Identification of metastasis-related microRNAs in hepatocellular carcinoma

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...

Hsa-miR-9 methylation status is associated with cancer development and metastatic recurrence in patients with clear cell renal cell carcinoma

“…Furthermore, studies of liver (Budhu et al, 2008), breast (Iorio et al, 2005) and colorectal (Bandres et al, 2009) cancers have shown that altered hsa-miR-9 expression was associated with metastatic tumors. Our findings are that both miR-9-1 and miR-9-3 are hypermethylated, and thus silenced in tumor compared with adjacent normal, and also in the primary tumors of those who developed recurrences compared with those who did not are in agreement with the published expression data.…”

The Roles of MicroRNAs in the Cancer Invasion-Metastasis Cascade

“…The mechanism by which down-regulation of miR-148a and miR-148b promote cancer metastasis is not well known. Down-regulation of the miR-9 family (including miR-9-1, miR-9-2, and miR-9-3) also seems to be a common metastasis feature in a number of solid tumors [120,121,124]. This observation is also supported by the report that the miR-9 family is specifically hypermethylated in metastatic cancers [107].…”

“…This finding is further supported by another report that illustrates a metastatic cancer miRNA signature in 43 metastatic lymph nodes of primary tumors (including Bmi1 BMI1 polycomb ring finger oncogene; CSC cancer stem cells; Gli1 GLI family zinc finger 1; HES1 hairy and enhancer of split 1, (Drosophila); HMGA2 high mobility group A2; MSC mesenchymal stem cells; SMO smoothened homolog (Drosophila); WNT3A wingless-type MMTV integration site family, member 3A DNMT3B DNA (cytosine-5-)-methyltransferase 3 beta; EMT epithelial-mesenchymal transition; TGIFB TGFB-induced factor homeobox 2 miRNAs Regulate Cancer Metastasiscolon, bladder, breast, and lung cancers) [120]. Downregulation of miR-148a and miR-148b seems to be a common metastasis feature in HCC and pancreatic cancer [119,121]. This observation is supported by the fact that miR-148 is specifically hypermethylated in metastatic cancers [107].…”

The role and clinical implications of microRNAs in hepatocellular carcinoma

“…Although expression of miR-122 is liver specific [111], high miR-122 levels have also been found in liver metastasis samples because of inevitable contamination from adjacent liver tissues, excluding the use of miR-122 as a good diagnostic marker. Members of the miR-200 family including miR-200a, miR-200b, miR-200c, miR-141, and miR-429 are strongly expressed in primary tumors of epithelial origin in the gastrointestinal (GI) tract, but are not found in HCC.…”