Liver Cancer Institute and Zhongshan Hospital, Institutes of Biomedical Sciences, Fudan University, 180 Feng Lin Road, 200032, Shanghai, People's Republic of China.
J Cancer Res Clin Oncol. 2010 Apr;136(4):595-601. doi: 10.1007/s00432-009-0695-0. Epub 2009 Oct 16.
We have demonstrated that overexpression of osteopontin (OPN) could contribute to metastasis in hepatocellular carcinoma (HCC), and that OPN-positive cancer cells are often localized in the periphery of cancer nodules adjacent to stromal cells. This study was to identify the difference of intratumor genomic aberrations between OPN-positive and OPN-negative HCC cells.
Immunohistochemical staining for OPN was performed in both archival and fresh HCC tumor tissues. Seven cases of OPN-positive HCC were chosen for laser capture microdissection. The OPN-positive and OPN-negative cancer cells were captured separately from serial frozen sections. Genomic DNA was extracted and quantified. Microarray-based comparative genomic hybridization (array-CGH) was used to achieve high-resolution analysis of whole-genome-wide aberrations.
The OPN expression level in HCC tissues was significantly associated with vascular or bile duct invasion (P = 0.003), Edmondson's grade (P = 0.047), and intrahepatic spreading (P = 0.011). When compared with the OPN-negative cancer cells, much more amplifications of chromosomal regions, including 4q13.1-q13.3, 4q21.23-q22.1, and 13q32.1-q32.3, were found in OPN-positive HCC cells. Some candidate tumor-related genes, such as SMR3B, MUC7, EPHA5, SPP1, and CLDN10 were detected with over 1.5-fold amplification.
There is a significant intratumor genomic heterogeneity between the OPN-positive and negative HCC cells, and OPN-positive HCC cells play a more important role in the development of HCC malignancy than their OPN-negative counterparts.
我们已经证明，骨桥蛋白（OPN）的过度表达可能导致肝细胞癌（HCC）的转移，并且 OPN 阳性的癌细胞通常位于毗邻基质细胞的癌结节的外围。本研究旨在确定 OPN 阳性和 OPN 阴性 HCC 细胞之间肿瘤内基因组畸变的差异。
对存档和新鲜 HCC 肿瘤组织进行 OPN 的免疫组织化学染色。选择 7 例 OPN 阳性 HCC 病例进行激光捕获微切割。从连续冷冻切片中分别捕获 OPN 阳性和 OPN 阴性的癌细胞。提取并定量基因组 DNA。使用基于微阵列的比较基因组杂交（array-CGH）实现全基因组广泛畸变的高分辨率分析。
HCC 组织中 OPN 的表达水平与血管或胆管侵犯（P = 0.003）、Edmondson 分级（P = 0.047）和肝内播散（P = 0.011）显著相关。与 OPN 阴性癌细胞相比，在 OPN 阳性 HCC 细胞中发现了更多的染色体区域扩增，包括 4q13.1-q13.3、4q21.23-q22.1 和 13q32.1-q32.3。检测到一些候选肿瘤相关基因，如 SMR3B、MUC7、EPHA5、SPP1 和 CLDN10，其扩增倍数超过 1.5 倍。
OPN 阳性和阴性 HCC 细胞之间存在显著的肿瘤内基因组异质性，并且 OPN 阳性 HCC 细胞在 HCC 恶性发展中比其 OPN 阴性对应物发挥更重要的作用。
