MicroRNA-223 is commonly repressed in hepatocellular carcinoma and potentiates expression of Stathmin1

被引:415
作者
Wong, Queenie W. -L. [1 ,2 ]
Lung, Raymond W. -M. [1 ,2 ]
Law, Priscilla T. -Y. [1 ,2 ]
Lai, Paul B. -S. [3 ]
Chan, Kathy Y. -Y. [4 ]
To, Ka-Fai [1 ,2 ,5 ]
Wong, Nathalie [1 ,2 ]
机构
[1] Chinese Univ Hong Kong, Dept Anat & Cellular Pathol, Li Ka Shing Inst Hlth Sci, Hong Kong, Hong Kong, Peoples R China
[2] Chinese Univ Hong Kong, State Key Lab Oncol S China, Hong Kong, Hong Kong, Peoples R China
[3] Chinese Univ Hong Kong, Dept Surg, Shatin, Hong Kong, Peoples R China
[4] Chinese Univ Hong Kong, Dept Pediat, Shatin, Hong Kong, Peoples R China
[5] Chinese Univ Hong Kong, Inst Digest Dis, Shatin, Hong Kong, Peoples R China
关键词
D O I
10.1053/j.gastro.2008.04.003
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
Background&Aims: Recent studies have emphasized causative links between rnicroRNA (miRNA) deregulations and cancer development. In hepatocellular carcinoma (HCC), information on differentially expressed miRNA remained largely undefined. Methods: Arraybased miRNA profiling was performed on HCC cells that were derived from chronic carriers of hepatitis B virus (HBV) and hepatitis C virus (HCV), and nonviralassociated patients. Specific microRNA (rniR)-223 and miR-222 deregulations were verified in an independent series of tumors. The functional effect of iniR-223 was examined further. An integrative analysis of messenger RNA (mRNA) array with in silico predictions defined potential downstream targets of miR-223. A luciferase reporter assay was conducted to confirm target association. Results: Distinct up-regulations of miR-222, miR-221, and miR-31, and down-regulations of miR-223, miR-126, and miR-122a were identified. Further investigations suggested the highly deregulated miR-223 and miR-222 could unequivocally distinguish HCC from adjacent nontumoral liver, irrespective of viral associations (P :5.0002). Re-expression of miR-223 in HBV, HCV, and non-HBV non-HCV-related HCC cell lines revealed a consistent inhibitory effect on cell viability (P <.01). Integrative analysis further implicated Stathmin 1 (STMN1) as a downstream target of miR-223. A strong inverse relationship between STMN1 mRNA and miR-223 expressions was shown (P =.006). A substantial reduction in STMN1 protein was further demonstrated upon restoration of miR-223 expression in HCC cell lines. We further showed that miR-223 readily could suppress the luciferase activity in reporter construct containing the STMN1 3' untranslated region (P =.02). Conclusions: Our study revealed specific miRNA differential expressions in HCC and underscores the potential importance of miR-223 down-regulations in the development of HCC.
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页码:257 / 269
页数:13
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