慢性炎症或可致癌的机制

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作者：Guido Marcucci 来源：《癌症细胞》 发布时间：2012-11-14 15:48:38. @5 B: H% {# E# m

科学家发现慢性炎症或可致癌机制 " S  W7 H$ X: U/ H( c 图片来源：en.wikipedia.org   L( N$ h% P  F( F' a3 z& ~ 近日，刊登在《癌症细胞》期刊上的一项新研究显示，人体制造的一种类似于激素的促进炎症的物质，在处于高水平的时候，可能会导致一种恶性白血病。$ g8 {! h3 K) V, M6 X5 R - i- e  ^+ L5 d) Y 虽然，人们知道诸如晒伤等慢性炎症有时候可能导致癌症，但是一直不清楚其背后的机理是什么。美国俄亥俄州立大学综合癌症中心，Arthur G. James癌症医院（OSUCCC-James）和Richard J. Solove研究所的科研人员发现，高水平的白细胞介素15（IL-15）可以在动物模型中导致大颗粒淋巴细胞（LGL）白血病—— 一种罕见的而且常常致命的癌症。+ X; n6 }' s, f) V1 Z* j0 R 1 J. i' G( |; N3 C) F: I3 K9 g通常，人体内释放白细胞介素15能刺激天然“杀手”细胞——破坏癌细胞和被病毒感染细胞的免疫细胞——的发育、生存和增殖。但是，当白细胞介素15在体内长期以高数量存在的时候——诸如在慢性炎症期间——它可能导致大颗粒淋巴细胞的特定免疫细胞变成癌细胞。8 P# O. D! e4 I* E - M' ~- K% r/ `% {, k4 y% _研究人员表示，白细胞介素15与正常的大颗粒淋巴细胞表面上的受体结合时，会提升细胞内部的致癌蛋白质的水平。高致癌蛋白质水平反过来会带来染色体不稳定和额外的基因突变，还会激活一个称为DNA甲基化的过程，这个过程会关闭一批基因，包括通常会抑制肿瘤生长的重要基因。2 P& j! Z  W; x/ {7 v/ p( m ( E" e+ `/ G9 V, a2 k8 _9 I与此同时，这组科研人员还开发出了针对这种白血病的疗法。他们研究出了一种蛋白酶体抑制剂硼替佐米的脂质体剂型，它能关闭致癌路径，有可能治愈这种恶性疾病。实验中，接受这种脂质体硼替佐米治疗的白血病小鼠在130天里表现出了100%的存活率，而对照组的动物在60~80天里表现出了100%的死亡率。并且这一疗法在动物模型中没有表现出可辨别的副作用。（来源：中国科学报  张章）5 C1 v+ q8 j% D7 z& G $ [& t$ h( y' o, M! I

Aberrant Overexpression of IL-15 Initiates Large Granular Lymphocyte Leukemia through Chromosomal Instability and DNA Hypermethylation : R" b8 M5 ^' i' l8 e, |! B
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Cancer Cell, Volume 22, Issue 5, 645-655, 13 November 2012
# o6 ?" i5 l- b& N1 p: y' YCopyright 2012 Elsevier Inc. All rights reserved.: i9 ]6 @9 K5 V- F7 V/ S9 L8 h: g8 G
10.1016/j.ccr.2012.09.009

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AuthorsAnjali Mishra, Shujun Liu, Gregory H. Sams, Douglas P. Curphey, Ramasamy Santhanam, Laura J. Rush, Deanna Schaefer, Lauren G. Falkenberg, Laura Sullivan, Laura Jaroncyk, Xiaojuan Yang, Harold Fisk, Lai-Chu Wu, Christopher Hickey, Jason C. Chandler, Yue-Zhong Wu, Nyla A. Heerema, Kenneth K. Chan, Danilo Perrotti, Jianying Zhang, Pierluigi Porcu, Frederick K. Racke, Ramiro Garzon, Robert J. Lee, Guido Marcucci, Michael A. CaligiuriSee Affiliations7 y* w6 g6 [" U7 _& w; |, @# }' a

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Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH 43210, USA Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, OH 43210, USA College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210, USA Department of Molecular Genetics, The Ohio State University, Columbus, OH 43210, USA Department of Pathology, The Ohio State University, Columbus, OH 43210, USA College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA Center for Biostatistics, The Ohio State University, Columbus, OH 43210, USA The Comprehensive Cancer Center and The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, OH 43210, USA Corresponding author These authors contributed equally to this work
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• Highlights
• A single pro-inflammatory cytokine, IL-15, can initiate malignant transformation
• IL-15-mediated induction of Myc is central to the genesis of leukemia
• Targeting miR-29b with a single therapeutic induces long-term remission of leukemia: z; a! |  X: b6 B: ~, ?4 G
  

SummaryHow inflammation causes cancer is unclear. Interleukin-15 (IL-15) is a pro-inflammatory cytokine elevated in human large granular lymphocyte (LGL) leukemia. Mice overexpressing IL-15 develop LGL leukemia. Here, we show that prolonged in vitro exposure of wild-type (WT) LGL to IL-15 results in Myc-mediated upregulation of aurora kinases, centrosome aberrancies, and aneuploidy. Simultaneously, IL-15 represses miR-29b via induction of Myc/NF-Bp65/Hdac-1, resulting in Dnmt3b overexpression and DNA hypermethylation. All this is validated in human LGL leukemia. Adoptive transfer of WT LGL cultured with IL-15 led to malignant transformation in vivo. Drug targeting that reverses miR-29b repression cures otherwise fatal LGL leukemia. We show how excessive IL-15 initiates cancer and demonstrate effective drug targeting for potential therapy of human LGL leukemia.
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, S# a! D' u' E  Z: Thttps://www.cell.com/cancer-cell/abstract/S1535-6108(12)00394-7