Hällström I P, Gustafsson J A, Blanck A
Department of Medical Nutrition, Karolinska Institute, Stockholm, Sweden.
Mol Carcinog. 1991;4(5):376-81. doi: 10.1002/mc.2940040509.
In this study, we extended the previous observations of a growth hormone-regulated sex difference in hepatic c-myc expression in the resistant hepatocyte model during the selection/promotion phase, when sex differences in growth rate of enzyme-altered foci are first identified, to studies of the regulation of this gene during later stages of hepatocarcinogenesis. The expression of the c-myc gene was studied in preneoplastic nodules, hepatocellular carcinomas, and the corresponding surrounding livers of male and female Wistar rats treated according to the resistant hepatocyte model. In males, nodules isolated 8 and 11-12 mo after initiation and hepatocellular carcinomas exhibited a 2.5- to threefold higher c-myc expression than the surrounding liver. In females, no increase in c-myc expression was observed in nodules 8 mo after initiation, while nodules isolated after 11-14 mo and tumors showed a twofold and threefold increase, respectively, when compared with the surrounding tissue. Increased transcription of the c-myc gene was observed in nuclei from male nodules isolated 11 mo after initiation compared with nuclei from the surrounding liver. The difference in transcription between male nodules and surrounding tissue is similar for the first and second exon of the gene. Continuous infusion of growth hormone to nodule-bearing male rats 8 and 11 mo after initiation decreased c-myc expression in the surrounding tissue and downregulated the expression in 8-mo nodules to the level in the surrounding liver. No significant decrease in response to growth hormone treatment was seen in 11-mo nodules. In hypophysectomized nodule-bearing males, nodular c-myc remained upregulated. Taken together, the data showed that the sex difference in c-myc expression was maintained during a large part of the progression period. Furthermore, the loss of growth hormone regulation of the c-myc gene in advanced male nodules indicated an escape from normal regulatory mechanisms during progression. These findings might reflect a role for the c-myc gene in sex-differentiated rat liver carcinogenesis.
在本研究中，我们将之前在抗性肝细胞模型的选择/促进阶段对生长激素调节的肝脏c-myc表达性别差异的观察结果（此时首次发现酶改变灶生长速率的性别差异）扩展到肝癌发生后期该基因调控的研究。根据抗性肝细胞模型处理的雄性和雌性Wistar大鼠的癌前结节、肝细胞癌及相应的周围肝脏组织中，研究了c-myc基因的表达。在雄性大鼠中，启动后8个月以及11 - 12个月分离出的结节和肝细胞癌中，c-myc表达比周围肝脏高2.5至3倍。在雌性大鼠中，启动后8个月的结节中未观察到c-myc表达增加，而11 - 14个月后分离出的结节和肿瘤与周围组织相比，分别增加了2倍和3倍。与周围肝脏细胞核相比，启动后11个月分离出的雄性结节细胞核中观察到c-myc基因转录增加。该基因的第一和第二外显子在雄性结节和周围组织之间的转录差异相似。启动后8个月和11个月，对携带结节的雄性大鼠持续输注生长激素可降低周围组织中的c-myc表达，并将8个月结节中的表达下调至周围肝脏的水平。11个月的结节对生长激素治疗未观察到明显的降低反应。在垂体切除的携带结节的雄性大鼠中，结节中的c-myc仍上调。综上所述，数据表明c-myc表达的性别差异在进展期的大部分时间内得以维持。此外，晚期雄性结节中c-myc基因生长激素调节的丧失表明在进展过程中逃脱了正常调节机制。这些发现可能反映了c-myc基因在性别分化的大鼠肝癌发生中的作用。
