Asaka Shiho, Liu Ying, Yu Zheng-Cheng, Rahmanto Yohan Suryo, Ono Motoki, Asaka Ryoichi, Miyamoto Tsutomu, Yen Ting-Tai, Ayhan Ayse, Wang Tian-Li, Shih Ie-Ming
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Laboratory Medicine, Shinshu University School of Medicine, Matsumoto, Japan.
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Mod Pathol. 2023 Feb;36(2):100045. doi: 10.1016/j.modpat.2022.100045. Epub 2023 Jan 10.
Loss of progesterone receptor (PR) expression is an established risk factor for unresponsiveness to progesterone therapy in patients with endometrial atypical hyperplasia and endometrioid carcinoma. ARID1A is one of the most commonly mutated genes in endometrioid carcinomas, and the loss of its expression is associated with tumor progression. In this study, we investigated the roles of ARID1A deficiency in PR expression in human and murine endometrial epithelial neoplasia. An analysis of genome-wide chromatin immunoprecipitation sequencing in isogenic ARID1A-/- and ARID1A+/+ human endometrial epithelial cells revealed that ARID1A-/- cells showed significantly reduced chromatin immunoprecipitation sequencing signals for ARID1A, BRG1, and H3K27AC in the PgR enhancer region. We then performed immunohistochemistry to correlate the protein expression levels of ARID1A, estrogen receptor, and PR in 50 human samples of endometrial atypical hyperplasia and 75 human samples of endometrial carcinomas. The expression levels of PR but not were significantly lower in ARID1A-deficient low-grade endometrial carcinomas and atypical hyperplasia (P = .0002). When Pten and Pten/Arid1a conditional knockout murine models were used, Pten-/-;Arid1a-/- mice exhibited significantly decreased epithelial PR expression in endometrial carcinomas (P = .003) and atypical hyperplasia (P < .0001) compared with that in the same tissues from Pten-/-;Arid1a+/+ mice. Our data suggest that the loss of ARID1A expression, as occurs in ARID1A-mutated endometrioid carcinomas, decreases PgR transcription by modulating the PgR enhancer region during early tumor development.
孕激素受体（PR）表达缺失是子宫内膜非典型增生和子宫内膜样癌患者对孕激素治疗无反应的既定风险因素。ARID1A是子宫内膜样癌中最常发生突变的基因之一，其表达缺失与肿瘤进展相关。在本研究中，我们调查了ARID1A缺陷在人和小鼠子宫内膜上皮肿瘤中PR表达的作用。对同基因ARID1A - / - 和ARID1A + / + 人子宫内膜上皮细胞进行全基因组染色质免疫沉淀测序分析显示，ARID1A - / - 细胞在PgR增强子区域的ARID1A、BRG1和H3K27AC染色质免疫沉淀测序信号显著降低。然后，我们进行免疫组织化学以关联50例人子宫内膜非典型增生样本和75例人子宫内膜癌样本中ARID1A、雌激素受体和PR的蛋白表达水平。在ARID1A缺陷的低级别子宫内膜癌和非典型增生中，PR的表达水平显著降低（P = .0002），而雌激素受体的表达水平未显著降低。当使用Pten和Pten/Arid1a条件性敲除小鼠模型时，与Pten - / - ;Arid1a + / + 小鼠相同组织相比，Pten - / - ;Arid1a - / - 小鼠子宫内膜癌（P = .003）和非典型增生（P < .0001）中的上皮PR表达显著降低。我们的数据表明，如在ARID1A突变的子宫内膜样癌中发生的ARID1A表达缺失，在肿瘤早期发展过程中通过调节PgR增强子区域降低了PgR转录。
