MicroRNA-21 modulates biological functions of pancreatic cancer cells including their proliferation, invasion, and chemoresistance

Moriyama, Taiki; Ohuchida, Kenoki; Mizumoto, Kazuhiro; Yu, Jun; Sato, Norihiro; Nabae, Toshinaga; Takahata, Shunichi; Toma, Hiroki; Nagai, Eishi; Tanaka, Masao

doi:10.1158/1535-7163.mct-08-0592

Cited by 302 publications

(251 citation statements)

References 35 publications

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“…In line with this assumption, pancreatic cancer cells transfected with the miR-21 precursor show significantly increased cell proliferation, invasiveness, and chemoresistance. 17 It is notable that a high miR-21 expression was associated with a poorer prognosis of the pancreatic ductal adenocarcinoma patients in the current study, and the association has also been described by Dillhoff et al 18 Moreover, the expression status of miR-21 was considered to be an independent prognostic factor for poor survival based on our statistical analysis. Zhu et al 19 described that miR-21 has a role not only in tumor growth, but also in invasion and tumor metastasis using several cancer cell lines.…”

Section: Discussionsupporting

confidence: 84%

Association of microRNA-21 expression with its targets, PDCD4 and TIMP3, in pancreatic ductal adenocarcinoma

et al. 2012

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Since the discovery of small non-coding RNAs, the analyses of microRNA (miRNA) expression patterns in human cancer have provided new insights into cancer biology. miRNA-21 has been suggested to be one of the miRNAs that have an important role in the development or biological behavior of a variety of malignancies, including pancreatic cancer. This study was conducted to evaluate the relationship between the expression of miRNA-21 and that of its molecular targets, programmed cell death 4 (PDCD4) and tissue inhibitor of metalloproteinase (TIMP3), in pancreatic ductal adenocarcinoma. The study included 65 pancreatic ductal adenocarcinomas and 5 normal pancreatic tissue specimens for comparison. The miRNA expression profiling of five selected pancreatic ductal adenocarcinomas and five normal pancreatic specimens was performed using a microarray platform, and was evaluated by a hierarchical clustering analysis. The miRNA most highly expressed in pancreatic ductal adenocarcinomas (ie, miRNA-21) was further assessed by quantitative real-time reverse transcription PCR (RT-PCR) assays in the 65 pancreatic ductal adenocarcinoma cases. The expression pattern of its molecular targets (eg, PDCD4 and TIMP3) in pancreatic ductal adenocarcinoma was examined immunohistochemically. In the microarray analyses, 28 miRNAs were upregulated in pancreatic ductal adenocarcinoma compared with normal pancreatic tissue, whereas 48 miRNAs were downregulated. miRNA-21 was the most significantly overexpressed miRNA in the pancreatic ductal adenocarcinomas analyzed, and was also highly expressed in 75% of the 65 pancreatic ductal adenocarcinomas examined by real-time RT-PCR. High miRNA-21 expression was correlated with a worse prognosis in the pancreatic ductal adenocarcinoma patients (P ¼ 0.045). The immunohistochemical expression patterns of PDCD4 (reduced nuclear staining pattern) and TIMP3 (downregulated expression) were significantly associated with both the upregulated miR-21 expression (Po0.05) and the poor survival of the patients (Po0.001 and P ¼ 0.001, respectively). Our data suggest that an overexpression of miRNA-21 is, therefore, associated with the biological behavior of pancreatic ductal adenocarcinoma via the downregulation of the expression of tumor suppressors, PDCD4 and TIMP3, thus resulting in tumor progression and the adverse clinical course of pancreatic ductal adenocarcinoma.

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Section: Discussionsupporting

confidence: 84%

Association of microRNA-21 expression with its targets, PDCD4 and TIMP3, in pancreatic ductal adenocarcinoma

et al. 2012

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“…For example, miR-122a is down-regulated in 70% of HCCs (14) and its ectopic expression can significantly increase the sensitivity to doxorubicin and sorafenib in HCC cells (15,16). miR-21 is up-regulated in many cancers and contributes to the chemoresistance to gemcitabine in cholangiocarcinoma and pancreatic cancer cells (17)(18)(19). Members of the let-7 family of miRNAs are downregulated in human HCC cells and tissues in association with enhanced expression of Bcl-xL, and ectopic expression of let-7c miRNA sensitizes HCC cells to sorafenib (20).…”

