Involvement of human micro-RNA in growth and response to chemotherapy in human cholangiocarcinoma cell lines.

By F. Meng, R. Henson, M. Lang, Hania Wehbe, S. Maheshwari, Joshua T. Mendell, Jinmai Jiang, Thomas D. Schmittgen, T. Patel. Gastroenterology, 2006

1,027 citations recorded by the source corpus.

BACKGROUND & AIMS Micro-RNA (miRNA) are endogenous regulatory RNA molecules that modulate gene expression. Alterations in miRNA expression can contribute to tumor growth by modulating the functional expression of critical genes involved in tumor cell proliferation or survival. Our aims were to identify specific miRNA involved in the regulation of cholangiocarcinoma growth and response to chemotherapy. METHODS miRNA expression in malignant and nonmalignant human cholangiocytes was assessed using a microarray. Expression of selected miRNA and their precursors was evaluated by Northern blots and real-time polymerase chain reaction, respectively. The effect of selected miRNA on cell growth and response to chemotherapy was assessed using miRNA-specific antisense oligonucleotides to decrease miRNA expression or with precursor miRNA to increase cellular expression. RESULTS miRNA expression was markedly different in malignant cholangiocytes, with decreased expression of many miRNA compared with nonmalignant cells. A cluster of miRNA, including miR-320, miR-200b, miR-21, miR-23a, miR-141, miR-27a, and miR-34a, were expressed in all cell lines. MiR-21, miR-141, and miR-200b were highly over-expressed in malignant cholangiocytes. Inhibition of miR-21 and miR-200b increased sensitivity to gemcitabine, whereas inhibition of miR-141 decreased cell growth. Treatment of tumor cell xenografts with systemic gemcitabine altered the expression of a significant number of miRNA. miR-21 modulates gemcitabine-induced apoptosis by phosphatase and tensin homolog deleted on chromosome 10 (PTEN)-dependent activation of PI 3-kinase signaling. Potential target genes that were modulated by selected miRNA were identified. CONCLUSIONS Alterations in miRNA expression contribute to tumor growth and response to chemotherapy. Aberrantly expressed miRNA or their targets will provide mechanistic insight and therapeutic targets for cholangiocarcinoma.

Subfields: Cancer Research, Molecular Biology, Surgery

View Paper: https://www.semanticscholar.org/paper/a24c52dde5214f1055363dfd270028abb42146fa

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Citations in the corpus

MicroRNA-21 targets a network of key tumor-suppressive pathways in glioblastoma cells. (2008, background): “Further studies showed that miR-21 had the same antiapoptotic role in other cancer types, such as cholangiocarcinomas and breast cancer cells (10, 11).”
MicroRNA expression patterns to differentiate pancreatic adenocarcinoma from normal pancreas and chronic pancreatitis. (2007, background): “While the role of miR-21 in neoplasia has not been fully elucidated, its inhibition using miRNA-specific antisense oligonucleotides increases in vitro susceptibility of cholangiocarcinoma cells to gemcitabine.(14) MiR-155 is also overexpressed in solid tumors such as those of the colon, lung, and br”
MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer (2008, background): “First cancerrelated target genes of miR-21 have been described, among them being PTEN and TPM1 (Meng et al., 2006; Zhu et al., 2007).”
MicroRNA dysregulation in cancer: diagnostics, monitoring and therapeutics. A comprehensive review (2012, neutral): “One of the ﬁrst reports describing the involvement of microRNAs in chemoresistance was performed in cholangiocarcinoma cell lines (Meng et al, 2006), where inhibition of miR-21 and miR-200b increased sensitivity to gemcitabine.”
Pathogenesis, Diagnosis, and Management of Cholangiocarcinoma (2013, background): “miR21 also was found to regulate phosphatase and tensin homolog deleted on chromosome ten–dependent activation of PI3K signaling in CCAs, to affect chemosensitivity.(84) miR200C prevents the epithelial–mesenchymal transition (EMT); changes in its level might be used as a prognostic factor.”
Interleukin-6 dependent survival of multiple myeloma cells involves the Stat3-mediated induction of microRNA-21 through a highly conserved enhancer. (2007, neutral): “Recently, miR-21 was reported to repress the expression of the tumor suppressor PTEN.12 Yet, we did not detect up-regulation of PTEN expression or AKT phosphorylation in INA-6 and XG-1 cells in response to IL-6 (data not shown).”
MicroRNA-21 promotes cell transformation by targeting the programmed cell death 4 gene (2008, background): “In addition, increased miR-21 has been associated with chemoresistance in human cholangiocarcinoma cell lines (Meng et al., 2006).”
MicroRNA: Biogenesis, Function and Role in Cancer (2010, background): “MiRNA signature profiles can be used to determine prognosis [338340], response to drug therapy [341], predict treatment efficiency [342, 343], race susceptibility [23] and patient susceptibility to cancer and metastasis [344-346].”