Different molecular pathways determining extrahepatic and intrahepatic recurrences of hepatocellular carcinoma

Abstract

Abstract. 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.

Sulfatase 1 and sulfatase 2 in hepatocellular carcinoma: Associated signaling pathways, tumor phenotypes, and survival

“…POSTN had the highest positive correlation and tenth highest correlation with SULF1 in the training and validation data sets, respectively. Although the role of POSTN is not well known in HCC, one study has shown that POSTN expression was associated with extrahepatic recurrence of HCC (Iizuka et al, 2006). POSTN is known to interact with multiple cell-surface receptors and pathways to promote cancer cell survival, epithelial-mesenchymal transition (EMT), invasion, and metastasis (Ruan et al, 2009; Hong et al, 2010).…”

Circulating cell-free DNA as a predictive marker for distant metastasis of hepatitis C virus-related hepatocellular carcinoma

“…Predictive systems that are developed will enable to accurately detect patients at high risk for early IHR, but there might be many problems to solve before these markers can be applied to daily clinical practice (Iizuka et al, 2004). Thus far, there have been few reports on a predictor for EHR after surgery, although several studies have identified several key genes or gene products related to distant metastasis (Schimanski et al, 2006;Iizuka et al, 2006b). It was reported that HCC recurred in distant organs in only 3 (7%) of 42 patients who underwent liver transplantation, a radical curative treatment strategies (Nart et al, 2003).…”

The “microscopic” revolution in breast carcinoma

“…POSTN had the highest positive correlation and tenth highest correlation with SULF1 in the training and validation data sets, respectively. Although the role of POSTN is not well known in HCC, one study has shown that POSTN expression was associated with extrahepatic recurrence of HCC (Iizuka et al,2006). POSTN is known to interact with multiple cell‐surface receptors and pathways to promote cancer cell survival, epithelial‐mesenchymal transition (EMT), invasion, and metastasis (Ruan et al,2009; Hong et al,2010).…”