Background/Objectives: Estrogens and HPV are necessary for cervical cancer (CC) development. The levels of the G protein-coupled estrogen receptor (GPER) increase as CC progresses, and HPV oncoproteins promote GPER expression. The role of this receptor is controversial due to its anti- and pro-tumor effects. This study aimed to determine the effect of GPER activation, using its agonist G-1, on the transcriptome, cell migration, and invasion in SiHa cells and non-tumorigenic keratinocytes transduced with the HPV16 E6 or E7 oncogenes. Methods: Transcriptome analysis was performed to identify G-1-enriched pathways in SiHa cells. We evaluated cell migration, invasion, and the expression of associated proteins in SiHa, HaCaT-16E6, and HaCaT-16E7 cells using various assays. Results: Transcriptome analysis revealed pathways associated with proliferation/apoptosis (TNF-α signaling, UV radiation response, mitotic spindle formation, G2/M cell cycle, UPR, and IL-6/JAK/STAT), cellular metabolism (oxidative phosphorylation), and cell migration (angiogenesis, EMT, and TGF-α signaling) in SiHa cells. Key differentially expressed genes included PTGS2 (pro/antitumor), FOSL1, TNFRSF9, IL1B, DIO2, and PHLDA1 (antitumor), along with under-expressed genes with pro-tumor effects that may inhibit proliferation. Additionally, DKK1 overexpression suggested inhibition of cell migration. G-1 increased vimentin expression in SiHa cells and reduced it in HaCaT-16E6 and HaCaT-16E7 cells. However, G-1 did not affect α-SMA expression or cell migration in any of the cell lines but increased invasion in HaCaT-16E7 cells. Conclusions: GPER is a promising prognostic marker due to its ability to activate apoptosis and inhibit proliferation without promoting migration/invasion in CC cells. G-1 could potentially be a tool in the treatment of this neoplasia.
背景/目的：雌激素和人乳头瘤病毒（HPV）是宫颈癌发生发展的必要条件。G蛋白偶联雌激素受体（GPER）水平随宫颈癌进展而升高，且HPV癌蛋白可促进GPER表达。由于该受体兼具抗肿瘤与促肿瘤双重作用，其功能存在争议。本研究旨在通过使用GPER激动剂G-1，探究GPER激活对SiHa细胞及转导HPV16 E6/E7癌基因的非致瘤角质形成细胞的转录组、细胞迁移和侵袭能力的影响。方法：通过转录组分析鉴定SiHa细胞中G-1富集的信号通路。采用多种实验方法评估SiHa、HaCaT-16E6和HaCaT-16E7细胞的迁移侵袭能力及相关蛋白表达。结果：转录组分析显示SiHa细胞中G-1影响的通路涉及增殖/凋亡（TNF-α信号、紫外线辐射应答、有丝分裂纺锤体形成、G2/M细胞周期、未折叠蛋白反应及IL-6/JAK/STAT通路）、细胞代谢（氧化磷酸化）和细胞迁移（血管生成、上皮间质转化及TGF-α信号）。关键差异表达基因包括PTGS2（促/抗肿瘤）、FOSL1、TNFRSF9、IL1B、DIO2和PHLDA1（抗肿瘤），以及可能抑制增殖的低表达促癌基因。此外，DKK1过表达提示细胞迁移受抑制。G-1能增加SiHa细胞波形蛋白表达，但在HaCaT-16E6和HaCaT-16E7细胞中降低其表达。然而G-1对所有细胞系的α-SMA表达及细胞迁移均无影响，但能增强HaCaT-16E7细胞的侵袭能力。结论：GPER因能激活宫颈癌细胞凋亡、抑制增殖且不促进迁移/侵袭，是具有潜力的预后标志物。G-1可能成为治疗此类肿瘤的有效工具。
肿瘤(癌症)患者之家