Different molecular pathways determining extrahepatic and intrahepatic recurrences of hepatocellular carcinoma

Recent genome-wide screens have identified genes associated with the metastatic potential of hepatocellular carcinoma (HCC); however, there is little overlap between the identified genes, and interpretations of the results remain controversial. These inconsistencies may be related to differences in the sample populations, use of distinct microarray platforms and algorithms, and the complicated modes of HCC recurrence. We investigated the gene expression profiles of extrahepatic recurrence (EHR) and early intrahepatic recurrence (IHR), which are two representative modes of recurrence of HCC attributable to metastasis. We used DNA microarray analysis and identified 46 signature genes for EHR in 35 HCCs in a supervised learning manner. The obtained gene expression profile was compared with that for early IHR that was determined previously in the same manner. The 46 signature genes for EHR included many cell adhesion-related genes (ITGA6, SPP1, DNMBP, CD44 and POSTN), which all showed higher expression in HCC with EHR than in HCC without EHR. The 46 signature genes for early IHR included 10 immune response-related genes, which all showed lower expression in HCC with early IHR than in HCC without early IHR. The signature genes for EHR included only two immune response-related genes (P=0.013). These results suggest that alteration of the cell adhesion system plays a central role in EHR and that reduction of the immune response is a specific step in early IHR. These results indicate that the metastatic processes in EHR and early IHR involve different molecular pathways.