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

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Involvement of Human Micro-RNA in Growth and Response to Chemotherapy in Human Cholangiocarcinoma Cell Lines View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Texas A&M Repository GASTROENTEROLOGY 2006;130:2113–2129 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,§ and TUSHAR PATEL* *Department of Internal Medicine, Scott and White Clinic, Texas A&M University System Health Science Center College of Medicine, Temple, Texas; ‡The Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; and §College of Pharmacy, The Ohio State University, Columbus, Ohio Background & Aims: Micro-RNA (miRNA) are endoge- age of target mRNA. Although several hundred miRNA nous regulatory RNA molecules that modulate gene have been cloned or predicted, a functional role for these expression. Alterations in miRNA expression can contrib- in many cellular processes has not been fully elucidated.1 ute to tumor growth by modulating the functional ex- The best characterized role of miRNA has been as a pression of critical genes involved in tumor cell prolifer- developmental regulator in Caenorhabditis elegans and ation or survival. Our aims were to identify specific Drosophilia. More recently, several other roles have been miRNA involved in the regulation of cholangiocarcinoma described including regulation of apoptosis and differen- growth and response to chemotherapy. Methods: miRNA tiation. miRNA are expressed as long precursor RNA expression in malignant and nonmalignant human that are processed by a single nuclease Drosha prior to cholangiocytes was assessed using a microarray. Ex- pression of selected miRNA and their precursors was transport into the cytoplasm by an exportin-5-dependent evaluated by Northern blots and real-time polymerase mechanism. In the cytoplasm, miRNA are further chain reaction, respectively. The effect of selected cleaved by Dicer. The result is a 17–24 nucleotide (nt) miRNA on cell growth and response to chemotherapy small miRNA that can complex with sequence comple- was assessed using miRNA-specific antisense oligonu- mentary in a manner similar to the RNA-induced silenc- cleotides to decrease miRNA expression or with precur- ing complex, which is also formed during the RNA sor miRNA to increase cellular expression. Results: interference process. The miRNA are then targeted to miRNA expression was markedly different in malignant sequences that are at least partially complementary to the cholangiocytes, with decreased expression of many miRNA. The translation of the bound mRNA is then miRNA compared with nonmalignant cells. A cluster of inhibited or the mRNA transcript degraded based on the miRNA, including miR-320, miR-200b, miR-21, miR- sequence match. Although the targets of miRNA have 23a, miR-141, miR-27a, and miR-34a, were expressed not been fully characterized, potential targets can be in all cell lines. MiR-21, miR-141, and miR-200b were predicted based on sequence complementarity. highly over-expressed in malignant cholangiocytes. Inhibi- A role for miRNA in cancer is emerging with the tion of miR-21 and miR-200b increased sensitivity to gem- recent identification that miRNA may be important citabine, whereas inhibition of miR-141 decreased cell contributors to cancer development. Studies of miRNA growth. Treatment of tumor cell xenografts with systemic gemcitabine altered the expression of a significant number expression profiles in cancer samples have identified a of miRNA. miR-21 modulates gemcitabine-induced apo- handful of miRNA that are differentially regulated in ptosis by phosphatase and tensin homolog deleted on tumors, suggesting a possible link between miRNA and chromosome 10 (PTEN)-dependent activation of PI 3-ki- oncogenesis.2,3 miRNA targets can include genes in- nase signaling. Potential target genes that were modu- volved in differentiation or transformation, such as tran- lated by selected miRNA were identified. Conclusions: Al- scription factors and cell-cycle control. Tumorigenesis terations in miRNA expression contribute to tumor growth might result from the perturbation of these pathways by and response to chemotherapy. Aberrantly expressed mutations in the miRNA genes, their 3=-untranslated miRNA or their targets will provide mechanistic insight and region (UTR) miRNA-binding sites, or in pathways that therapeutic targets for cholangiocarcinoma. regulate their expression. Through modulation of cell icro-RNA (miRNA) are a group of endogenous Abbreviations used in this paper: miRNA, micro-RNA. © 2006 by the American Gastroenterological Association Institute Msmall, noncoding RNA that can modulate protein 0016-5085/06/$32.00 expression by regulating translational efficiency or