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Nature:慢性炎症是恶性淋巴瘤的导火线

来源:新华网 2009-05-11 15:51

专题:Nature报道

日本东京大学研究人员在最新一期《自然》杂志网络版上报告说,长期患胃炎等慢性炎症是诱发部分恶性淋巴瘤的导火线。

恶性淋巴瘤是承担免疫功能的淋巴细胞癌变生成的。东京大学研究人员开发出一种能高效检测碱基排列个体差异的技术,并利用这项技术对约300名恶性淋巴瘤患者进行分析。

结果显示,主要发生在消化道的“黏膜相关淋巴组织淋巴瘤”等恶性淋巴瘤患者中,约20%的人A20基因的碱基序列存在变异,导致A20基因不能正常工作。

A20基因在人体出现炎症时发挥“刹车”作用,使得淋巴细胞不会无限增殖。研究人员将A20基因不起作用的淋巴癌细胞移植到实验鼠体内,结果实验鼠一旦出现炎症,炎症所产生的物质就会刺激淋巴癌细胞,导致其异常增殖,最后生成恶性淋巴瘤。

如果给实验鼠植入A20基因不能正常工作的淋巴癌细胞,但其体内没有炎症,那么淋巴癌细胞就不会增殖。因此,日本研究人员认为,炎症是诱发某些恶性淋巴瘤的导火线。(生物谷Bioon.com)

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Nature advance online publication 3 May 2009 | doi:10.1038/nature07969

Frequent inactivation of A20 in B-cell lymphomas

Motohiro Kato1,2, Masashi Sanada1,5, Itaru Kato6, Yasuharu Sato7, Junko Takita1,2,3, Kengo Takeuchi8, Akira Niwa6, Yuyan Chen1,2, Kumi Nakazaki1,4,5, Junko Nomoto9, Yoshitaka Asakura9, Satsuki Muto1, Azusa Tamura1, Mitsuru Iio1, Yoshiki Akatsuka11, Yasuhide Hayashi12, Hiraku Mori13, Takashi Igarashi2, Mineo Kurokawa4, Shigeru Chiba3, Shigeo Mori14, Yuichi Ishikawa8, Koji Okamoto10, Kensei Tobinai9, Hitoshi Nakagama10, Tatsutoshi Nakahata6, Tadashi Yoshino7, Yukio Kobayashi9 & Seishi Ogawa1,5

1 Cancer Genomics Project, Department of,
2 Pediatrics,
3 Cell Therapy and Transplantation Medicine, and,
4 Hematology and Oncology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
5 Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, 4-1-8, Honcho, Kawaguchi-shi, Saitama 332-0012, Japan
6 Department of Pediatrics, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
7 Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan
8 Division of Pathology, The Cancer Institute of Japanese Foundation for Cancer Research, Japan, 3-10-6 Ariake, Koto-ku, Tokyo 135-8550, Japan
9 Hematology Division, Hospital, and,
10 Early Oncogenesis Research Project, Research Institute, National Cancer Center, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
11 Division of Immunology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan
12 Gunma Children's Medical Center, 779 Shimohakoda, Hokkitsu-machi, Shibukawa 377-8577, Japan
13 Division of Hematology, Internal Medicine, Showa University Fujigaoka Hospital, 1-30, Fujigaoka, Aoba-ku, Yokohama-shi, Kanagawa 227-8501, Japan
14 Department of Pathology, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan

A20 is a negative regulator of the NF-B pathway and was initially identified as being rapidly induced after tumour-necrosis factor- stimulation1. It has a pivotal role in regulation of the immune response and prevents excessive activation of NF-B in response to a variety of external stimuli2, 3, 4, 5, 6, 7; recent genetic studies have disclosed putative associations of polymorphic A20 (also called TNFAIP3) alleles with autoimmune disease risk8, 9. However, the involvement of A20 in the development of human cancers is unknown. Here we show, using a genome-wide analysis of genetic lesions in 238 B-cell lymphomas, that A20 is a common genetic target in B-lineage lymphomas. A20 is frequently inactivated by somatic mutations and/or deletions in mucosa-associated tissue lymphoma (18 out of 87; 21.8%) and Hodgkin's lymphoma of nodular sclerosis histology (5 out of 15; 33.3%), and, to a lesser extent, in other B-lineage lymphomas. When re-expressed in a lymphoma-derived cell line with no functional A20 alleles, wild-type A20, but not mutant A20, resulted in suppression of cell growth and induction of apoptosis, accompanied by downregulation of NF-B activation. The A20-deficient cells stably generated tumours in immunodeficient mice, whereas the tumorigenicity was effectively suppressed by re-expression of A20. In A20-deficient cells, suppression of both cell growth and NF-B activity due to re-expression of A20 depended, at least partly, on cell-surface-receptor signalling, including the tumour-necrosis factor receptor. Considering the physiological function of A20 in the negative modulation of NF-B activation induced by multiple upstream stimuli, our findings indicate that uncontrolled signalling of NF-B caused by loss of A20 function is involved in the pathogenesis of subsets of B-lineage lymphomas.

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