High-resolution analysis of genomic profiles of hepatocellular carcinoma cells with different osteopontin expression

Abstract

Objective To characterize intratumor genomic profiles between OPN-positive and OPN-negative HCC cancer cells and evaluate the relationship between OPN expression and clinicopath-ological features. Methods OPN expression was examined immunohistochemically in 71 cases of HCC. The cytogenetic changes were analyzed by array-CGH between microdiessected OPN-positive and -negative fresh HCC tissues. Results Out of the 71 HCC samples, 29 (42.9%) showed positive staining for OPN. Dispersed OPN-positive cancer cells were localized in the periphery of cancer nod-ules adjacent to stromal cells, especially in the area with a high density of vasculature. In some cases, extensively granular staining of OPN was observed in cancer nodules. Fourteen samples (19.7%) showed OPN immunoreactivity in cirrhotic parenehyma cells. OPN expression was significantly related to histologic grade, intrahepatic spread and vascular or bile duct invasion in HCC. Compared to OPN-negative cancer cells, the OPN-positive cancer ceils showed much more regions of copy number altera-tion with amplified 4q13.1-q13.3, 4q21.23-22.1, 13q32. 1-q32.3. Some candidate tumor related genes (SMR3B, MUC7, EPHA5, SPP1, CLDN10) were detected with over 1.5-fold amplification. Conclusions OPN increases invasive ability and promotes metastatic potential of HCC cells and might mediate tumor cell proliferation and conversion to the malignant phenotype in cirrhotic parenchyma cells. Intratumor genomic heterogeneity is found between OPN-positive and -negative cancer cells. Key words: Carcinoma,hepatocellular; Osteopontin; Immunohistochemistry; Array com-parative genomic hybridizationa; Tumor heterogeneity