publications

References 42 publications

Overexpression of miR-200a suppresses epithelial-mesenchymal transition of liver cancer stem cells

Overexpression of miR-200a suppresses epithelial-mesenchymal transition of liver cancer stem cells

Doublecortin-Like Kinase 1 (DCLK1) Regulates B Cell-Specific Moloney Murine Leukemia Virus Insertion Site 1 (Bmi-1) and is Associated with Metastasis and Prognosis in Pancreatic Cancer

Expression Levels of microRNAs miR-93 and miR-200a in Pancreatic Adenocarcinoma with Special Reference to Differentiation and Relapse-Free Survival

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