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Overexpression of microRNA-21 regulating PDCD4 during tumorigenesis of liver fluke-associated cholangiocarcinoma contributes to tumor growth and metastasis

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Tumor Biology

Abstract

MicroRNA, an endogenous noncoding RNA modulating gene expression, is a key molecule that by its dysregulation plays roles in inflammatory-driven carcinogenesis. This study aimed to investigate the role of oncomiR miR-21 and its target, the programmed cell death 4 (PDCD4) in tumor growth and metastasis of the liver fluke Opisthorchis viverrini-associated cholangiocarcinoma (CCA). The expression levels of miR-21 and PDCD4 were analyzed using the TaqMan miRNA expression assay and immunohistochemistry in liver tissues of both O. viverrini plus N-nitrosodimethylamine (NDMA)-treated hamsters and human CCA samples (n = 23 cases). The functional assay for miR-21 was performed in CCA cell lines by the anti-miR-21 and pre-miR-21 transfection procedures. The peak of miR-21 levels were reached at 2 (hyperplastic lesions) and 6 (CCA) months of the O. viverrini plus NDMA-induced group and had a reverse response with its target PDCD4 proteins. In human CCA, miR-21 was overexpressed in tumor tissues when compared with nontumor tissues (P = 0.0034) and had a negative correlation with PDCD4 protein (P = 0.026). It was also found that high expression of miR-21 was significantly correlated with shorter survival (P < 0.05) and lymph node metastasis (P = 0.037) of CCA patients. Transient transfection of pre-miR-21 reduced the PDCD4 level and resulted in an increase of M213 CCA cell growth and wound-induced migration ability. These results indicated that miR-21 plays a role in the carcinogenesis and metastasis of O. viverrini-associated CCA by suppressing the function of PDCD4. Modulation of aberrantly expressed miR-21 may be a useful strategy to inhibit tumor cell phenotypes or improve response to chemotherapy.

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Acknowledgments

This study was supported by the Thailand Research Fund through the Royal Golden Jubilee Ph.D. Program (grant no PHD/0226/2551) to PC and PY, the Higher Education Research Promotion and National Research University Project of Thailand, Office of the Higher Education Commission, through the Health Cluster (SHeP-GMS) Khon Kaen University to PY, a grant from Khon Kaen University to NN, a grant from a Mid-Career Grant (RSA5280007), Thailand Research Fund, to NN and a grant from the Faculty of Medicine, Khon Kaen University to PY.

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Authors and Affiliations

  1. Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand

    P. Chusorn, N. Namwat, W. Loilome, A. Techasen & P. Yongvanit

  2. Department of Pathology, Khon Kaen University, Khon Kaen, 40002, Thailand

    C. Pairojkul

  3. Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand

    N. Khuntikeo

  4. Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University, Khon Kaen, 40002, Thailand

    P. Chusorn, N. Namwat, W. Loilome, A. Techasen, C. Pairojkul, N. Khuntikeo & P. Yongvanit

  5. Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand

    A. Techasen

  6. Faculty of Thai Traditional and Alternative Medicine, Ubonratchathani Rajabhat University, Ubonratchathani, Thailand

    A. Dechakhamphu

  7. School of Biochemistry, Institute of Science, Suranaree University of Technology, Nakhon Ratchasima, Thailand

    C. Talabnin

  8. NCCS-VARI Translational Research Laboratory, National Cancer Centre Singapore, Singapore, Singapore

    W. Chan-On, C. K. Ong & B. T. Teh

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  1. P. Chusorn
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  2. N. Namwat
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Chusorn, P., Namwat, N., Loilome, W. et al. Overexpression of microRNA-21 regulating PDCD4 during tumorigenesis of liver fluke-associated cholangiocarcinoma contributes to tumor growth and metastasis. Tumor Biol. 34, 1579–1588 (2013). https://doi.org/10.1007/s13277-013-0688-0

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