New research has shown that a unique pattern of microRNAs, small RNA molecules that regulate gene activity, can accurately predict whether liver cancer will spread and whether liver cancer patients will have shorter or longer survival, even patients with early stage disease. The study, which appeared online January 7, 2008 in Hepatology, was conducted by researchers at the National Cancer Institute (NCI), part of the National Institutes of Health, and colleagues at Ohio State University, Columbus, and the Liver Cancer Institute in Shanghai, China.

"The aggressive nature of hepatocellular carcinoma, a prevalent type of liver cancer, is largely due to its tendency to spread or recur after surgery," said the study's lead author, Anuradha Budhu, Ph.D., a staff scientist in the laboratory of Xin Wei Wang, Ph.D., head of the Liver Carcinogenesis Section of NCI's Center for Cancer Research (CCR). "Identifying new diagnostic and prognostic biomarkers for liver cancer is a first step in alleviating the dismal outcome of this disease."

MicroRNAs, or miRNAs, have been implicated in various aspects of human disease, including cancer. Their abundance in different tissues and cancer types indicate that miRNAs are functionally significant and have the potential to be used as cancer biomarkers. Since miRNAs can effectively regulate the activity of multiple cancer-related genes and pathways, they are prime candidates for coordinating the intricate events that lead to the spread of cancer, which is known as metastasis.

In this study, Budhu and her colleagues used miRNA microarray techniques, which allow researchers to examine the expression of thousands of genes simultaneously. They analyzed the miRNA expression profiles (showing the extent to which individual miRNAs are turned on or off) in cancerous and noncancerous liver samples from 131 patients with or without metastasis who underwent surgery at the Liver Cancer Institute and Zhongshan Hospital in Shanghai. The analysis revealed a set of 20 miRNAs with different patterns of expression in tumors with metastasis compared to tumors without metastasis. MiRNAs are capable of regulating the expression of one or more genes, including cancer-related genes, potentially affecting multiple cell functions that could lead to malignancy.

"This is an important and unique finding because it is the first study to show that miRNAs play a significant role in liver metastasis," explained Budhu. "In fact, miRNAs have not previously been related to cancer spread in any other organ."

Using the new gene expression profile, the researchers found that patients with the metastasis-miRNA profile had a two-fold higher risk of shorter survival compared to those without the profile. This latest finding in hepatocellular carcinoma, or HCC, in combination with earlier research by this team on early stage HCC and the tumor microenvironment, suggests a real potential for increasing the accuracy of liver cancer diagnosis and prognosis, as well as in monitoring recurrence.

"MiRNAs are also very stable molecules, which is an ideal property that could allow for more dependable measurements in clinical diagnostic or prognostic methods. Since miRNAs can affect multiple genes, including those related to cancer, they are also promising new targets for therapeutic approaches to liver cancer treatment," said Budhu.

HCC is the most common liver cancer diagnosed in adults and has a high prevalence in Asian and African populations. The rate of new HCC cases has been rising over the past 10 years in the United States and occurs twice as often in men as in women. HCC is a very aggressive disease; patients usually survive less than one year after diagnosis. In 2007, an estimated 19,160 Americans were newly diagnosed with liver cancer and an estimated 16,780 people died of the disease.

Budhu A, Jia H, Forgues M, Liu C, Goldstein D, Lam A, Zanetti KA, Ye Q, Qin L, Croce CM, Tang ZY, Wang, XW. Identification of Metastasis-related MicroRNAs in Hepatocellular Carcinoma HEP-07-1296. Hepatology. Online January 7, 2008. Vol. 47 No. 1.

Budhu A, Forgues M, Ye Q, Jia H, He P, Zanetti KA, Kammula US, Chen Y, Qin L, Tang Z, and Wang XW. Prediction of venous metastases, recurrence and prognosis in hepatocellular carcinoma based on a unique immune response signature of the liver microenvironment. Cancer Cell. August 2006, Vol. 10, Issue 2.

For more information about cancer, please visit the NCI Web site at http://www.cancer.gov, or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

For more information on Dr. Wang's research, go to http://ccr.cancer.gov/staff/staff.asp?profileid=5764.

For more information on Dr. Budhu's research, go to http://ccr.cancer.gov/staff/staff.asp?profileid=6709.

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