Department of Obstetrics and Gynecology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
Department of Disaster Obstetrics and Gynecology, International Research Institute of Disaster Science (IRIDeS), Tohoku University, Sendai 980-8577, Japan.
Int J Mol Sci. 2018 Apr 10;19(4):1139. doi: 10.3390/ijms19041139.
Endometrial cancer is one of the most common female pelvic cancers and has been considered an androgen-related malignancy. Several studies have demonstrated the anti-cell proliferative effect of androgen on endometrial cancer cells; however, the mechanisms of the anti-cancer effect of androgen remain largely unclear. 17β-hydroxysteroid dehydrogenase type 2 (17β-HSD2), which catalyzes the conversion of E2 to E1, is known to be upregulated by androgen treatment in breast cancer cells. In this study, we therefore focused on the role of androgen on estrogen dependence in endometrial cancer. Dihydrotestosterone (DHT) was found to induce mRNA and protein expression in HEC-1B endometrial cancer cells. DHT could also inhibit cell proliferation of HEC-1B when induced by estradiol treatment. In 19 endometrioid endometrial adenocarcinoma (EEA) tissues, intratumoral DHT concentration was measured by liquid chromatography/electrospray tandem mass spectrometry and was found to be significantly correlated with 17β-HSD2 immunohistochemical status. We further examined the correlations between 17β-HSD2 immunoreactivity and clinicopathological parameters in 53 EEA tissues. 17β-HSD2 status was inversely associated with the histological grade, clinical stage, and cell proliferation marker Ki-67, and positively correlated with progesterone receptor expression. 17β-HSD2 status tended to be positively associated with androgen receptor status. In 53 EEA cases, the 17β-HSD2-positive group tended to have better prognosis than that for the negative group with respect to progression-free survival and endometrial cancer-specific survival. These findings suggest that androgen suppresses the estrogen dependence of endometrial cancer through the induction of 17β-HSD2 in endometrial cancer.
子宫内膜癌是最常见的女性盆腔恶性肿瘤之一，被认为是一种与雄激素相关的恶性肿瘤。几项研究表明，雄激素对子宫内膜癌细胞具有抗增殖作用；然而，雄激素抗癌作用的机制在很大程度上仍不清楚。17β-羟类固醇脱氢酶 2（17β-HSD2）可将 E2 催化转化为 E1，已知在乳腺癌细胞中雄激素治疗可上调 17β-HSD2。在本研究中，我们因此专注于雄激素对子宫内膜癌中雌激素依赖性的作用。二氢睾酮（DHT）被发现可诱导 HEC-1B 子宫内膜癌细胞的 mRNA 和蛋白表达。当用雌二醇处理诱导时，DHT 也可抑制 HEC-1B 细胞的增殖。在 19 例子宫内膜样腺癌（EEA）组织中，通过液相色谱/电喷雾串联质谱法测量肿瘤内 DHT 浓度，发现其与 17β-HSD2 免疫组化状态显著相关。我们进一步检查了 53 例 EEA 组织中 17β-HSD2 免疫反应性与临床病理参数之间的相关性。17β-HSD2 状态与组织学分级、临床分期和细胞增殖标志物 Ki-67 呈负相关，与孕激素受体表达呈正相关。17β-HSD2 状态与雄激素受体状态呈正相关趋势。在 53 例 EEA 病例中，17β-HSD2 阳性组在无进展生存和子宫内膜癌特异性生存方面的预后优于阴性组。这些发现表明，雄激素通过诱导子宫内膜癌中的 17β-HSD2 来抑制子宫内膜癌对雌激素的依赖性。
