Research shows a higher incidence of colorectal cancer in men. However, the molecular mechanisms for this gender disparity remain unknown. We report the roles of androgen in proliferation and differentiation of intestinal stem cells via targeting of the androgen receptor (AR) on intestinal stromal cells by negatively regulating BMP signaling. Orchidectomy (ORX) or the AR antagonist promotes expansion of intestinal epithelium but suppresses intestinal stem cell (ISC) proliferation. Conversely, the AR agonist inhibits ISC differentiation but augments proliferation in ovariectomized mice. Mechanistically, activation of the AR increases expression of BMP antagonists but lowers expression of BMP4 and Wnt antagonists in primary stromal cells, which promotes intestinal organoid growth. Interestingly, the BMP pathway inhibitor LDN-193189 reverses the ORX-induced effects. Our results highlight that stromal cells constitute the intestinal stem cell niche and provide a possible explanation for higher incidence rates of colorectal cancer in men.

研究表明，男性结直肠癌的发病率更高。然而，这种性别差异的分子机制仍然未知。我们通过负向调节 BMP 信号传导靶向肠道基质细胞上的雄激素受体 (AR)，报告了雄激素在肠道干细胞增殖和分化中的作用。睾丸切除术 (ORX) 或 AR 拮抗剂促进肠上皮细胞的扩张，但抑制肠干细胞 (ISC) 增殖。相反，AR 激动剂抑制 ISC 分化，但增加卵巢切除小鼠的增殖。从机制上讲，AR 的激活会增加 BMP 拮抗剂的表达，但会降低原代基质细胞中 BMP4 和 Wnt 拮抗剂的表达，从而促进肠道类器官的生长。有趣的是，BMP 通路抑制剂 LDN-193189 可逆转 ORX 诱导的作用。我们的研究结果强调，基质细胞构成了肠道干细胞生态位，并为男性结直肠癌的高发病率提供了可能的解释。