Estrogen receptor alpha inhibits mesenchymal and amoeboidal movement of
liver cancer cell via G protein subunit alpha 12
Abstract
Background and Purpose Hepatocellular carcinoma (HCC) is the second most
common cancer worldwide, demonstrating aggressiveness and mortality more
frequently in men than in women. Despite reports regarding the
inhibitory ability of estrogen receptor alpha (ERα, ESR1) in certain
cancer progression, targets and the basis of underlying gender disparity
in HCC worsening remain elusive. Experimental Approach Human HCC samples
were used for immunoblottings and immunohistochemistry. Estradiol (E2)
was treated to HCC cell lines and were evaluated by immunoblottings,
polymerase chain reaction, immunofluorescence, and live imaging. Key
Results Here, we report the ability of ERα to transcriptionally inhibit
G protein subunit alpha 12 (Gα12). First, using human samples and public
database, the expression of ERα and Gα12 in HCC was examined. Then,
quantitative real-time PCR, chromatin immunoprecipitation-assay,
luciferase assay, and immunoblottings confirmed the inhibitory ability
of ERα on Gα12 and EMT. Additionally, we found microRNA-141 and -200a as
downstream targets of the Gα12 signaling axis for cancer malignancy
regulation under the control of ERα. As for in-depth mechanism, PTP4A1
was found to be directly inhibited by microRNA-141 and -200a. Gα12 and
PTP4A1 promoted epithelial-mesenchymal transition, as well as
mesenchymal to amoeboidal transition, antagonized by ERα modulations.
Conclusion and Implications The identified targets and ESR1 levels
inversely correlated in human specimens, as well as with sex-biased
survival rates of HCC patients. Collectively, ERα-dependent repression
of Gα12 and consequent changes in the Gα12 signaling may explain the
gender disparity in HCC, providing pharmacological clues for the control
of metastatic HCC.