De Souza A T, Hankins G R, Washington M K, Fine R L, Orton T C, Jirtle R L
Department of Safety of Medicines, Zeneca Pharmaceuticals, Macclesfield, Cheshire, UK.
Oncogene. 1995 May 4;10(9):1725-9.
The mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGFIIr) is required for the activation of transforming growth factor beta, and previously we have found its expression to be significantly reduced in both rat and human hepatocellular carcinomas (HCCs). Therefore, we have postulated that loss of the M6P/IGFIIr gene may be mechanistically involved in liver carcinogenesis. Using the polymerase chain reaction, we utilized two polymorphisms in the 3' untranslated region of the M6P/IGFIIr gene to screen non-cirrhotic, hepatitis virus negative patients with hepatocellular tumors for LOH. Twenty-two of 36 (61%) patients were informative (heterozygous), and 14/22 (64%) liver tumors had LOH; 11/16 (69%) carcinomas, 1/3 (33%) fibrolamellar tumors and 2/3 (67%) adenomas. This is the first report of LOH at the M6P/IGFIIr locus in human hepatocellular tumors, and the presence of LOH in adenomas suggests that allelic loss may be an early event in the etiology of HCCs. These results support the hypothesis that the M6P/IGFIIr gene may function as a tumor suppressor gene in the liver.
甘露糖6-磷酸/胰岛素样生长因子II受体（M6P/IGFIIr）是转化生长因子β激活所必需的，我们之前发现其在大鼠和人类肝细胞癌（HCC）中的表达均显著降低。因此，我们推测M6P/IGFIIr基因的缺失可能在肝癌发生机制中起作用。我们使用聚合酶链反应，利用M6P/IGFIIr基因3'非翻译区的两个多态性来筛查非肝硬化、无肝炎病毒的肝细胞肿瘤患者的杂合性缺失（LOH）。36例患者中有22例（61%）为信息性（杂合子），14/22（64%）的肝肿瘤存在LOH；11/16（69%）为癌，1/3（33%）为纤维板层瘤，2/3（67%）为腺瘤。这是关于人类肝细胞肿瘤中M6P/IGFIIr基因座杂合性缺失的首次报道，腺瘤中存在杂合性缺失表明等位基因缺失可能是肝癌病因中的早期事件。这些结果支持了M6P/IGFIIr基因可能在肝脏中作为肿瘤抑制基因发挥作用的假说。
