Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Japan.
Cancer Sci. 2021 Jan;112(1):16-21. doi: 10.1111/cas.14702. Epub 2020 Nov 17.
The turnover of intestinal epithelial cells (IECs) is relatively rapid (3-5 days in mouse and human), and this short existence and other aspects of the homeostasis of IECs are tightly regulated by various signaling pathways including Wnt-β-catenin signaling. Dysregulation of IEC homeostasis likely contributes to the development of intestinal inflammation and intestinal cancer. The roles of receptor protein tyrosine kinases and their downstream signaling molecules such as Src family kinases, Ras, and mTOR in homeostatic regulation of IEC turnover have recently been evaluated. These signaling pathways have been found to promote not only the proliferation of IECs but also the differentiation of progenitor cells into secretory cell types such as goblet cells. Of note, signaling by Src family kinases, Ras, and mTOR has been shown to oppose the Wnt-β-catenin signaling pathway and thereby to limit the number of Lgr5 intestinal stem cells or of Paneth cells. Such cross-talk of signaling pathways is important not only for proper regulation of IEC homeostasis but for the development of intestinal tumors and potentially for anticancer therapy.
肠上皮细胞（IECs）的周转率相对较快（在小鼠和人类中为 3-5 天），而 IECs 的这种短暂存在和其他方面的内稳态受到包括 Wnt-β-catenin 信号通路在内的各种信号通路的严格调节。IEC 内稳态的失调可能导致肠道炎症和肠癌的发展。最近已经评估了受体蛋白酪氨酸激酶及其下游信号分子（如 Src 家族激酶、Ras 和 mTOR）在 IEC 周转率的稳态调节中的作用。这些信号通路不仅促进了 IEC 的增殖，而且促进了祖细胞向分泌细胞类型（如杯状细胞）的分化。值得注意的是，Src 家族激酶、Ras 和 mTOR 的信号转导已被证明与 Wnt-β-catenin 信号通路相拮抗，从而限制了 Lgr5 肠道干细胞或 Paneth 细胞的数量。这种信号通路的串扰不仅对 IEC 内稳态的适当调节很重要，而且对肠道肿瘤的发展以及潜在的抗癌治疗也很重要。