Section: Technology In Cancer Research and Treatment Volume 13 Numbermentioning

confidence: 99%

MicroRNA-34a Targets Bcl-2 and Sensitizes Human Hepatocellular Carcinoma Cells to Sorafenib Treatment

Yang

Liu

Gong

et al. 2014

Technol Cancer Res Treat

142

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MiR-34a, a direct target of p53, has been shown to target several molecules associated with the cell cycle and cell survival pathways, and its dysregulation is implicated in cancer drug resistance or sensitivity in several human cancers. However, the correlation between miR-34a expression and chemoresistance has not been explored in HCC. In this study, we confirmed that miR-34a was significantly down-regulated in HCC tissues and HCC cell lines by qRT-PCR. HCC tissues with lower miR-34a expression displayed higher expression of Bcl-2 protein than those with high expression of miR-34a; therefore, an inverse correlation is evident between the miR-34a level and Bcl-2 expression. Moreover, patients with lower miR-34a expression had significantly poorer overall survival. Bioinformatics and luciferase reporter assays revealed that miR-34a binds the 3-UTR of the Bcl-2 mRNA and represses its translation. Western blotting analysis and qRT-PCR confirmed that Bcl-2 is inhibited by miR-34a overexpression. Functional analyses indicated that the restoration of miR-34a reduced cell viability, promoted cell apoptosis and potentiated sorafenib-induced apoptosis and toxicity in HCC cell lines by inhibiting Bcl-2 expression. This study is the first to demonstrate that miR-34a induces sensitivity to the anti-tumor effect of sorafenib in human HCC cells, suggesting a potential role of miR-34a in the treatment of HCC.

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“…However, a recent report showed that miR-369-3p can upregulate the expression of tumor necrosis factor alpha (Vasudevanet al, 2007). In addition, miRNAs have been shown to function as tumor suppressors or oncogenes (Bracken et al, 2009;Esquela-Kerscher et al, 2006;Huang et al, 2008;Kumar et al, 2007;Lee et al, 2007;Liu et al, 2009;Moriyama et al, 2009;Ryan et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-590-5p Regulates Proliferation and Invasion in Human Hepatocellular Carcinoma Cells by Targeting TGF-β RII

Jiang

Xiang

Wang

et al. 2012

Molecules and Cells

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MicroRNAs (miRNAs) are regulatory small non-coding RNAs that can regulate gene expression by binding to gene elements, such as the gene promotor 5′UTR, mainly in the 3′UTR of mRNA. One miRNA targets many mRNAs, which can be regulated by many miRNAs, leading to a complex metabolic network. In our study, we found that the expression level of miR-590-5p is higher in the human hepatocellular carcinoma cell line HepG2 than in the normal hepatocellular cell line L02. Downregulation of miR-590-5p inhibited proliferation and invasion of hepatocellular carcinoma cells (HCCs). We also showed that expression of TGF-beta RII, which has been regarded as a regulator of tumor proliferation, invasion, and migration in hepatocellular carcinoma, is regulated by miRNA-590-5p. In addition, miR-590-5p downregulated the expression of TGFbeta RII by targeting the 3′UTR of mRNA. We also found that downregulation of miR-590-5p was associated with an elevation of TGF-beta RII and inhibition of proliferation and invasion in HepG2 cells. Furthermore, overexpression of miR-590-5p was associated with upregulation of TGF-beta RII and could promote proliferation and invasion in L02 cells. In conclusion, we determined that TGF-beta RII is a novel target of miRNA-590-5p. Thus, the role of TGF-beta RII in regulating proliferation and invasion of human HCCs is controlled by miR-590-5p. In other words, miR-590-5p promotes proliferation and invasion in human HCCs by directly targeting TGF-beta RII.

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MicroRNA-21 modulates biological functions of pancreatic cancer cells including their proliferation, invasion, and chemoresistance

Cited by 302 publications

References 35 publications

Association of microRNA-21 expression with its targets, PDCD4 and TIMP3, in pancreatic ductal adenocarcinoma

Association of microRNA-21 expression with its targets, PDCD4 and TIMP3, in pancreatic ductal adenocarcinoma

MicroRNA-34a Targets Bcl-2 and Sensitizes Human Hepatocellular Carcinoma Cells to Sorafenib Treatment

MicroRNA-590-5p Regulates Proliferation and Invasion in Human Hepatocellular Carcinoma Cells by Targeting TGF-β RII

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