No abstract

MicroRNAs (miRNAs) have been used as cancer-related biomarkers. Hepatocellular carcinoma (HCC) is an aggressive cancer with a dismal outcome largely due to metastasis and postsurgical recurrence. We investigated whether the expression of certain miRNAs are associated with HCC metastasis. We examined the miRNA expression profiles of 482 cancerous and noncancerous specimens from radical resection of 241 patients with HCC. Using a supervised algorithm and a clinically well-defined cohort of 131 cases, we built a unique 20-miRNA metastasis signature that could significantly predict (P < 0.001) primary HCC tissues with venous metastases from metastasis-free solitary tumors with 10-fold crossvalidation. However, significant miRNAs could not be identified from the corresponding noncancerous hepatic tissues. A survival risk prediction analysis revealed that a majority of the metastasis-related miRNAs were associated with survival. Furthermore, the 20-miRNA tumor signature was validated in 110 additional cases as a significant independent predictor of survival (P ‫؍‬ 0.009) and was significantly associated with both survival and relapse in 89 cases of early stage HCC (P ‫؍‬ 0.022 and 0.002, respectively). These 20 miRNAs may provide a simple profiling method to assist in identifying patients with HCC who are likely to develop metastases/recurrence. In addition, functional analysis of these miRNAs may enhance our biological understanding of HCC metastasis. (HEPATOLOGY 2008;47:897-907.) H epatocellular carcinoma (HCC) represents an extremely poor prognostic cancer that remains one of the most common and aggressive human malignancies worldwide. 1,2 The dismal outcome has been attributed to the major hallmarks of HCC, intrahepatic metastases or postsurgical recurrence. New tumor colonies frequently invade into the major branches of the portal vein and possibly other parts of the liver. 3-6 Resection or liver transplantation are the best options for a potential cure; however, only about 10%-20% of patients with HCC, defined by parameters of relatively normal liver function and a manageable tumor lesion as determined by the available clinical staging systems, are currently eligible for surgical intervention. Moreover, patients who were resected often have a high frequency of metastasis/recurrence, and postoperative 5-year survival is only 30%-40%.Metastasis is a complex process that involves multiple alterations. 7,8 Our understanding of such complexity has been improved by the advent of global microarray technology which allows for the molecular profiling of changes in gene expression that are associated with particular phenotypes, such as metastasis. In fact, several arraybased metastasis markers have also been demonstrated to be useful as prognostic molecular biomarkers, potentially offering additional tools for advanced diagnosis of HCC. For example, using complementary DNA (cDNA) microarray technology, we developed a unique tumor messenger RNA (mRNA) gene expression signature to predict prognosis and metastasis in pati...