Non-nuclear activation of Signal transducer and activator of transcription 3 by 17β- estradiol in endometrial cancer cells

Abstract

Why estrogen hyperstimulation can lead to endometrial carcinogenesis has not been fully clear yet. Non-nuclear action of estrogen has arised much attention of many experts. Signal transducer and activator of transcription 3 is a very important signal molecule, which plays vital role in endometrial canver. The present study is oriented to the problem whether estrogen can activate STAT3 by non-nuclear action in endometrial cancer cells. So, the levels of phosphorylated STAT3 (P-STAT3) and total STAT3 were examined by western blot in endometrial cancer cells including Ishikawa with rich-expressed estrogen receptor (ER) and HEC-1A with poor-expressed ER after stimulation with 1μM estradiol (E2) at different time points and at varied doses of E2 for optimal time. Inhibitory role of AG490 on activation of STAT3 induced by E2 was also tested. P-STAT3/ STAT3 was used as a measure of activation of STAT3. We found that maximum P-STAT3/STAT3 took place at 15min in both Ishikawa cells and HEC-1A cells. The activation of STAT3 elicited gradually with increasing doses of E2. AG490 stopped the activating STAT3 in the same dose-dependent manner in both endometrial cancer cells. The results demonstrate that E2 is able to activate STAT3 in both Ishikawa with rich-expressed ER and HEC-1A with poor-expressed ER endometrial cancer cells by non-nuclear action, which provides the preliminary laboratory basis for the probability of endometrial adenocarcinoma treatment with blockage of STAT3 signaling, especially for ER-poor endometrial adenocarcinoma. Key words: endometrial cancer, signal transducer and activator of transcription 3, estrogen, non-nuclear action, carcinogenesis, estrogen receptorEndometrial carcinoma is one of the most common female genital tract malignancies. It is well-known that risk for endometrial adenocarcinoma increases in patients with high estrogen levels that are unopposed by progestins. Estrogen has been shown to exhibit growth-promoting properties in endometrial cancer cell [1]. The mechanism responsible for this promoting growth effect of estrogen involves 'classical' or 'genomic' mechanism, estrogen molecules penetrate into the cell and bind to the ER, which are members of the nuclear hormone receptors, and interact with the estrogen response element located in the regulatory region of target genes. The resulting fluctuations in mRNAs and the proteins they encode underlie series of responses that take place within hours following estrogen exposure. But the 'genomic' mechanism can't explain the truth that why some ER-positive endometrial carcinomas have no responses to endocrinal therapy while some ER-negative ones have responses. There must be other mechanisms involved. Indeed, there are rapid biochemical and physiological responses to estrogen occurring more rapidly (within seconds to minutes) than gene transcription events attributed to the ER (over the course of several hours) that cannot be accounted for by changes in gene expression mediated by nuclear ER. Our former data demonstrated that 17β-estradi...

Expression of STAT family and its potency to prognosis in uterine corpus endometrial carcinoma

“…According to the reports, in UCEC, abnormal STAT1 acted as an oncogene driver positively correlated with tumor progression such as tumorigenicity, proliferation, anchorage-independent growth and invasion (Kharma et al 2014), and could enhance platinum-resistance to induce poor clinical outcome (Zeng et al 2019). Aberrant-activation of STAT3 in UCEC was able to enhance the UCEC cells proliferation, anchorage-independent and xenograft growth ability, and promoted EMT ability (Chen et al 2007;Chu et al 2018;Guo et al 2011;Tang et al 2010). Nevertheless, an overall analysis of the correlation between the expression of STATs and prognosis in UCEC has not been manipulated yet, much less the distinct STAT factor function and the underlying mechanism.…”

“…Though, the upon regulatory mechanism is not distinctly assessed in this report and needs to be further clari ed.STAT3 has been deliberated among the STAT family in UCEC. Prior studies found it was activated and demonstrated an oncogenic role (mediates oncogenicity) in UCEC(Chen et al 2007;Chu et al 2018;Guo et al 2011;Tang et al 2010). Whereas, STAT3 indicated a down-regulated expression in our study which was controversial with previous studies.…”