State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, China.
Acta Biochim Biophys Sin (Shanghai). 2012 Mar;44(3):224-32. doi: 10.1093/abbs/gmr124. Epub 2012 Jan 10.
The human transmembrane 4 superfamily member 4 or intestinal and liver tetraspan membrane protein (TM4SF4/il-TMP) was originally cloned as an intestinal and liver tetraspan membrane protein and mediates density-dependent cell proliferation. The rat homolog of TM4SF4 was found to be up-regulated in regenerating liver after two-thirds hepatectomy and overexpression of TM4SF4 could enhance liver injury induced by CCl(4). However, the expression and significance of TM4SF4/il-TMP in liver cancer remain unknown. Here, we report that TM4SF4/il-TMP is frequently and significantly overexpressed in hepatocellular carcinoma (HCC). Real-time quantitative reverse transcription polymerase chain reaction (RT-PCR) and western blot analysis showed that TM4SF4/il-TMP mRNA and protein levels were up-regulated in ∼80% of HCC tissues. Immunohistochemical analysis of a 75 paired HCC tissue microarray revealed that TM4SF4/il-TMP was significantly overexpressed in HCC tissues (P< 0.001), and high immunointensity of TM4SF4/il-TMP tended to be in well-to-moderately differentiated HCC compared with poorly differentiated tumors. Functional studies showed that overexpression of TM4SF4/il-TMP in QGY-7701 and BEL-7404 HCC cell lines through stable transfection of TM4SF4 expression plasmid significantly promoted both cell growth and colony formation of HCC cells. Reduction of TM4SF4/il-TMP expression in QGY-7701 and BEL-7404 cells by stably transfecting TM4SF4 antisense plasmid caused great inhibition of cell proliferation. Our findings suggest that TM4SF4/il-TMP has the potential to be biomarker in HCC and plays a crucial role in promotion of cancer cell proliferation.
人类跨膜 4 超家族成员 4 或肠和肝四跨膜蛋白（TM4SF4/il-TMP）最初作为肠和肝四跨膜蛋白被克隆，并介导密度依赖性细胞增殖。TM4SF4 的大鼠同源物在三分之二肝切除术后的再生肝中被发现上调，并且 TM4SF4 的过表达可以增强 CCl(4)诱导的肝损伤。然而，TM4SF4/il-TMP 在肝癌中的表达和意义尚不清楚。在这里，我们报告 TM4SF4/il-TMP 在肝细胞癌（HCC）中经常且显著过表达。实时定量逆转录聚合酶链反应（RT-PCR）和 Western blot 分析显示，TM4SF4/il-TMP mRNA 和蛋白水平在约 80%的 HCC 组织中上调。对 75 对 HCC 组织微阵列的免疫组织化学分析表明，TM4SF4/il-TMP 在 HCC 组织中显著过表达（P<0.001），并且与低分化肿瘤相比，TM4SF4/il-TMP 的高免疫强度倾向于在中到高分化 HCC 中。功能研究表明，通过稳定转染 TM4SF4 表达质粒在 QGY-7701 和 BEL-7404 HCC 细胞系中过表达 TM4SF4/il-TMP 显著促进了 HCC 细胞的生长和集落形成。通过稳定转染 TM4SF4 反义质粒降低 QGY-7701 和 BEL-7404 细胞中的 TM4SF4/il-TMP 表达导致细胞增殖受到极大抑制。我们的研究结果表明，TM4SF4/il-TMP 有可能成为 HCC 的生物标志物，并在促进癌细胞增殖中发挥关键作用。
