You Hui, Meng Kun, Wang Zhao-Yi
Beijing Shenogen Biomedical Co., Ltd, Beijing, PR China.
Beijing Shenogen Biomedical Co., Ltd, Beijing, PR China.
Steroids. 2018 Jun;134:78-87. doi: 10.1016/j.steroids.2018.02.007. Epub 2018 Feb 23.
Hepatocellular carcinoma (HCC) is the common primary liver cancer and the third leading cause of cancer related mortality worldwide. It is generally thought that the estrogen-signaling pathway is not related to the development and progression of human HCC. However, accumulating evidences indicate the existence of a rapid estrogen signaling in HCC cells that is able to promote cell growth. However, the receptor that mediates the rapid estrogen signaling in HCC cells has not been established. Previously, our laboratory identified a variant of ER-α, ER-α36, and found that ER-α36 mediates the rapid estrogen signaling such as the activation of the MAPK/ERK signaling in breast carcinoma cells. Our current experiments studied the role of the rapid estrogen signaling mediated by ER-α36 in growth of HCC HepG2 and PLC/PRF/5 cells that highly express ER-α36 and found these cells were strongly responsive to the rapid estrogen signaling. Knockdown of ER-α36 expression in these HCC cells using the shRNA method attenuated their responsiveness to estrogen and destabilized EGFR protein. ER-α36 mediated estrogen-induced phosphorylation of Src and the MAPK/ERK as well as cyclin D1 expression. In addition, there existed an ER-α36/EGFR positive regulatory loop in HCC cells that was important for the maintenance and positive regulation of HCC tumorsphere cells. Our results thus indicated that the rapid estrogen receptor is mediated by ER-α36 in HCC cells through the EGFR/Src/ERK signaling pathway and suggested that the ER-α36/EGFR signaling loop is a potential target to develop novel therapeutic approaches for HCC treatment.
肝细胞癌（HCC）是常见的原发性肝癌，也是全球癌症相关死亡的第三大主要原因。一般认为，雌激素信号通路与人类HCC的发生和发展无关。然而，越来越多的证据表明，HCC细胞中存在一种能够促进细胞生长的快速雌激素信号。然而，介导HCC细胞中快速雌激素信号的受体尚未明确。此前，我们实验室鉴定出一种雌激素受体α（ER-α）的变体，即ER-α36，并发现ER-α36介导快速雌激素信号，如在乳腺癌细胞中激活丝裂原活化蛋白激酶/细胞外信号调节激酶（MAPK/ERK）信号。我们目前的实验研究了由ER-α36介导的快速雌激素信号在高表达ER-α36的HCC HepG2和PLC/PRF/5细胞生长中的作用，发现这些细胞对快速雌激素信号有强烈反应。使用短发夹RNA（shRNA）方法敲低这些HCC细胞中ER-α36的表达，减弱了它们对雌激素的反应，并使表皮生长因子受体（EGFR）蛋白不稳定。ER-α36介导雌激素诱导的Src和MAPK/ERK磷酸化以及细胞周期蛋白D1的表达。此外，HCC细胞中存在一个ER-α36/EGFR正调控环，这对HCC肿瘤球细胞的维持和正调控很重要。因此，我们的结果表明，HCC细胞中快速雌激素受体由ER-α36通过EGFR/Src/ERK信号通路介导，并提示ER-α36/EGFR信号环是开发HCC治疗新方法的潜在靶点。