cleav- doi:10.1053/j.gastro.2006.02.057 2114 MENG ET AL GASTROENTEROLOGY Vol. 130, No. 7 differentiation and proliferation, miRNA can control and Diego, CA). All other cell culture media and supplements were regulate many cellular processes germane to tumor gen- obtained from Invitrogen (Carlsbad, CA). esis, growth, and survival. Many miRNA genes are lo- Transfections cated at chromosomal fragile sites or regions of cytoge- netic abnormalities associated with cancer.4 Moreover, Transfections were performed by electroporation using the pattern of expression of miRNA has been shown to the Nucleofector system (Amaxa Biosystems, Koln, Germany). Transfection conditions for each cell type were first optimized define accurately the specific cancer types.5 However, the to result in 20%–30% transfection efficiency with viability biologic consequences of alterations in miRNA expres- Ͼ80%. All studies were performed in quadruplicate. Cells sion in cancer cells remain undefined. (1–2 ϫ 106) were spun down at 1000 rpm for 5 minutes, and Cholangiocarcinomas are enigmatic malignancies of the the medium was removed. Cells were then resuspended in 100 biliary tract that are highly chemoresistant.6–8 The need for ␮L Nucleofector solution (Amaxa Biosystems) at room tem- improved treatments for this cancer is highlighted by the perature followed by addition of 20 ␮L of 100 nmol/L mi- dramatic increases in the incidence of cholangiocarcinoma croRNA precursor, antisense inhibitor, or controls (all ob- in several regions of the world.9–11 The mechanisms regu- tained from Ambion Inc., Austin, TX). Electroporation was lating cholangiocarcinoma growth and resistance to chemo- performed using the Nucleofector (Amaxa Biosystems). Trans- therapy are poorly understood. Although miRNA are be- fected cells were then resuspended in regular culture media coming increasingly recognized as regulatory molecules in containing 10% serum for 48–72 hours prior to study. human cancers, their involvement in functional responses to Isolation of miRNA environmental changes such as exposure to chemotherapy is unknown. We postulated that aberrant expression of Total RNA from cell lines and tumor tissue samples were isolated using the Totally RNA isolation kit (Ambion). miRNA in cancer cells could modulate the functional ex- The miRNA fraction was obtained by mixing RNA with 2X pression of critical genes involved in tumor cell behavior, sample buffer and flashPAGE purification using flashPAGE such as genes contributing to cell survival in response to precast Gels and the flashPAGE Fractionator System (Am- chemotherapeutic stress. Our aims were, thus, to identify bion). The size of the miRNA fractions were confirmed using the miRNA that were differentially expressed in malignant an Agilent 2100 Bioanalyzer (Agilent Technologies, Inc., Palo human cholangiocytes and to recognize specific miRNA Alto, CA). involved in the regulation of tumor cell growth and re- miRNA Array Hybridization and Analysis sponse to chemotherapy. We asked the following questions: Are miRNA differentially activated in malignant cholan- The isolated miRNA from the pooled sample were giocytes? If so, does their expression reflect cytogenetic appended 3= amine-modified tails using the mirVana miRNA abnormalities? Can aberrantly expressed miRNA regulate Array Labeling Kit (Ambion) and then fluorescently coupled tumor cell growth or survival? Are miRNA involved in with Cy3 or Cy5 using the Post Labeling Reactive Dye kit chemotherapeutic responses in cholangiocarcinoma? (Amersham Bioscience, Pittsburgh, PA). The Cy3 (control) and Cy5 (treated) labeled samples were washed 3 times using miRNA washing buffer, mixed in the same labeling cartridge, Materials and Methods eluted, and stored at Ϫ70°C or analyzed by hybridizing to miRNA arrays. miRNA arrays were generated on glass slides Cell Lines and Cultures using the mirVana miRNA Array Probe Set (Ambion) and an The KMCH-1, Mz-ChA-1, and TFK human cholan- OmniGrid Microarrayer (Gene Machines, San Carlos, CA). giocarcinoma cell lines and the nonmalignant human cholan- Each probe was printed in duplicate. Following hybridization, giocyte H69 cell lines were obtained as previously de- the miRNA arrays were scanned using a GenePix 4000A array scribed.12–14 Mz-ChA-1 cells are derived from metastatic scanner (Axon Instruments, Union City, CA). Raw data were gallbladder cancer, TFK-1 cells from common bile duct can- normalized and analyzed using GeneSpring 7.0 Software (Sil- cer, and KMCH from an intrahepatic mixed cholangiocellular- icon Genetics, Redwood City, CA). Normalization was per- hepatocellular carcinoma. H69 cells are derived from nonma- formed by expressing each miRNA replicate relative to a lignant cholangiocytes
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