| Literature DB >> 31853061 |
Nobuyuki Kakiuchi1,2,3, Kenichi Yoshida1, Motoi Uchino4, Takako Kihara5, Kotaro Akaki6, Yoshikage Inoue1,2,7, Kenji Kawada7, Satoshi Nagayama8, Akira Yokoyama1,9, Shuji Yamamoto3, Minoru Matsuura3,10, Takahiro Horimatsu9, Tomonori Hirano1,2,3, Norihiro Goto3, Yasuhide Takeuchi1,2,11,12, Yotaro Ochi1,2, Yusuke Shiozawa1, Yasunori Kogure1,13, Yosaku Watatani1,2, Yoichi Fujii1,2, Soo Ki Kim1,3, Ayana Kon1,2, Keisuke Kataoka1,13, Tetsuichi Yoshizato1, Masahiro M Nakagawa1,2, Akinori Yoda1,2, Yasuhito Nanya1,2, Hideki Makishima1,2, Yuichi Shiraishi14, Kenichi Chiba14, Hiroko Tanaka15, Masashi Sanada1,16, Eiji Sugihara17, Taka-Aki Sato17, Takashi Maruyama18, Hiroyuki Miyoshi19, Makoto Mark Taketo19, Jun Oishi20, Ryosaku Inagaki1,20, Yutaka Ueda20, Shinya Okamoto21, Hideaki Okajima21,22, Yoshiharu Sakai7, Takaki Sakurai11, Hironori Haga12, Seiichi Hirota5, Hiroki Ikeuchi4, Hiroshi Nakase3,23, Hiroyuki Marusawa3, Tsutomu Chiba3,24, Osamu Takeuchi6, Satoru Miyano14,15, Hiroshi Seno3, Seishi Ogawa25,26,27.
Abstract
Chronic inflammation is accompanied by recurring cycles of tissue destruction and repair and is associated with an increased risk of cancer1-3. However, how such cycles affect the clonal composition of tissues, particularly in terms of cancer development, remains unknown. Here we show that in patients with ulcerative colitis, the inflamed intestine undergoes widespread remodelling by pervasive clones, many of which are positively selected by acquiring mutations that commonly involve the NFKBIZ, TRAF3IP2, ZC3H12A, PIGR and HNRNPF genes and are implicated in the downregulation of IL-17 and other pro-inflammatory signals. Mutational profiles vary substantially between colitis-associated cancer and non-dysplastic tissues in ulcerative colitis, which indicates that there are distinct mechanisms of positive selection in both tissues. In particular, mutations in NFKBIZ are highly prevalent in the epithelium of patients with ulcerative colitis but rarely found in both sporadic and colitis-associated cancer, indicating that NFKBIZ-mutant cells are selected against during colorectal carcinogenesis. In further support of this negative selection, we found that tumour formation was significantly attenuated in Nfkbiz-mutant mice and cell competition was compromised by disruption of NFKBIZ in human colorectal cancer cells. Our results highlight common and discrete mechanisms of clonal selection in inflammatory tissues, which reveal unexpected cancer vulnerabilities that could potentially be exploited for therapeutics in colorectal cancer.Entities:
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Year: 2019 PMID： 31853061 DOI： 10.1038/s41586-019-1856-1
Source DB: PubMed Journal: Nature ISSN： 0028-0836 Impact factor: 49.962