miR-204 targets Bcl-2 expression and enhances responsiveness of gastric cancer

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Abstract

Micro RNAs (miRs) are small non-coding RNAs aberrantly expressed in human tumors. Here, we aim to identify miRs whose deregulated expression leads to the activation of oncogenic pathways in human gastric cancers (GCs). Thirty nine out of 123 tumoral and matched uninvolved peritumoral gastric specimens from three independent European subsets of patients were analyzed for the expression of 851 human miRs using Agilent Platform. The remaining 84 samples were used to validate miRs differentially expressed between tumoral and matched peritumoral specimens by qPCR. miR-204 falls into a group of eight miRs differentially expressed between tumoral and peritumoral samples. Downregulation of miR-204 has prognostic value and correlates with increased staining of Bcl-2 protein in tumoral specimens. Ectopic expression of miR-204 inhibited colony forming ability, migration and tumor engraftment of GC cells. miR-204 targeted Bcl-2 messenger RNA and increased responsiveness of GC cells to 5-fluorouracil and oxaliplatin treatment. Ectopic expression of Bcl-2 protein counteracted miR-204 pro-apoptotic activity in response to 5-fluorouracil. Altogether, these findings suggest that modulation of aberrant expression of miR-204, which in turn releases oncogenic Bcl-2 protein activity might hold promise for preventive and therapeutic strategies of GC.

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Most cited references 17

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miR-15b and miR-16 modulate multidrug resistance by targeting BCL2 in human gastric cancer cells.

Lin Xia, Dexin Zhang, Rui Du … (2008)

microRNAs are endogenous small noncoding RNAs that regulate gene expression negatively at posttranscriptional level. This latest addition to the complex gene regulatory circuitry revolutionizes our way to understanding physiological and pathological processes in the human body. Here we investigated the possible role of microRNAs in the development of multidrug resistance (MDR) in gastric cancer cells. microRNA expression profiling revealed a limited set of microRNAs with altered expression in multidrug- resistant gastric cancer cell line SGC7901/VCR compared to its parental SGC7901 cell line. Among the downregulated microRNAs are miR-15b and miR-16, members of miR-15/16 family, whose expression was further validated by qRT-PCR. In vitro drug sensitivity assay demonstrated that overexpression of miR-15b or miR-16 sensitized SGC7901/VCR cells to anticancer drugs whereas inhibition of them using antisense oligonucleotides conferred SGC7901 cells MDR. The downregulation of miR-15b and miR-16 in SGC7901/VCR cells was concurrent with the upregulation of Bcl-2 protein. Enforced mir-15b or miR-16 expression reduced Bcl-2 protein level and the luciferase activity of a BCL2 3' untranslated region-based reporter construct in SGC7901/VCR cells, suggesting that BCL2 is a direct target of miR-15b and miR-16. Moreover, overexpression of miR-15b or miR-16 could sensitize SGC7901/VCR cells to VCR-induced apoptosis. Taken together, our findings suggest that miR-15b and miR-16 could play a role in the development of MDR in gastric cancer cells at least in part by modulation of apoptosis via targeting BCL2. (c) 2008 Wiley-Liss, Inc.

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Global cancer statistics

A. JEMAL, F Bray, MM Center … (2012)

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miR-181b modulates multidrug resistance by targeting BCL2 in human cancer cell lines.

Wei Zhu, Xia Shan, Tongshan Wang … (2010)

MicroRNAs (miRNAs) are short noncoding RNA molecules, which posttranscriptionally regulate genes expression and play crucial roles in diverse biological processes, such as development, differentiation, apoptosis and proliferation. Here, we investigated the possible role of miRNAs in the development of multidrug resistance (MDR) in human gastric and lung cancer cell lines. We found that miR-181b was downregulated in both multidrug-resistant human gastric cancer cell line SGC7901/vincristine (VCR) and multidrug-resistant human lung cancer cell line A549/cisplatin (CDDP), and the downregulation of miR-181b in SGC7901/VCR and A549/CDDP cells was concurrent with the upregulation of BCL2 protein, compared with the parental SGC7901 and A549 cell lines, respectively. In vitro drug sensitivity assay demonstrated that overexpression of miR-181b sensitized SGC7901/VCR and A549/CDDP cells to anticancer drugs, respectively. The luciferase activity of a BCL2 3'-untranslated region-based reporter construct in SGC7901/VCR and A549/CDDP cells suggests that a new target site in the 3'UTR of BCL2 of the mature miR-181s (miR-181a, miR-181b, miR-181c and miR-181d) was found. Enforced miR-181b expression reduced BCL2 protein level and sensitized SGC7901/VCR and A549/CDDP cells to VCR-induced and CDDP-induced apoptosis, respectively. Taken together, our findings suggest that miR-181b could play a role in the development of MDR in both gastric and lung cancer cell lines, at least in part, by modulation of apoptosis via targeting BCL2.

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Author and article information

Journal

Journal ID (nlm-ta): Cell Death Dis

Journal ID (iso-abbrev): Cell Death Dis

Title: Cell Death & Disease

Publisher: Nature Publishing Group

ISSN (Electronic): 2041-4889

Publication date (Print): November 2012

Publication date (Electronic): 15 November 2012

Publication date PMC-release: 1 November 2012

Volume: 3

Issue: 11

Page: e423

Affiliations

[1 ]Translational Oncogenomic Unit, Italian National Cancer Institute ‘Regina Elena' , Rome, Italy

[2 ]Molecular Chemoprevention Group, ‘Regina Elena' National Cancer Institute , Rome, Italy

[3 ]Department of Pathology, ‘Regina Elena' National Cancer Institute, Rome, Italy

[4 ] ⁴Faculty of Medicine and Psychology, Surgical and Medical Department of Clinical Sciences, Biomedical Technologies and Translational Medicine, University of Rome ‘La Sapienza', Sant'Andrea Hospital , Rome, Italy

[5 ]Department of Oncology, Division of Pathology S. Vincenzo Hospital , Taormina, Italy

[6 ]SAFU, ‘Regina Elena' National Cancer Institute , Rome, Italy

[7 ]Department of Oncology, Division of Oncological Surgery S. Vincenzo Hospital , Taormina, Italy

[8 ]Department of GI Surgery, ‘Regina Elena' National Cancer Institute , Rome, Italy

[9 ]Department of Oncology, Juravinski Cancer Center, McMaster University Hamilton , Hamilton, Ontario, Canada

Author notes

[* ]Translational Oncogenomic Unit, Italian National Cancer Institute ‘Regina Elena' , Via Elio Chianesi, 53, 00144 Rome, Italy. Tel: +3906 5266 2911; Fax: +39 06 5266 2880; E-mail: blandino@ 123456ifo.it

[10]

These authors contributed equally to this work

Article

Publisher Item ID: cddis2012160

DOI: 10.1038/cddis.2012.160

PMC ID: 3542596

PubMed ID: 23152059

SO-VID: 90a73ea8-7661-4a50-b875-b8fc8846e1c2

License:

This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/

History

Date received : 27 September 2012

Date accepted : 28 September 2012

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