ERa-36 instead of ERa mediates the stimulatory effects of estrogen on the expression of viral oncogenes HPV E6/E7 and the malignant phenotypes in cervical cancer cells.

Abstract

High risk human papillomavirus (HPV) is the main causative factor of cervical cancer. In addition, estrogen and its receptors are also involved in the development of carcinogenesis. The canonical estrogen receptor ERα is frequently deficient while its variant ERα-36 is highly expressed in cervical cancer cells. The biological significance for this receptor transition from ERα to ERα-36 remains unclear. In the present study, the results of RT-PCR and Western blot demonstrated that ERα and ERα-36 function antagonistically on the expression of the viral oncogenes HPV E6 and E7. At mRNA and protein levels, ERα inhibited HPV E6/E7 expression whereas ERα-36 stimulated HPV E6/E7 expression. Overexpression of ERα-36 promoted cell proliferation while reintroduction of ERα into cervical cancer cells did not significantly affect cell proliferation which is in line with the different effects of . ERα-36 and ERα on the expression of cell cycle regulator, namely p53, p21 and cyclin D1. Furthermore, ERα suppressed whereas ERα-36 promoted the migration and invasion of cervical cancer cells, which should be related to the oppositive roles of ERα and ERα-36 in the Wnt/β-catenin/MRTF-A signaling pathway which is activated by HPV E7. Results of this study suggest that ERα functions as a tumor suppressor whereas ERα-36 is an oncoprotein in cervical cancer cells. ERα deficiency together with ERα-36 overexpression might enhance the expression of HPV E6/E7 genes and facilitate the development of cervical cancer. Targeting ERα-36 with selective antagonists should be a promising strategy for cervical cancer therapy.