雌激素受体ER-α36在子宫颈癌发病中的作用及机制研究

It has been widely accepted that high-risk human papillomavirus (HPV) persistent infection is a major etiological factor for cervical cancer. However, other cofactors may contribute to the genesis of cervical cancer because only a minor fraction of patients infected with HPV develop cervical cancer. Several studies have confirmed that female steroid hormones may play an important role in cervical carcinogenesis. Estrogen works by the receptor (estrogen receptor, ER) . Recently, studies have reported that ER-α36 (36 kDa) is a smaller isoform of ER-α, which primarily localizes to the plasma membrane and cytoplasm. Previous studies have reported that ER-α36may activate various protein kinases and phospholipases, leading to the activation of signaling cascades that result in rapid and non-genomic responses and may play an important role in the carcinogenesis and progression of tumors in breast cancer and endometrial cancer and so on. Our former study found that ER-α36 is negative or weak expressed in normal cervical tissues while possesses positive staining in the membrane and cytoplasm of cervical squamous cell carcinoma. Further, ER-α36 mediates cell invasion, migration, and proliferation in vitro. In this study, we will enlarge the clinical sample size to explore the clinical pathological characteristics between ER-α 36 and cervical cancer, to explore the correlation between ER-α36 and the outcome of cervical intraepithelial neoplasia in vivo and in vitro. Besides, our research aims to study the biological effects and molecular mechanism of ER-α36, to improve the mechanism of estrogen signaling pathway in the occurrence of cervical cancer and to explore whether ER-α36 can be used as a potential indicator for cervical lesions.

高危型HPV持续感染是引起宫颈癌发生的主要原因，但只有少部分高危HPV感染者发展为宫颈癌，因此宫颈癌的发生是含其他因素共同作用的过程。已有多项研究证实雌激素在宫颈癌的发生发展中起重要作用，雌激素通过受体发挥作用，雌激素受体α（ER-α）亚型之一为ER-α36，与传统ER-α66不同，它主要位于胞膜和胞浆，除介导雌激素效应外，还可发挥雌激素的非基因组效应，在多种肿瘤的进展中发挥重要作用。我们前期研究发现其在正常宫颈组织基本不表达，在宫颈癌组织高强表达，细胞学实验证实它与宫颈癌细胞的迁移、侵袭及增殖相关。本课题拟通过大样本临床病理分析探究ER-α36与宫颈癌临床病理特征的关系，体内、外实验及临床研究探索ER-α36与HPV感染及宫颈病变转归的相关性，并对其生物学效应及作用机制进行研究，为完善雌激素信号通路在宫颈癌发生中的作用机制提供理论依据，并探索ER-α36能否作为宫颈病变潜在的检测指标。

宫颈癌是女性最常见的恶性肿瘤之一，其发病率及死亡率均排在女性癌症的第四位。多项研究提示，17β-雌二醇（17β-estradiol，E2）参与了高危型HPV所致的宫颈癌发生发展过程。E2通过与雌激素受体（Estrogen Receptor，ER）结合发挥生物学效应。雌激素受体-α（Estrogen receptor-α，ER-α）是表达于宫颈组织的主要雌激素受体，包括ER-α66、ER-α46及ER-α36三种亚型。ER-α36是最新发现的ER-α亚型，既往研究发现ER-α36在多种恶性肿瘤中呈高表达且与临床不良预后相关。然而，ER-α36在宫颈癌中的表达及作用却鲜有报道。.因此，本研究旨在分析ER-α36在宫颈癌中的表达及临床意义，探究ER-α36对宫颈癌增殖、侵袭、迁移和顺铂耐药的影响及潜在机制，以期为宫颈癌的临床治疗提供新的分子靶标。.本课题研究发现ER-α36在正常宫颈组织、宫颈癌前病变组织及宫颈癌组织中表达呈升高趋势；而作为经典ER-α亚型的ER-α66在宫颈癌组织中表达呈下调趋势。单因素及多因素Cox回归分析证实ER-α36的表达水平及淋巴结转移是评估宫颈鳞癌预后的独立因素。体外实验发现ER-α36促进E2介导的宫颈癌细胞的增殖、侵袭、迁移及周期进展，而ER-α66并不影响宫颈癌细胞增殖及转移。体内实验证实ER-α36促进E2介导的宫颈癌细胞的增殖。通过二代测序技术，筛选ER-α36下游靶基因HMGA2。挽救实验证实ER-α36通过调控HMGA2促进E2介导的宫颈癌细胞的恶性行为。顺铂是宫颈癌一线化疗药物，体外实验发现ER-α36通过调控于HMGA2促进宫颈癌细胞顺铂耐药。