Sleeping Beauty transposon mutagenesis identified genes and pathways involved in inflammation-associated colon tumor development

Kana Shimomura, Naoko Hattori, Naoko Iida, Yukari Muranaka, Kotomi Sato, Yuichi Shiraishi, Yasuhito Arai, Natsuko Hama, Tatsuhiro Shibata, Daichi Narushima, Mamoru Kato, Hiroyuki Takamaru, Koji Okamoto and Haruna Takeda ()
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Kana Shimomura: National Cancer Center Research Institute
Naoko Hattori: National Cancer Center Research Institute
Naoko Iida: National Cancer Center Research Institute
Yukari Muranaka: National Cancer Center Research Institute
Kotomi Sato: National Cancer Center Research Institute
Yuichi Shiraishi: National Cancer Center Research Institute
Yasuhito Arai: National Cancer Center Research Institute
Natsuko Hama: National Cancer Center Research Institute
Tatsuhiro Shibata: National Cancer Center Research Institute
Daichi Narushima: National Cancer Center Research Institute
Mamoru Kato: National Cancer Center Research Institute
Hiroyuki Takamaru: National Cancer Center Hospital
Koji Okamoto: Teikyo University
Haruna Takeda: National Cancer Center Research Institute

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-42228-z

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