The expression of members of the progesterone receptor membrane component (PGRMC) family, particularly PGRMC1, is elevated in diverse types of cancers, particularly those of the female reproductive system. While xenograft tumor studies using human transformed cell lines in immunocompromised mice have suggested thatPGRMC1enhances tumor growth and chemoresistance, the exact role of members of the PGRMC family in cancer development in vivo remains unclear. In this study, we examined the effect of deletingPgrmc2on the development of endometrial hyperplasia and cancer using a murinephosphatase and tensin homologue(Pten) conditional loss-of-function model. We previously established that PGRMCs are cell survival factors that are required for normal estrogen-induced uterine epithelial cell proliferation and normal female fertility. The deletion ofPgrmc2reduced the incidence and severity of endometrial hyperplasia and cancer in mice with conditionalPten-heterozygous uteri and increased lifespan in mice with conditionalPten-knockout uteri. Mechanistically, the deletion ofPgrmc2decreased uterine glandular epithelial cell proliferation.Ptenloss-of-function-induced endometrial hyperplasia and cancer elevated uterine inflammation, but this was not impacted by PGRMC2 deficiency. This study identifies PGRMC2 as a potential therapeutic target to be inhibited in the treatment of endometrial hyperplasia and cancer, particularly where PTEN activity is reduced due to gene mutation or loss.
孕酮受体膜组分（PGRMC）家族成员，特别是PGRMC1，在多种癌症尤其是女性生殖系统肿瘤中表达升高。尽管利用免疫缺陷小鼠移植人类转化细胞系进行的异种移植瘤研究表明PGRMC1能促进肿瘤生长并增强化疗耐药性，但PGRMC家族成员在体内癌症发生发展中的确切作用仍不明确。本研究采用小鼠磷酸酶与张力蛋白同源物（Pten）条件性功能缺失模型，探讨了敲除Pgrmc2对子宫内膜增生及癌症发生的影响。我们前期已证实PGRMCs是维持正常雌激素诱导的子宫上皮细胞增殖及女性生育能力所必需的细胞存活因子。在条件性Pten杂合缺失子宫的小鼠中，Pgrmc2敲除降低了子宫内膜增生及癌症的发生率和严重程度；在条件性Pten敲除子宫的小鼠中，Pgrmc2敲除延长了其生存期。机制研究表明，Pgrmc2敲除可抑制子宫腺上皮细胞增殖。Pten功能缺失诱导的子宫内膜增生及癌症会加剧子宫炎症反应，但该过程不受PGRMC2缺失的影响。本研究发现PGRMC2可作为潜在治疗靶点，通过抑制其活性来治疗子宫内膜增生及癌症，特别是在因基因突变或缺失导致PTEN活性降低的病例中。
肿瘤(癌症)患者之家