Article

MicroRNA Expression, Survival, and Response to Interferon in Liver Cancer

Junfang JiLiver Carcinogenesis Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USAJiong ShiLiver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong KongAnuradha BudhuLiver Carcinogenesis Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MDZhipeng YuLiver Carcinogenesis Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MDMarshonna ForguesLiver Carcinogenesis Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MDStéphanie RoesslerLiver Carcinogenesis Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MDStefan AmbsBreast and Prostate Unit, Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MDYidong ChenGenetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MDPaul S. MeltzerCenter for Cancer ResearchCarlo M. CroceComprehensive Cancer Center, Ohio State University, Columbus, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong KongLun‐Xiu QinLiver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong KongKwan ManDepartments of Surgery, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong KongChung Mau LoDepartments of Surgery, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong KongJoyce LeePathology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong KongIrene Oi‐Lin NgPathology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong KongJia FanLiver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong KongZhao-You TangLiver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong KongHui‐Chuan SunLiver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong KongXin Wei WangLiver Carcinogenesis Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD

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Abstract

BACKGROUND: Hepatocellular carcinoma is a common and aggressive cancer that occurs mainly in men. We examined microRNA expression patterns, survival, and response to interferon alfa in both men and women with the disease. METHODS: We analyzed three independent cohorts that included a total of 455 patients with hepatocellular carcinoma who had undergone radical tumor resection between 1999 and 2003. MicroRNA-expression profiling was performed in a cohort of 241 patients with hepatocellular carcinoma to identify tumor-related microRNAs and determine their association with survival in men and women. In addition, to validate our findings, we used quantitative reverse-transcriptase-polymerase-chain-reaction assays to measure microRNAs and assess their association with survival and response to therapy with interferon alfa in 214 patients from two independent, prospective, randomized, controlled trials of adjuvant interferon therapy. RESULTS: In patients with hepatocellular carcinoma, the expression of miR-26a and miR-26b in nontumor liver tissue was higher in women than in men. Tumors had reduced levels of miR-26 expression, as compared with paired noncancerous tissues, which indicated that the level of miR-26 expression was also associated with hepatocellular carcinoma. Moreover, tumors with reduced miR-26 expression had a distinct transcriptomic pattern, and analyses of gene networks revealed that activation of signaling pathways between nuclear factor kappaB and interleukin-6 might play a role in tumor development. Patients whose tumors had low miR-26 expression had shorter overall survival but a better response to interferon therapy than did patients whose tumors had high expression of the microRNA. CONCLUSIONS: The expression patterns of microRNAs in liver tissue differ between men and women with hepatocellular carcinoma. The miR-26 expression status of such patients is associated with survival and response to adjuvant therapy with interferon alfa.

Identifiers

DOI: 10.1056/nejmoa0901282

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