Eventual proapoptotic or anti-apoptotic impact of aberrantly expressed Cx43 and Cx26 can depend on ER-alpha overexpression in human endometrioid adenocarcinoma

Abstract

Estrogen receptor (ER) and progesterone receptor (PgR) accumulations lead to impairment of gap junctional intercellular communication in endometrial cancer. The task of this study was to explore relationships of Cx26 and Cx43 with anti-apoptotic protein Bcl-xL and proapoptotic agent Bak in ER-alpha and PgR negative or variably positive endometrioid adenocarcinomas. Cx26, Cx43, Bak, Bcl-xL, PgR and ER-alpha were detected in 78 endometrioid adenocarcinomas with immunohistochemistry. There was a remarkable cellular re-distribution of Cx26 and Cx43 from normally membranous location in normal endometrium to aberrantly cytoplasmic expression in endometrioid adenocarcinomas, thus suggesting the decrease of functional membranous gap junctions in the malignancy. Bak failed to correlate with Cx43 regardless of either PgR or ER-alpha status of tumors, while Bcl-xL positively correlated with Cx43 in ER-alpha positive tumors (p = 0.001, r = 0.427) and both PgR positive (p = 0.019, r = 0.312) and negative (p = 0.015, r = 0.509) cancers. Similarly, Bcl-xL significantly associated with Cx26 in ER-alpha positive tumors (p = 0.036, r = 0.267) and both PgR positive (p = 0.026, r = 0.297) and negative (p = 0.046, r = 0.429) cancers. On the contrary, Bak exclusively correlated with Cx26 only in ER-alpha negative tumors (p = 0.027, r = 0.551). ER-alpha status of endometrioid adenocarcinomas could restrict eventual proapoptotic or anti-apoptotic impact of aberrantly expressed Cx43 and Cx26 in these tumors.

Influence of gap junction intercellular communication composed of connexin 43 on the antineoplastic effect of adriamycin in breast cancer cells

“…Multiples studies have revealed that, in breast cancer patients, the expression of connexin proteins is correlated with clinicopathological biomarkers, including estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2), which are normally used to predict the response of mammary cancer patients to therapy (33,53). The Hs578T cell line used in the current study is a type of triple-negative breast cancer (TNBC), while the MCF-7 cell line is non-TNBC (ER+ and PR+) (54,55).…”

Single-cell RNA-sequencing reveals transcriptional dynamics of estrogen-induced dysplasia in the ovarian surface epithelium

“…Without E2, control cells become stressed with increasing confluence and upregulate genes associated with hypoxia ( Ptgis , Cryab [ 24 ]), cell death ( Casp1 , Fas [ 25 ]), and inflammatory responses involving immune cell recruitment through the TNF signalling pathway ( Ccl2 , Icam1 ) [ 26 , 27 ]. E2-treated cells appear to overcome hypoxia via up-regulation of E2-responsive Hif1a [ 28 ] and Connexin 43 ( Gja1 ) [ 29 , 30 ]. Inflammatory immunogenic signals were suppressed in E2-treated cells, suggesting that E2 may contribute to an immune-restricted microenvironment, allowing pre-neoplastic lesions to develop and evade immune surveillance [ 31 ].…”

Roles of estrogen receptor α in endometrial carcinoma (Review)

“…Moreover, it has been suggested that ERα may enhance the interaction between STAT3 and the apoptosis regulator BCL-extra large, which is crucial for the development of endometrioid adenocarcinoma (112). Furthermore, ERα expression has been indicated to influence the pro-apoptotic or anti-apoptotic effects of abnormally expressed Cx43 and Cx26 in EC (113). Regarding drug resistance, Abe et al (114) found that ERα upregulates the expression of BCL2-associated athanogene 3 (BAG3) in EC cells, inhibits the expression of miR-29b, and increases the expression of Mcl-1, which is a downstream mediator of BAG3.…”