The Laboratory of Molecular Genetics, National Cancer Center Research Institute, Tokyo, Japan.
Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan.
Nat Commun. 2023 Oct 16;14(1):6514. doi: 10.1038/s41467-023-42228-z.
Chronic inflammation promotes development and progression of colorectal cancer (CRC). To comprehensively understand the molecular mechanisms underlying the development and progression of inflamed CRC, we perform in vivo screening and identify 142 genes that are frequently mutated in inflammation-associated colon tumors. These genes include senescence and TGFβ-activin signaling genes. We find that TNFα can induce stemness and activate senescence signaling by enhancing cell plasticity in colonic epithelial cells, which could act as a selective pressure to mutate senescence-related genes in inflammation-associated colonic tumors. Furthermore, we show the efficacy of the Cdk4/6 inhibitor in vivo for inflammation-associated colonic tumors. Finally, we functionally validate that Arhgap5 and Mecom are tumor suppressor genes, providing possible therapeutic targets for CRC. Thus, we demonstrate the importance of the inactivation of senescence pathways in CRC development and progression in an inflammatory microenvironment, which can help progress toward precision medicine.
慢性炎症促进结直肠癌（CRC）的发生和发展。为了全面了解炎症相关 CRC 发生和发展的分子机制，我们进行了体内筛选，鉴定出 142 个在炎症相关结肠肿瘤中经常发生突变的基因。这些基因包括衰老和 TGFβ-激活素信号基因。我们发现 TNFα 可以通过增强结肠上皮细胞的细胞可塑性来诱导干性和激活衰老信号，这可能成为炎症相关结肠肿瘤中衰老相关基因发生突变的选择压力。此外，我们还展示了 CDK4/6 抑制剂在体内对炎症相关结肠肿瘤的疗效。最后，我们从功能上验证了 Arhgap5 和 Mecom 是肿瘤抑制基因，为 CRC 提供了可能的治疗靶点。因此，我们证明了在炎症微环境中，衰老通路的失活在 CRC 的发生和发展中具有重要作用，这有助于推动精准医学的发展。
