6月11日，J Clin Invest.雜志在線報(bào)道了DNA損傷修復(fù)酶在炎癥與腫瘤中的最新研究進(jìn)展。世界上超過(guò)15%的腫瘤死亡與其伴發(fā)的感染或炎癥有關(guān),。因此,，理解炎癥如何促進(jìn)腫瘤發(fā)生對(duì)于腫瘤的防治具有重要意義,。
由于活化的中性粒細(xì)胞和巨噬細(xì)胞釋放活化氧和氮家族（RONS）,，炎性組織常常具有脂類過(guò)氧化造成的亞乙烯基堿基(ε-base)DNA損傷。炎癥的促癌變作用,，部分是通過(guò)RONS誘導(dǎo)的細(xì)胞毒和突變性DNA損傷（包括ε-base損傷）發(fā)揮的,。小鼠烷基腺嘌呤DNA轉(zhuǎn)葡糖基酶（AAG，也稱為MPG）識(shí)別此類堿基損傷,，因此可防止炎癥相關(guān)的結(jié)腸癌,。另兩種DNA修復(fù)酶ALKBH2和ALKBH3可修復(fù)ε-base損傷。研究者想探索這些DNA加雙氧酶可否保護(hù)機(jī)體免受慢性炎癥引發(fā)的結(jié)腸癌,。
利用化學(xué)試劑誘導(dǎo)結(jié)腸炎和結(jié)腸癌的小鼠模型,，研究者發(fā)現(xiàn)ALKBH2和ALKBH3發(fā)揮類似于AAG的防癌效果,。更為重要的是,，Alkbh2 和 Alkbh3 分別表現(xiàn)出與Aag基因之間的顯著異位顯性。這3種DNA修復(fù)酶的缺陷造成顯著的協(xié)同效應(yīng)表型,。僅一輪化學(xué)誘導(dǎo)性結(jié)腸炎就可導(dǎo)致缺乏這3種酶的實(shí)驗(yàn)動(dòng)物死亡,。（生物谷bioon.com）
doi:10.1016/j.cell.2011.10.017
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DNA repair is indispensable for survival after acute inflammation
Jennifer A. Calvo1,2, Lisiane B. Meira1,2, Chun-Yue I. Lee2,3, Catherine A. Moroski-Erkul1,2, Nona Abolhassani1,2, Koli Taghizadeh2, Lindsey W. Eichinger1,2, Sureshkumar Muthupalani4, Line M. Nordstrand5, Arne Klungland5 and Leona D. Samson1,2,6,7
More than 15% of cancer deaths worldwide are associated with underlying infections or inflammatory conditions, therefore understanding how inflammation contributes to cancer etiology is important for both cancer prevention and treatment. Inflamed tissues are known to harbor elevated etheno-base (ε-base) DNA lesions induced by the lipid peroxidation that is stimulated by reactive oxygen and nitrogen species (RONS) released from activated neutrophils and macrophages. Inflammation contributes to carcinogenesis in part via RONS-induced cytotoxic and mutagenic DNA lesions, including ε-base lesions. The mouse alkyl adenine DNA glycosylase (AAG, also known as MPG) recognizes such base lesions, thus protecting against inflammation-associated colon cancer. Two other DNA repair enzymes are known to repair ε-base lesions, namely ALKBH2 and ALKBH3; thus, we sought to determine whether these DNA dioxygenase enzymes could protect against chronic inflammation-mediated colon carcinogenesis. Using established chemically induced colitis and colon cancer models in mice, we show here that ALKBH2 and ALKBH3 provide cancer protection similar to that of the DNA glycosylase AAG. Moreover, Alkbh2 and Alkbh3 each display apparent epistasis with Aag. Surprisingly, deficiency in all 3 DNA repair enzymes confers a massively synergistic phenotype, such that animals lacking all 3 DNA repair enzymes cannot survive even a single bout of chemically induced colitis.
