Abstract
ObjectivesEstrogen is proven to promote the malignant behaviors of many cancers via its receptors. Estrogen receptor alfa 36 (ER-α36) is a newly identified isoform of estrogen receptor alfa (ER-α), the role of ER-α36 in regulating the effects of estrogen and its potential impact on human cervical cancer is poorly understood.MethodsImmunohistochemistry staining was used to evaluate the expression of ER-α36, estrogen receptor alfa 66 (ER-α66) and their prognostic values in cervical cancer. The effects of ER-α36 and ER-α66 on the proliferation and metastasis of cervical cancer were measured in vitro. A xenograft tumor assay was used to study the tumorigenesis role of ER-α36 in vivo. Furthermore, the functional gene at the downstream of ER-α36 was obtained via next-generation sequencing, and the biological functions of high mobility group A2 (HMGA2) in cervical cancer cells were investigated in vitro.ResultsER-α36 was over-expressed in cervical cancer tissues and elevated ER-α36 expression was associated with poor prognosis in cervical cancer patients. High expression of ER-α36 promoted the proliferation, invasion and metastasis of cervical cancer cells mediated by estrogen, while silencing ER-α36 had the opposite effects. Further research showed that HMGA2 was a downstream target of ER-α36 in cervical cancer cells. The oncogenic effect of ER-α36 was attenuated after HMGA2 knockdown.ConclusionsHigh expression of ER-α36 was correlated with a poor prognosis in cervical cancer by regulating HMGA2. ER-α36 could be a prognostic biomarker and a target for cervical cancer treatment.
Highlights
Cervical cancer (CC) is the fourth leading cause of cancer death in women
Through in vitro and vivo experiments, we demonstrated that ER-a36 promoted the malignant progression of CC mediated by estrogen, and these effects on biological behavior were achieved by regulating the expression of HMGA2
We detected the expressions of ER-a36 and ER-a66 in CC tissues and cervix tissues with qRT-PCR and western blotting, the results showed that the mRNA and protein levels of ER-a36 were higher in cancer tissues, while the mRNA and protein levels of ER-a66 were higher in cervix tissues (Figures 1A–C). we detected their expressions in H8,siha,hela,caski and C33a cell lines, western blotting demonstrated that ER-a36 was significantly over-expressed in four CC cell lines compared with H8, the normal cervical epithelial cells, while ER-a66 was over-expressed in H8 cells (Figure 1D).These results indicated the possible roles of ER-a36 and ER-a66 in CC
Summary
Cervical cancer (CC) is the fourth leading cause of cancer death in women. According to the latest statistics, there were 604127 incident cases and 341831 deaths due to CC worldwide in 2020 [1]. Squamous cell Carcinoma (SCC) and adenocarcinoma (AC) are the most common histological subtypes accounting for about 70% and 25% of all cervical cancers, respectively [2]. Radical surgery is the first‐ line treatment for early‐stage CC, the combination of g- irradiation and ER-a36 Promotes Proliferation and Metastasis cisplatin-based chemotherapy is the standard treatment for advanced CC [3]. Great progress has been made in disease prevention with the emergence of HPV vaccination and early screening, the incidence and mortality of CC are still high in low and middle-income countries [4]. It is important to elucidate the potential oncogenic molecular mechanisms in CC and develop new therapy methods
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