ERa suppresses liver cancer EMT and amoeboid movement by targeting Ga12

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Several reports demonstrate the association of certain cancer progression and estrogen receptor alpha (ERa) expression. Due to poor prognosis and high relapse, hepatocellular carcinoma (HCC) is the second most common cancer worldwide. Moreover, aggressiveness and mortality of HCC is more frequent in men than women. Ga12 gep oncogene plays a critical role in promoting epithelial‐mesenchymal transition (EMT), a well‐established mechanism for tumor invasion. We previously showed that Ga12 is overly expressed in HCC patients. Here, we report an inverse correlation of ERa and Ga12 expression in HCC, which may contribute to the cancer metastasis and patient mortality. ERa transcriptionally inhibited Ga12 expression in a cancer cell model. In addition, tumor cells can take another modes of movement, characterized as amoeboid movement. Both EMT and amoeboid movement are necessary for an efficient metastasis of cancer cell. Since ROCK is one of the main downstream molecules of the Ga12 pathway and is known to activate amoeboid motility, we hypothesized whether ERa may affect amoeboid phenotype by modulating Ga12 signaling pathway, and found that ERa activation inhibited amoeboidal cell migration/invasion in conjunction with Ga12 repression. Moreover, we found microRNA‐141 and ‐200a as functional molecules affected downstream from the ERa‐Ga12 pathway, and their targeting of PTP4A1. Together, our results show that the ERa‐Ga12 pathway may play a role in targeting EMT and amoeboid movement plasticity of liver cancer, which may account for the gender disparity in HCC incidence and malignant progression.Support or Funding InformationThis work was financially supported by the Bio & Medical Technology Development Program of the NRF funded by the Korean government, MSIP (2015M3A9B6074045).