Involvement of Human Micro-RNA in Growth and Response to Chemotherapy in Human Cholangiocarcinoma Cell Lines

Fanyin Meng, Roger Henson, Molly Lang, Hania Wehbe, Shail Maheshwari, Joshua T. Mendell, Jinmai Jiang, Thomas D. Schmittgen, Tushar C Patel

Research output: Contribution to journalArticle

805 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2113-2129
Number of pages17
JournalGastroenterology
Volume130
Issue number7
DOIs
StatePublished - Jul 2006
Externally publishedYes

Fingerprint

Cholangiocarcinoma
MicroRNAs
Drug Therapy
Cell Line
Growth
gemcitabine
Neoplasms
Gene Expression
Chromosomes, Human, Pair 10
Antisense Oligonucleotides
RNA Precursors
Phosphatidylinositol 3-Kinases
Phosphoric Monoester Hydrolases
Heterografts
Northern Blotting

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Involvement of Human Micro-RNA in Growth and Response to Chemotherapy in Human Cholangiocarcinoma Cell Lines. / Meng, Fanyin; Henson, Roger; Lang, Molly; Wehbe, Hania; Maheshwari, Shail; Mendell, Joshua T.; Jiang, Jinmai; Schmittgen, Thomas D.; Patel, Tushar C.

In: Gastroenterology, Vol. 130, No. 7, 07.2006, p. 2113-2129.

Research output: Contribution to journalArticle

Meng, F, Henson, R, Lang, M, Wehbe, H, Maheshwari, S, Mendell, JT, Jiang, J, Schmittgen, TD & Patel, TC 2006, 'Involvement of Human Micro-RNA in Growth and Response to Chemotherapy in Human Cholangiocarcinoma Cell Lines', Gastroenterology, vol. 130, no. 7, pp. 2113-2129. https://doi.org/10.1053/j.gastro.2006.02.057
Meng, Fanyin ; Henson, Roger ; Lang, Molly ; Wehbe, Hania ; Maheshwari, Shail ; Mendell, Joshua T. ; Jiang, Jinmai ; Schmittgen, Thomas D. ; Patel, Tushar C. / Involvement of Human Micro-RNA in Growth and Response to Chemotherapy in Human Cholangiocarcinoma Cell Lines. In: Gastroenterology. 2006 ; Vol. 130, No. 7. pp. 2113-2129.
@article{d88fedfbf855483cbe9da232de010139,
title = "Involvement of Human Micro-RNA in Growth and Response to Chemotherapy in Human Cholangiocarcinoma Cell Lines",
abstract = "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.",
author = "Fanyin Meng and Roger Henson and Molly Lang and Hania Wehbe and Shail Maheshwari and Mendell, {Joshua T.} and Jinmai Jiang and Schmittgen, {Thomas D.} and Patel, {Tushar C}",
year = "2006",
month = "7",
doi = "10.1053/j.gastro.2006.02.057",
language = "English (US)",
volume = "130",
pages = "2113--2129",
journal = "Gastroenterology",
issn = "0016-5085",
publisher = "W.B. Saunders Ltd",
number = "7",

}

TY - JOUR

T1 - Involvement of Human Micro-RNA in Growth and Response to Chemotherapy in Human Cholangiocarcinoma Cell Lines

AU - Meng, Fanyin

AU - Henson, Roger

AU - Lang, Molly

AU - Wehbe, Hania

AU - Maheshwari, Shail

AU - Mendell, Joshua T.

AU - Jiang, Jinmai

AU - Schmittgen, Thomas D.

AU - Patel, Tushar C

PY - 2006/7

Y1 - 2006/7

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=33744521896&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33744521896&partnerID=8YFLogxK

U2 - 10.1053/j.gastro.2006.02.057

DO - 10.1053/j.gastro.2006.02.057

M3 - Article

C2 - 16762633

AN - SCOPUS:33744521896

VL - 130

SP - 2113

EP - 2129

JO - Gastroenterology

JF - Gastroenterology

SN - 0016-5085

IS - 7

ER -