Ogawa Masahiro, Masuzaki Ryota, Kanda Tatsuo, Matsumura Hiroshi, Nakamura Hitomi, Yamazaki Motomi, Shibata Toshikatu, Kogure Hirofumi, Moriyama Mitsuhiko
Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-Kamimachi, Itabashi-ku, Tokyo 173-8610, Japan.
Sashiogi Recuperation Hospital, 1348-1 Hourai, Nishi-ku, Saitama, 331-0074, Japan.
J Clin Biochem Nutr. 2023 Sep;73(2):138-144. doi: 10.3164/jcbn.13-16. Epub 2023 Sep 1.
We have reported that extent of proliferation of atypical hepatocytes (POAH) in non-cancerous liver in hepatocellular carcinoma and chromatin licensing and DNA replication factor 1 (CDT1) are associated with postoperative recurrence. Here, we investigated whether extent of POAH and expression of CDT1 in liver are also associated with chemically induced liver cancer in rats. Male Fisher strain rats were orally administered diethylnitrosamine (DEN) in their drinking water and sacrificed at 6, 8, 12, or 14 weeks after start of DEN administration. We serially monitored changes in extent of POAH, CDT1 expression by immunohistochemistry (IHC), and mRNA expression in liver by real-time quantitative PCR. The extent of POAH in liver progressed in a time-dependent manner after start of DEN administration. CDT1 expression was higher at 8 weeks than at 6 weeks by IHC, suggesting that CDT1 expression may be a marker of POAH severity. mRNA expression in liver was significantly higher at 12 weeks than at 6 weeks (<0.0001). We found that extent of POAH and the expression of CDT1 are also important factors in the development of chemical carcinogen-induced hepatocarcinogenesis. Furthermore, the association with POAH and CDT1 expression in carcinogenic process is important regardless of the cause of hepatocarcinogenesis.
我们曾报道，在肝细胞癌患者的非癌性肝脏中，非典型肝细胞的增殖程度（POAH）以及染色质许可和DNA复制因子1（CDT1）与术后复发相关。在此，我们研究了肝脏中POAH的程度和CDT1的表达是否也与大鼠化学诱导的肝癌有关。雄性Fisher品系大鼠通过饮用含二乙基亚硝胺（DEN）的水进行口服给药，并在开始给予DEN后的第6、8、12或14周处死。我们通过免疫组织化学（IHC）连续监测POAH程度、CDT1表达的变化，并通过实时定量PCR监测肝脏中的mRNA表达。在开始给予DEN后，肝脏中POAH的程度呈时间依赖性进展。通过IHC检测，CDT1在第8周的表达高于第6周，这表明CDT1表达可能是POAH严重程度的一个标志物。肝脏中的mRNA表达在第12周时显著高于第6周（<0.0001）。我们发现，POAH的程度和CDT1的表达也是化学致癌物诱导肝癌发生发展的重要因素。此外，无论肝癌发生的原因如何，在致癌过程中POAH与CDT1表达之间的关联都很重要。
