The Hippo-YAP signaling pathway plays an essential role in epithelial cells during intestinal regeneration and tumorigenesis. However, the molecular mechanism linking stromal signals to YAP-mediated intestinal regeneration and tumorigenesis is poorly defined. Here, we report a stroma-epithelium ISLR-YAP signaling axis essential for stromal cells to modulate epithelial cell growth during intestinal regeneration and tumorigenesis. Specifically, upon inflammation and in cancer, an oncogenic transcription factor ETS1 in stromal cells induces expression of a secreted protein ISLR that can inhibit Hippo signaling and activate YAP in epithelial cells. Deletion of Islr in stromal cells in mice markedly impaired intestinal regeneration and suppressed tumorigenesis in the colon. Moreover, the expression of stromal cell-specific ISLR and ETS1 significantly increased in inflamed mucosa of human IBD patients and in human colorectal adenocarcinoma, accounting for the epithelial YAP hyperactivation. Collectively, our findings provide new insights into the signaling crosstalk between stroma and epithelium during tissue regeneration and tumorigenesis.

中文翻译：

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分泌的基质蛋白ISLR通过抑制上皮河马信号传导来促进肠道再生。

在肠道再生和肿瘤发生过程中，Hippo-YAP信号通路在上皮细胞中起重要作用。但是，将基质信号与YAP介导的肠道再生和肿瘤发生联系起来的分子机制尚不清楚。在这里，我们报告基质-上皮ISLR-YAP信号轴对于基质细胞在肠道再生和肿瘤发生过程中调节上皮细胞生长至关重要。具体而言，在炎症和癌症中，基质细胞中的致癌转录因子ETS1诱导分泌蛋白ISLR的表达，该蛋白可抑制Hippo信号传导并激活上皮细胞中的YAP。小鼠基质细胞中Islr的删除显着损害肠道再生并抑制结肠中的肿瘤发生。此外，在人IBD患者发炎的黏膜和人大肠腺癌中，基质细胞特异性ISLR和ETS1的表达显着增加，这说明上皮YAP过度活化。总的来说，我们的发现为组织再生和肿瘤发生过程中基质与上皮之间的信号串扰提供了新的见解。