| [Background] Metastasis, the main cause of death and postoperative recurrence for most patients with hepatocellular carcinoma (HCC), remains one of the most important but least understood aspects of HCC. Recently, a structurally distinct family of membrane glycoproteins including MRP1/CD9, CD37, CD53, ME491/CD63 and KAI1/CD82, has been called transmembrane 4 superfamily (TM4SF). All its members-now numbering more than 18-have four transmembrane domains and a large extracellular N-glycosylated domain. Although the precise biological functions of TM4SF are still unknown, a substantial body of evidence has shown that TM4SF members are involved in regulating cell adhesion ,motility, and proliferation, all of which are important in tumor invasion and metastasis. Three members of the TM4SF, KAI1/CD82, MRP1/CD9 and ME491/CD63, have been reported to be associated with the metastatic potential of some tumors, including prostate cancer, breast cancer and malignant melanoma. However, it is not known whether expression of KAI1/CD82, MRP1/CD9 and ME491/CD63 may predict the metastatic potential of HCC cells in viva.[Objective] To investigate the relationship between expression of KAI1/CD82, MRP1/CD9 and ME491/CD63 and invasion and metastasis in human hepatocellular carcinoma (HCC).[Methods] A tissue microarray of specimens from 167 hepatocellular carcinomas with neighboring nonumor liver tissues, 29 cancer thrombi, 4 intrhepatic satellite metastases, 17 extrahepatic metastases, and 6 normal livers was constructed , and then the expression levels of KAT1/CD82, MRP1/CD9 and ME491/CD63 proteins in these samples were detected by immunohistochemistry. In addition, a multiplex reverse transcriptase olymerase chain reaction method wasdeveloped to measure, in a single reaction, the relative levels of gene expression using a simultaneously amplified sequence of 13ctin mRNA as an internal control for the target sequences of KAIl/CD82, MRP1/CD9 and ME491/CD63 mRNA in 18 hepatocellular carcinomas and corresponding nonumor livers. Finally, whether expression levels of KAI1/CD82, MRP1/CD9 and ME491/CD63 are associated with specific clinicopathologic characteristics of HCC patients was determined.[Results] 1) The expression levels of KAI1/CD82, MRP1/CD9 and ME491/CD63 proteins in neighboring nonumor livers were higher than those in HCCs (100%vs6l. 29% , 99. 35%vs26. 97% , and 78. 85%vs55. 77%, respectively; P (0.01). 2) Ninetyive (61.29%) HCCs were positive for KAI1/CD82 protein whereas only 7 (31.82%) cancer thrombi positive for KAI1/CD82 protein (JkO.O5). In four patients, both the primary tumors and corresponding intrahepatic metastases were negative for the detection of KAI1/CD82 protein. KAI1/CD82 protein expression was inversely correlated with the formation of cancer thrombus (P(0.0l), intrahepatic metastasis (P <0.01), and extrahepatic metastasis (P 0.038). There was also a significant correlation between KAI1/CD82 protein expression and the status of capsule (P <0.05), the tumor size (<5cm vs 5cm,P<0.0l), the degree of differentiation (P<0.01), the histological pattern (P <0.01), and the serum level of AFP ≥400μg/L vs <400μ/L, P =0.036). In addition, the expression level of KAI1/CD82 mRNA in HCCs was inversely related to the formation of cancer thrombus (0.997±0.384vs0.659±0.217 , P<0.05). 3) The expression of MRP1/CD9 protein was higher in HCCs without cancer thrombi than in those with cancer thrombi (40.48%vs2l.82%, P<0.05). MRP1/CD9 protein expression was also inversely correlated with the tumor size (10cm vs >10cm, P <0.01), the degree of differentiation (P=0.043), and the serum level of AFP ≤20μg/L vs >20μg/L, P 0.029). 4) MRP1/CD9 mRNA expression was higher in HCCs without cancer thrombi than in those with cancer thrombi (0.855±0.201vs0.452±0.250, P <0.01). Moreover, the expression level of MRP1/CD9 mRNA was inversely correlated with intrahepatic metastase (0. 665±0. 291vsO. 31±0. 128 , P<0. 05). 5) The expressionlevels of ME491/CD63 protein in cancer thrombi and extrahepatic metastas...
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