Researchers Identify MicroRNA That Predicts Interferon Therapy Response and Prognosis in Liver Cancer Patients
November 4, 2009
The aberrant expression of several microRNA (miRNA) molecules, which play a crucial role in the regulation of gene expression, has been associated with hepatocarcinogenesis. Now, researchers at the National Cancer Institute, in collaboration with Fudan University, University of Hong Kong, and Ohio State University, have identified a miRNA molecule that could help predict the survival of patients with hepatocellular carcinoma (HCC), and also their response to interferon alpha adjuvant treatment, post-surgery. The findings of the study are published in the recent issue of The New England Journal of Medicine.
Xin Wei Wang, Senior Investigator and Head of Liver Carcinogenesis Section, National Cancer Institute, USA, and co-workers, conducted the study to analyze the expression profile of microRNAs, survival and response to alpha interferon therapy in 455 patients (from 3 independent cohorts) who underwent radical tumor resection during 1999-2003. The researchers performed miRNA-expression profiling to probe tumor-related microRNAs, and studied their association with the survival of male and female HCC patients in one of the cohorts involving 241 patients. Further, the microRNAs investigated in the previous step were quantified, and their association with the survival and response to interferon therapy was evaluated using quantitative reverse transcriptase polymerase chain reaction (RT-PCR) assays in 214 patients from two other cohorts. These patients had earlier participated in independent, randomized, controlled trials that examined adjuvant interferon therapy along with other conventional therapies following surgery.
The expression levels of miR-26a and miR-26b microRNAs were found to be higher in non-tumor liver tissues of female HCC patients compared to male HCC patients. It was also noted that the expression of miR-26 was lower in tumors than in paired non-cancerous tissues, suggesting the association of miR-26 levels with HCC. Patients with reduced miR-26 expression in their tumors had poor overall survival but showed a better response to interferon therapy in comparison to patients whose tumors expressed higher levels of the miRNA. It was also observed that tumors with lower miR-26 expression exhibited a unique transcriptomic pattern. Further analyses showed that the activation of signaling pathways between interleukin-6 and nuclear factor kappaB may play a role in tumor development. The findings suggest that microRNAs expression vary between male and female HCC patients, and the expression pattern of miR-26 is associated with survival as well as its response to interferon alpha therapy in HCC patients.
Hepatocellular tumors could exhibit distinct miRNA expressions depending on risk factors, malignancy, and oncogene or tumor suppressor gene variations. Further understanding of these associations may help in analyzing the impact of deregulation of miRNAs in liver cancer, and the role of these miRNAs as diagnostic biomarkers. An earlier study by Ladeiro et al (Hepatology, 2008) reported over expression of miR-224 in all tumors, miR-96 in hepatitis B virus (HBV) tumors. They also noted down regulation of microRNAs such as miR-126 in alcohol-related hepatocellular carcinoma, and miR-107 and miR-375 associated with HNF1 alpha and beta-catenin gene mutations, respectively.
According to the American Cancer Society (ACS) statistics, over 500,000 people globally are diagnosed with liver cancer every year, with an overall five-year survival rate of <10%. The incidence of the disease is higher in men than in women. Therapeutic options are limited, and are available exclusively for patients with an early stage HCC, as the signs and symptoms usually appear in later stages of the disease. Conventional chemotherapy during advanced stages is marginally effective or may be toxic. Although surgery is effective, only a small percentage (10-20%) of patients are eligible for the option, with the relapse rate being high.
The current findings, demonstrating lower miR-26 expression levels in liver tumors, could aid physicians in determining the prognosis of HCC patients, and selecting patients who would benefit from post-operative interferon therapy, in order to thwart the disease relapse.
References
1. Ji J, Shi J, Budhu A, et al. MicroRNA expression, survival, and response to interferon in liver cancer. N Engl J Med. 2009 Oct 8;361(15):1437-47.
2. Short Strand of RNA May Help Predict Survival and Response to Treatment for Patients with Liver Cancer. Press Release. NIH. Last accessed Oct 20, 2009.
3. Ladeiro Y, Couchy G, Balabaud C, et al. MicroRNA profiling in hepatocellular tumors is associated with clinical features and oncogene/tumor suppressor gene mutations. Hepatology. 2008 Jun;47(6):1955-63.
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