Regulation of semaphorin 4D expression and cell proliferation of ovarian cancer by ERalpha and ERbeta

Abstract

Ovarian cancer is one of the most common malignancies in women. Semaphorin 4D (sema 4D) is involved in the progress of multiple cancers. In the presence of estrogen-like ligands, estrogen receptors (ERα and ERβ) participate in the progress of breast and ovarian cancers by transcriptional regulation. The aim of the study was to investigate the role of sema 4D and elucidate the regulatory pattern of ERα and ERβ on sema 4D expression in ovarian cancers. Sema 4D levels were up-regulated in ovarian cancer SKOV-3 cells. Patients with malignant ovarian cancers had significantly higher sema 4D levels than controls, suggesting an oncogene role of sema 4D in ovarian cancer. ERα expressions were up-regulated in SKOV-3 cells compared with normal ovarian IOSE80 epithelial cells. Conversely, down-regulation of ERβ was observed in SKOV-3 cells. Forced over-expression of ERα and ERβ in SKOV-3 cells was manipulated to establish ERα+ and ERβ+ SKOV-3 cell lines. Incubation of ERα+ SKOV-3 cells with ERs agonist 17β-estradiol (E2) significantly enhanced sema 4D expression and rate of cell proliferation. Incubated with E2, ERβ+ SKOV-3 cells showed lower sema 4D expression and cell proliferation. Blocking ERα and ERβ activities with ICI182-780 inhibitor, sema 4D expressions and cell proliferation of ERα+ and ERβ+ SKOV-3 cells were recovered to control levels. Taken together, the data showed that sema 4D expression was positively correlated with the progress of ovarian cancer. ERα positively regulated sema 4D expression and accelerated cell proliferation. ERβ negatively regulated sema 4D expression and inhibited cell multiplication.

Transcriptomic and genomic profiling of early-stage ovarian carcinomas associated with histotype and overall survival

“…Moreover, novel mutation signatures in relation to histotypes were identified. Among these, increased DNA methylation of the CASP8AP2 gene has previously been associated with less sensitivity to cisplatin and taxol in a breast cancer cell line (MDA-MB-231) [ 22 ], elevated UBR5 gene expression levels have been observed in cisplatin-resistant ovarian cancer patients in comparison with cisplatin-responsive patients [ 23 ], and SEMA4D has been shown to play a role in progression of multiple cancers, such as ovarian cancer [ 24 ]. The IPMK gene has been shown to be involved in cell cycle arrest and apoptosis in ovarian cancer [ 25 ] and the BECN1 gene has been suggested to be a tumor-suppressor gene and its expression levels to be associated with ovarian cancer prognosis [ 26 ].…”

Hormonal regulation of Semaphorin 7a in ER+ breast cancer drives therapeutic resistance

“…Studies of other semaphorins have also described hormone receptor regulation. In ovarian cancer, pro-proliferative SEMA4D is positively regulated by ER (27). Expression of SEMA3B and SEMA3F, which are both growthsuppressive, in ovarian cancer is positively regulated by E2 and P4 (28).…”

Hormonal Regulation of Semaphorin 7a in ER+ Breast Cancer Drives Therapeutic Resistance

“…Other semaphorins also have previously described relationships with hormone receptors. In ovarian cancer, SEMA4D is pro-proliferative and its expression is positively regulated by ER 24 . Expression of growth-suppressive SEMA3B and SEMA3F in ovarian cancer is also positively regulated by E2 and P4 25 .…”