Harada K, Zen Y, Kanemori Y, Chen T C, Chen M F, Yeh T S, Jan Y Y, Masuda S, Nimura Y, Takasawa S, Okamoto H, Nakanuma Y
Department of Pathology (II), Kanazawa University School of Medicine, Kanazawa, Japan.
Hepatology. 2001 May;33(5):1036-42. doi: 10.1053/jhep.2001.24168.
The Reg I gene (regenerating gene) and its product (Reg protein) are a regenerating and/or proliferating factor(s) of pancreatic islet cells. The ectopic expression of REG Ialpha was shown in colorectal carcinomas, suggesting that REG Ialpha is related to their carcinogenesis. In this study, we examined the expression of REG I in intrahepatic cholangiocarcinoma (ICC) and its precursor lesion (biliary dysplasia). By polymerase chain reaction and in situ hybridization (ISH) studies using a total of 16 fresh liver specimens, REG Ialpha mRNA was demonstrated in 6 of 11 (55%) ICC cases, but in 0 of 5 (0%) normal livers. Immunohistochemistry for REG I protein was performed in 100 formalin-fixed, paraffin-embedded sections obtained from the 18 cases of ICC alone, 45 hepatolithiasis with ICC (n = 19) or biliary dysplasia (n = 26), 21 hepatolithiasis alone (all with hyperplasia), and 16 normal livers. In ICC, the expression of REG I protein was significantly dependent on the histologic differentiation; 12 of 13 (92%) cases in papillary and well-differentiated, 6 of 16 (38%) cases in moderately differentiated, and 0 of 8 (0%) cases in poorly differentiated types. Moreover, in the lesions of hyperplasia, low-grade dysplasia, and high-grade dysplasia in hepatolithiasis, REG I protein was expressed in 4 of 21 (19%), 7 of 12 (58%), and 13 of 14 (93%) cases, respectively. In normal liver, intrahepatic bile ducts were constantly negative for REG I protein. These findings suggest that neoexpression of REG I is a good marker for biliary mucosa at risk for development of ICC, and also that REG I plays a role in the early stages of biliary carcinogenesis, probably via a cell-proliferative effect.
Reg I基因（再生基因）及其产物（Reg蛋白）是胰岛细胞的再生和/或增殖因子。REG Iα在结直肠癌中呈异位表达，提示REG Iα与结直肠癌的发生有关。在本研究中，我们检测了REG I在肝内胆管癌（ICC）及其前驱病变（胆管发育异常）中的表达。通过聚合酶链反应和原位杂交（ISH）研究，使用总共16份新鲜肝脏标本，在11例ICC病例中的6例（55%）检测到REG Iα mRNA，但在5例正常肝脏中均未检测到（0%）。对仅来自18例ICC、45例合并ICC（n = 19）或胆管发育异常（n = 26）的肝内胆管结石、21例单纯肝内胆管结石（均伴有增生）以及16例正常肝脏的100份福尔马林固定、石蜡包埋切片进行REG I蛋白的免疫组织化学检测。在ICC中，REG I蛋白的表达显著依赖于组织学分化；乳头状和高分化类型的13例病例中有12例（92%）、中分化类型的16例病例中有6例（38%）、低分化类型的8例病例中无1例（0%）表达。此外，在肝内胆管结石的增生、低级别发育异常和高级别发育异常病变中，REG I蛋白分别在21例中的4例（19%）、12例中的7例（58%）和14例中的13例（93%）表达。在正常肝脏中，肝内胆管REG I蛋白始终呈阴性。这些发现提示REG I的新表达是胆管黏膜发生ICC风险的良好标志物，并且REG I可能通过细胞增殖作用在胆管癌发生的早期阶段发挥作用。
