Institute of Cancer Research, Medical University Vienna & Comprehensive Cancer Center (CCC), Vienna, Austria.
Institute of Immunology, Medical University Vienna, Austria.
Mol Oncol. 2018 Apr;12(4):514-528. doi: 10.1002/1878-0261.12178. Epub 2018 Feb 20.
The interferon-inducible transcription factor STAT1 is a tumor suppressor in various malignancies. We investigated sex-specific STAT1 functions in colitis and colitis-associated colorectal cancer (CRC) using mice with specific STAT1 deletion in intestinal epithelial cells (STAT1 ). Male but not female STAT1 mice were more resistant to DSS-induced colitis than sex-matched STAT1 controls and displayed reduced intraepithelial infiltration of CD8 TCRαβ granzyme B T cells. Moreover, DSS treatment failed to induce expression of T-cell-attracting chemokines in intestinal epithelial cells of male but not of female STAT1 mice. Application of the AOM-DSS protocol for induction of colitis-associated CRC resulted in increased intestinal tumor load in male but not in female STAT1 mice. A sex-specific stratification of human CRC patients corroborated the data obtained in mice and revealed that reduced tumor cell-intrinsic nuclear STAT1 protein expression is a poor prognostic factor in men but not in women. These data demonstrate that epithelial STAT1 is a male-specific tumor suppressor in CRC of mice and humans.
干扰素诱导转录因子 STAT1 是多种恶性肿瘤的肿瘤抑制因子。我们使用肠道上皮细胞中特异性缺失 STAT1（STAT1 ）的小鼠，研究了 STAT1 在结肠炎和结肠炎相关结直肠癌（CRC）中的性别特异性功能。与性别匹配的 STAT1 对照相比，雄性而非雌性 STAT1 小鼠对 DSS 诱导的结肠炎具有更强的抵抗力，并且上皮内浸润的 CD8 TCRαβ 颗粒酶 B T 细胞减少。此外，DSS 处理未能诱导雄性而非雌性 STAT1 小鼠肠道上皮细胞中 T 细胞吸引趋化因子的表达。应用 AOM-DSS 方案诱导结肠炎相关 CRC 导致雄性而非雌性 STAT1 小鼠的肠道肿瘤负荷增加。对人类 CRC 患者的性别特异性分层与在小鼠中获得的数据相吻合，并表明肿瘤细胞内在核 STAT1 蛋白表达减少是男性而不是女性的预后不良因素。这些数据表明，上皮 STAT1 是雄性小鼠和人类 CRC 中的一种性别特异性肿瘤抑制因子。
