Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, No. 1 Xuefu North Road, University Town, Fuzhou, Fujian Province, 350112, China.
School of Biomedical Sciences, University of Western Australia, QE II, M Block 225C, Crawley, WA, 6009, Australia.
Biochem Biophys Res Commun. 2023 Sep 10;672:103-112. doi: 10.1016/j.bbrc.2023.06.018. Epub 2023 Jun 13.
Estrogen receptor alpha (ERα)-mediated estrogen signaling has also shown to prevent hepatic tumorigenesis in mice. Consistent with this, hormone replacement therapy with estrogen supplementation dramatically reduced the risk of hepatocellular carcinoma. Silencing of ERα is also a key event for the transformation of ERα-positive breast cancer cells into malignant triple-negative breast cancer cells. However, the mechanisms underlying ERα-mediated prevention of both hepatic and mammary tumorigenesis in humans are still unclear. Here, we present a functional genomics study of ERα targeting by comparing human liver cancer cells with human breast cancer cells using "loss or gain of function" genetic assays of ERα in vitro and in vivo. We discover that cellular communication network factor 5 (CCN5) is a direct downstream target of ERα; ERα suppresses growth and prevents tumorigenesis and malignant transformation of both liver and breast cancer cells through CCN5 in humans. The ERα-CCN5 regulatory axis functions as suppressors for both hepatic and mammary tumors, which is a common mechanism of preventing tumorigenesis for both liver cancer and breast cancer in humans.
雌激素受体 alpha（ERα）介导的雌激素信号也被证明可以预防小鼠的肝肿瘤发生。与此一致的是，雌激素补充的激素替代疗法显著降低了肝细胞癌的风险。ERα 的沉默也是 ERα 阳性乳腺癌细胞转化为恶性三阴性乳腺癌细胞的关键事件。然而，ERα 介导的人类肝肿瘤和乳腺肿瘤发生的预防机制仍不清楚。在这里，我们通过在体外和体内使用 ERα 的“丧失或获得功能”遗传测定比较人肝癌细胞和人乳腺癌细胞，对 ERα 的靶向作用进行了功能基因组学研究。我们发现细胞通讯网络因子 5（CCN5）是 ERα 的直接下游靶标；ERα 通过 CCN5 抑制生长并预防人类肝癌和乳腺癌细胞的肿瘤发生和恶性转化。ERα-CCN5 调节轴作为肝和乳腺肿瘤的抑制剂，这是人类预防肝癌和乳腺癌肿瘤发生的共同机制。
