Department of Pathology, Tohoku University Graduate School of Medicine 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan.
Cancer Med. 2013 Jun;2(3):305-15. doi: 10.1002/cam4.85. Epub 2013 Apr 30.
Estrogens play important roles in the cell proliferation and invasion of estrogen-dependent human neoplasms. Aromatase overexpression has been also reported in hepatitis and hepatocellular carcinoma (HCC) compared with normal liver but its details in these hepatic disorders have remained unclear. Therefore, in this study, we first immunolocalized aromatase using immunohistochemistry in patients with liver cirrhosis, steatosis, hepatitis, HCC, and metastasis liver carcinoma (MLC) in order to study the detailed status of intrahepatic aromatase. Aromatase immunoreactivity was predominantly detected in nonneoplastic hepatocytes around tumor cells. We then evaluated the effects of an interaction between hepatocytes and carcinoma cells upon aromatase mRNA expression, using HepG2 as a substitute model of hepatocytes by coculture systems. Aromatase mRNA levels in HepG2 were significantly increased by coculture with all carcinoma cell lines examined. We also evaluated alternative splicing of aromatase exon 1 but the same splicing variant was used in HepG2 cells regardless of carcinoma cell lines employed in the coculture system. These findings obtained in HepG2 indicated that carcinoma cells, whether metastatic or primary, induced aromatase expression in adjacent normal hepatocytes possibly through the soluble aromatase inducible factors in human hepatic microenvironments.
雌激素在雌激素依赖性人类肿瘤的细胞增殖和侵袭中发挥重要作用。与正常肝脏相比，芳香化酶在肝炎和肝细胞癌（HCC）中也有过表达的报道，但这些肝脏疾病中的细节仍不清楚。因此，在这项研究中，我们首先使用免疫组织化学方法在肝硬化、脂肪变性、肝炎、HCC 和转移性肝癌（MLC）患者中对芳香酶进行免疫定位，以研究肝内芳香酶的详细情况。芳香酶免疫反应性主要在肿瘤细胞周围的非肿瘤性肝细胞中检测到。然后，我们通过共培养系统，使用 HepG2 作为肝细胞的替代模型，评估了肝细胞和癌细胞之间相互作用对芳香酶 mRNA 表达的影响。HepG2 与所有检查的癌细胞系共培养后，芳香酶 mRNA 水平显著增加。我们还评估了芳香酶外显子 1 的选择性剪接，但共培养系统中使用的癌细胞系对 HepG2 细胞使用相同的剪接变体。HepG2 中获得的这些发现表明，癌 细胞，无论是转移性还是原发性的，可能通过人类肝微环境中的可溶性芳香酶诱导因子，诱导邻近正常肝细胞中的芳香酶表达。
