因感染或慢性腸炎等疾病而引發(fā)的慢性炎癥與近四分之一的癌癥相關(guān),。然而，它們之間到底存在著什么樣的關(guān)聯(lián)呢？最近，PNAS雜志上的一篇論文講述了炎癥如何導(dǎo)致癌癥。
這篇論文的作者是俄亥俄州立大學(xué)醫(yī)學(xué)中心和綜合癌癥中心的研究人員,，他們發(fā)現(xiàn)炎癥刺激了一種microRNA分子（miR-155）水平的升高,。這導(dǎo)致參與DNA修復(fù)的蛋白水平下降，使基因自發(fā)突變率更高,，從而導(dǎo)致癌癥,。
文章的第一作者Esmerina Tili博士談到：“人們懷疑炎癥在癌癥中扮演了重要角色，而我們的研究提出了一種分子機制,。研究表明炎癥刺激上調(diào)了miR-155,，而miR-155的過表達又提高了自發(fā)突變率，這可能導(dǎo)致腫瘤生成,。”
MicroRNA（miRNA）雖然只有短短22個堿基,，但卻在體內(nèi)發(fā)揮著重要的基因表達調(diào)控作用。它們通過抑制特定蛋白的表達來執(zhí)行調(diào)控功能,，一個miRNA可能調(diào)控了若干個蛋白,，而一個蛋白又受到多個miRNA的調(diào)控。
miR-155這種分子能影響血細胞成熟,，免疫反應(yīng)和自體免疫疾病,，而高水平的分子更是與白血病、乳腺癌,、肺癌等疾病直接關(guān)聯(lián),。
在這項研究中，Till和她的同事研究了促炎癥物質(zhì)（如腫瘤壞死因子或脂多糖）對miR-155表達以及對幾種乳腺癌細胞系中自發(fā)突變頻率的影響,。
當乳腺癌細胞暴露在兩種炎癥因子下,，miR-155水平異常升高，突變率也提高2-3倍,。為了研究這種現(xiàn)象出現(xiàn)的原因,，她們將目光投向WEE1基因，這種基因停止了細胞分裂的過程，讓受損DNA得以修復(fù),。
研究人員知道m(xù)iR-155會靶定WEE1,，且高水平的miR-155導(dǎo)致了低水平的WEE1。她們推斷,，低水平的WEE1讓存在DNA損傷的細胞繼續(xù)分裂,，從而產(chǎn)生更多突變。
俄亥俄州立大學(xué)的PI Carlo M. Croce教授表示：“普遍認為,，癌癥是由機體細胞的突變累積而引發(fā)的,。我們的研究表明miR-155提高了突變率，可能在炎癥引發(fā)的癌癥中扮演了關(guān)鍵角色,。”
這項研究成果表明,，miR-155可能成為一個新的治療靶點，那些能降低miR-155水平的藥物有望改善炎癥相關(guān)癌癥的治療,。（生物谷Bioon.com）
生物谷推薦原文出處：
Proceedings of the National Academy of Sciences DOI：10.1073/pnas.1101795108
Mutator activity induced by microRNA-155 (miR-155) links inflammation and cancer
Tili, Esmerina; Michaille, Jean-Jacques; Wernicke, Dorothee; Alder, Hansjuerg; Costinean, Stefan; Volinia, Stefano; Croce, Carlo M.
Infection-driven inflammation has been implicated in the pathogenesis of ~15–20% of human tumors. Expression of microRNA-155(miR-155) is elevated during innate immune response and autoimmune disorders as well as in various malignancies. However, the molecularmechanisms providing miR-155 with its oncogenic properties remain unclear. We examined the effects of miR-155 overexpression and proinflammatory environment on the frequency of spontaneous hypoxanthine phosphoribosyltransferase (HPRT) mutations that can be detected based on the resistance to 6-thioguanine. Both miR-155 overexpression and inflammatory environment increased the frequency of HPRT mutations and down-regulated WEE1 (WEE1 homolog-S. pombe), a kinase that blocks cell-cycle progression. The increased frequencyof HPRT mutation was only modestly attributable to defects in mismatch repair machinery. This result suggests that miR-155 enhances the mutation rate by simultaneously targeting different genes that suppress mutations and decreasing the efficiencyof DNA safeguard mechanisms by targeting of cell-cycle regulators such as WEE1. By simultaneously targeting tumor suppressorgenes and inducing a mutator phenotype, miR-155 may allow the selection of gene alterations required for tumor development and progression. Hence, we anticipate that thedevelopment of drugs reducing endogenous miR-155 levels might be key in the treatment of inflammation-related cancers.
