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研究揭示溃疡性结肠炎NFKBIZ通路存在频繁突变
2019-12-19 14:57

溃疡性结肠炎中NFKBIZ通路存在频繁突变,这一成果由日本京都大学Seishi Ogawa研究组取得。该研究成果2019年12月18日在线发表在国际学术期刊《自然》上。

研究人员发现在溃疡性结肠炎患者中,发炎的肠道内会发生因遍布的克隆而产生的重塑,其中许多克隆是通过获得涉及NFKBIZ、TRAF3IP2、ZC3H12A、PIGRHNRNPF基因突变而被正向选择的,并参与了下调IL-17和其他促炎信号。在溃疡性结肠炎中,与结肠炎相关癌症的突变谱不同于非增生性组织,这表明在两种组织中都有不同的阳性选择机制。例如,溃疡性结肠炎患者的上皮细胞中普遍存在NFKBIZ突变,但该突变在偶发性以及结肠炎相关的癌症中均很少见,这表明结直肠癌发生过程中会选择性针对NFKBIZ突变的细胞。为了进一步支持这种负向选择机制,研究人员发现在Nfkbiz突变小鼠中肿瘤形成显著减弱,并且人结肠直肠癌细胞中NFKBIZ的突变降低了细胞的竞争力。该研究结果突出了炎症组织中克隆选择的普遍和离散机制,意外的揭示了癌症的脆弱性,这些脆弱性可能会被用于结直肠癌的治疗。

据了解,慢性炎症伴随着频繁的组织破坏和修复过程,并且增加了癌症发生的风险。然而,这种循环如何影响组织的克隆组成,特别是在癌症发展方面,仍然未知。

附:英文原文

Title: Frequent mutations that converge on the NFKBIZ pathway in ulcerative colitis

Author: Nobuyuki Kakiuchi, Kenichi Yoshida, Motoi Uchino, Takako Kihara, Kotaro Akaki, Yoshikage Inoue, Kenji Kawada, Satoshi Nagayama, Akira Yokoyama, Shuji Yamamoto, Minoru Matsuura, Takahiro Horimatsu, Tomonori Hirano, Norihiro Goto, Yasuhide Takeuchi, Yotaro Ochi, Yusuke Shiozawa, Yasunori Kogure, Yosaku Watatani, Yoichi Fujii, Soo Ki Kim, Ayana Kon, Keisuke Kataoka, Tetsuichi Yoshizato, Masahiro M. Nakagawa, Akinori Yoda, Yasuhito Nanya, Hideki Makishima, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Masashi Sanada, Eiji Sugihara, Taka-aki Sato, Takashi Maruyama, Hiroyuki Miyoshi, Makoto Mark Taketo, Jun Oishi, Ryosaku Inagaki, Yutaka Ueda, Shinya Okamoto, Hideaki Okajima, Yoshiharu Sakai, Takaki Sakurai, Hironori Haga, Seiichi Hirota, Hiroki Ikeuchi, Hiroshi Nakase, Hiroyuki Marusawa, Tsutomu Chiba, Osamu Takeuchi, Satoru Miyano, Hiroshi Seno, Seishi Ogawa

Issue&Volume: 2019-12-18

Abstract: Chronic inflammation is accompanied by recurring cycles of tissue destruction and repair and is associated with an increased risk of cancer13. 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. In patients with ulcerative colitis, chronic inflammation can lead to remodelling of the colorectal epithelium through positive selection of clones with mutations in genes related to IL-17 signalling, which, however, might be negatively selected during colitis-associated carcinogenesis.

DOI: 10.1038/s41586-019-1856-1

Source: https://www.nature.com/articles/s41586-019-1856-1

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:69.504
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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