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

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

Automated summary

In cervical cancer cells, ER alpha and ER alpha-36 have antagonistic effects on the expression of HPV E6/E7. ER alpha-36 promotes cell proliferation, migration, and invasion, while ER alpha inhibits these processes. This suggests that targeting ER alpha-36 with selective antagonists may be a promising strategy for cervical cancer therapy.