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MicroRNA expression, survival, and response to interferon in liver cancer.

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.

SUBMITTER: Ji J

PROVIDER: S-EPMC2786938 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature

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MicroRNA expression, survival, and response to interferon in liver cancer.

Ji Junfang J Shi Jiong J Budhu Anuradha A Yu Zhipeng Z Forgues Marshonna M Roessler Stephanie S Ambs Stefan S Chen Yidong Y Meltzer Paul S PS Croce Carlo M CM Qin Lun-Xiu LX Man Kwan K Lo Chung-Mau CM Lee Joyce J Ng Irene O L IO Fan Jia J Tang Zhao-You ZY Sun Hui-Chuan HC Wang Xin Wei XW

The New England journal of medicine 20091001 15

<h4>Background</h4>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.<h4>Methods</h4>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 hepatoce ...[more]

PMID: 19812400

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Project description:Abnormal miRNA expression has been evidenced to be directly linked to HCC initiation and progression. This study was designed to detect possible prognostic, diagnostic, and/or therapeutic miRNAs for HCC using computational analysis of miRNAs expression. Methods: miRNA expression datasets meta-analysis was performed using the YM500v2 server to compare miRNA expression in normal and cancerous liver tissues. The most significant differentially regulated miRNAs in our study undergone target gene analysis using the mirWalk tool to obtain their validated and predicted targets. The combinatorial target prediction tool; miRror Suite was used to obtain the commonly regulated target genes. Functional enrichment analysis was performed on the resulting targets using the DAVID tool. A network was constructed based on interactions among microRNAs, their targets, and transcription factors. Hub nodes and gatekeepers were identified using network topological analysis. Further, we performed patient data survival analysis based on low and high expression of identified hubs and gatekeeper nodes, patients were stratified into low and high survival probability groups. Results: Using the meta-analysis option in the YM500v2 server, 34 miRNAs were found to be significantly differentially regulated (P-value ⩽ .05); 5 miRNAs were down-regulated while 29 were up-regulated. The validated and predicted target genes for each miRNA, as well as the combinatorially predicted targets, were obtained. DAVID enrichment analysis resulted in several important cellular functions that are directly related to the main cancer hallmarks. Among these functions are focal adhesion, cell cycle, PI3K-Akt signaling, insulin signaling, Ras and MAPK signaling pathways. Several hub genes and gatekeepers were found that could serve as potential drug targets for hepatocellular carcinoma. POU2F1 and PPARA showed a significant difference between low and high survival probabilities (P-value ⩽ .05) in HCC patients. Our study sheds light on important biomarker miRNAs for hepatocellular carcinoma along with their target genes and their regulated functions.

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MicroRNA expression, survival, and response to interferon in liver cancer.

Publications

MicroRNA expression, survival, and response to interferon in liver cancer.

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