17β-Estradiol (E2) has been proven to exert protective effects against HCC; however, its mechanism on HCC proliferation and suppression of invasion remains to be further explored. Because HCC up-regulates serum Interleukin-6 (IL-6) levels and Signal Transducer and Activator of Transcription 3 (STAT3), molecular agents that attenuate IL-6/STAT3 signaling can potentially suppress HCC development. In this study, we examined involvement of E2 in anoikis resistance that induces invasion capacities and chemo-resistance. Huh-BAT and HepG2 cells grown under anchorage-independent condition were selected. The anoikis-resistant (AR) cells showed stronger chemo-resistance against sorafenib, doxorubicin, 5-fluorouracil and cisplatin compared to adherent HCC cells. AR HCC cells exhibited decreased expression of E-cadherin and increased expression of the N-cadherin and vimentin compared to adherent HCC cells. We then demonstrated that E2 suppressed cell proliferation in AR HCC cells. IL-6 treatment enhanced invasive characteristics, and E2 reversed it. Regarding mechanism of E2, it decreased in the phosphorylation of STAT3 that overexpressed on AR HCC cells. The inhibitory effect of E2 on cell growth was accompanied with cell cycle arrest at G2/M phase and caspase-3/9/PARP activation through c-Jun N-terminal Kinase (JNK) phosphorylation. Taken together, these findings suggested that E2 inhibited the proliferation of AR HCC cells through down-regulation of IL-6/STAT3 signaling. Thus, E2 can be a potential therapeutic drug for treatment of metastatic or chemo-resistant HCC.
|Original language||English (US)|
|Number of pages||8|
|Journal||Biochemical and Biophysical Research Communications|
|State||Published - May 13 2016|
Bibliographical noteFunding Information:
This study was supported by grants from the Seoul National University Hospital Research Fund (grant number: 0320140200 (2014-1290)), Yuhan Coporation (grant number: 800-20150030) and Ministry of Health and Welfare of Korea (grant number: 07-2016-1022).
All authors approve the final version of the manuscript for publication. YJK was in charge of the general supervision of the research. The order of authorship was based on a joint decision. This study was supported by grants from the Seoul National University Hospital Research Fund (grant number: 0320140200 (2014-1290) ), Yuhan Coporation (grant number: 800-20150030 ) and Ministry of Health and Welfare of Korea (grant number: 07-2016-1022 ).
- Aniokis resistance
- Drug resistance
- Hepatocellular carcinoma