Estradiol-ERβ2 signaling axis confers growth and migration of CRPC cells through TMPRSS2-ETV5 gene fusion
نویسندگان
چکیده
Estrogen receptor beta (ERβ) splice variants are implicated in prostate cancer (PC) progression; however their underlying mechanisms remain elusive. We report that non-canonical activation of estradiol (E2)-ERβ2 signaling axis primes growth, colony-forming ability and migration of the androgen receptor (AR)-null castration-resistant PC (CRPC) cells under androgen-deprived conditions (ADC). The non-classical E2-ERβ2 mediates phosphorylation and activation of Src-IGF-1R complex, which in turn triggers p65-dependent transcriptional upregulation of the androgen-regulated serine protease TMPRSS2:ETV5a/TMPRSS2:ETV5b gene fusions under ADC. siRNA silencing of TMPRSS2 and/or ETV5 suggests that TMPRSS2:ETV5 fusions facilitates the E2-ERβ induced growth and migration effects via NF-κB-dependent induction of cyclin D1 and MMP2 and MMP9 in PC-3 cells. Collectively, our results unravel the functional significance of oncogenic TMPRSS2:ETV5 fusions in mediating growth and migration of E2-ERβ2 signaling axis in CRPC cells. E2-ERβ2 signaling axis may have significant therapeutic and prognostic implications in patients with CRPC.
منابع مشابه
Inactivation of AR/TMPRSS2-ERG/Wnt signaling networks attenuates the aggressive behavior of prostate cancer cells.
The development of prostate cancer and its progression to castrate-resistant prostate cancer (CRPC) after antiandrogen ablation therapy are driven by persistent biological activity of androgen receptor (AR) signaling. Moreover, studies have shown that more than 50% of human prostate cancers overexpress ERG (v-ets avian erythroblastosis virus E26 oncogene related gene) due to AR-regulated TMPRSS...
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