Vielhauer V, Sarafoff M, Gais P, Rabes H M
Institute of Pathology, Ludwig-Maximilians-University Munich, Germany.
J Cancer Res Clin Oncol. 2001 Oct;127(10):591-602. doi: 10.1007/s004320100263.
To investigate the potential role of an aberrant cellular DNA repair in target cells during malignant transformation we studied cell type-specific mRNA expression of the DNA repair protein O6-alkylguanine-DNA alkyltransferase (O6-AGT) in normal and regenerating rat liver, chronic hepatitis and preneoplastic liver lesions by in situ hybridization and semiautomatic image analysis.
O6-AGT mRNA expression was found to be four to five times higher in hepatocytes than in nonparenchymal cells. A 1.9-fold increase in O6-AGT mRNA was observed after partial hepatectomy. Intraperitoneal injection of diethylnitrosamine led to a 1.3-fold and 2.6-fold rise in periportal and perivenous hepatocytes, respectively. Ethylnitrosourea produced an enhancement of mRNA levels up to 1.6-fold in hepatocytes without regional differences. In megalocytic hepatocytes of Long-Evans Cinnamon rats with chronic hepatitis, a 4.4-fold mRNA induction was found. In small preneoplastic lesions induced after chronic diethylnitrosamine-exposure, O6-AGT mRNA expression was identical to that of adjacent normal tissue. Intermediate and large lesions revealed 1.5- to 1.6-fold higher mRNA levels.
These results suggest an induction of O6-AGT mRNA expression in hepatocellular target tissue under conditions of increased carcinogen sensitivity . The O6-AGT expression in early preneoplastic lesions did not differ from normal surrounding liver tissue, thus excluding the possibility that progression of preneoplasia in rat liver is associated with a deficient mRNA expression of this DNA repair protein. On the contrary, enhanced O6-AGT mRNA expression in more advanced foci and early neoplastic nodules may confer a selective advantage upon early malignant hepatocytes with regard to further tumor progression.
为了研究在恶性转化过程中异常细胞DNA修复在靶细胞中的潜在作用，我们通过原位杂交和半自动图像分析，研究了DNA修复蛋白O6-烷基鸟嘌呤-DNA烷基转移酶（O6-AGT）在正常和再生大鼠肝脏、慢性肝炎及癌前肝损伤中的细胞类型特异性mRNA表达。
发现肝细胞中O6-AGT mRNA表达比非实质细胞高4至5倍。部分肝切除后，O6-AGT mRNA增加了1.9倍。腹腔注射二乙基亚硝胺分别导致门静脉周围和肝静脉周围肝细胞中该mRNA增加1.3倍和2.6倍。乙基亚硝基脲使肝细胞中mRNA水平提高至1.6倍，且无区域差异。在患有慢性肝炎的Long-Evans Cinnamon大鼠的巨细胞肝细胞中，发现mRNA诱导增加了4.4倍。在慢性二乙基亚硝胺暴露后诱导的小癌前病变中，O6-AGT mRNA表达与相邻正常组织相同。中等和大病变显示mRNA水平高1.5至1.6倍。
这些结果表明，在致癌物敏感性增加的情况下，肝细胞靶组织中O6-AGT mRNA表达会被诱导。早期癌前病变中的O6-AGT表达与周围正常肝组织无差异，因此排除了大鼠肝脏癌前病变进展与该DNA修复蛋白mRNA表达缺陷相关的可能性。相反，在更晚期病灶和早期肿瘤结节中增强的O6-AGT mRNA表达可能在肿瘤进一步进展方面赋予早期恶性肝细胞选择性优势。
