卵巢癌是女性生殖器官最常見的腫瘤之一,，發(fā)病率僅次于子宮頸癌和子宮體癌而列居第三位。但因卵巢癌致死者，卻占各類婦科腫瘤的首位，對(duì)婦女生命造成嚴(yán)重威脅,。為了更好地了解疾病，并不斷地改善治療方案,，研究人員一直致力于揭示基因組中基因失常導(dǎo)致惡性腫瘤的機(jī)制,。
近日科學(xué)家們發(fā)現(xiàn)了一個(gè)年齡相關(guān)性的基因特異性DNA甲基化累積，并證實(shí)它可通過抑制一個(gè)關(guān)鍵性的細(xì)胞信號(hào)從而導(dǎo)致卵巢癌發(fā)生,。這一發(fā)現(xiàn)對(duì)于未來卵巢癌的轉(zhuǎn)譯研究具有決定性的意義,。研究論文在線發(fā)表在Genome Research雜志上。
DNA甲基化是指通過一種化學(xué)修飾作用導(dǎo)致基因沉默的現(xiàn)象,。研究證實(shí)DNA甲基化可引起機(jī)體抑癌基因失活從而導(dǎo)致多種惡性腫瘤例如卵巢癌發(fā)生,。然而一直以來科學(xué)家們對(duì)于整個(gè)癌癥基因組中DNA甲基化的情況卻了解得不是很清楚，從而阻礙了對(duì)于疾病生物學(xué)基礎(chǔ)的理解,。
在新研究中，由來自美國和日本的研究人員組成的一個(gè)國際研究小組利用轉(zhuǎn)錄子分析的方法對(duì)建系的卵巢癌細(xì)胞及原代培養(yǎng)的卵巢癌細(xì)胞進(jìn)行了全基因組基因表達(dá)分析,，尋找與疾病相關(guān)的DNA甲基化沉默的基因,。然后研究人員在這些細(xì)胞中加入化學(xué)試劑處理阻斷細(xì)胞中的DNA甲基化，再次分析了這些處理細(xì)胞的基因表達(dá)情況,。通過這一策略研究人員在卵巢癌中鑒定了378個(gè)候選的甲基化基因,。當(dāng)研究人員開始著手研究惡性腫瘤中這些甲基化基因的功能時(shí)，發(fā)現(xiàn)了一條與卵巢癌生物學(xué)有關(guān)的線索,。
“我們起初只是希望找到候選的甲基化基因,，”論文的資深作者、杜克大學(xué)醫(yī)學(xué)中心的研究員Susan Murphy說：“我們沒有預(yù)料到我們會(huì)發(fā)現(xiàn)甲基化介導(dǎo)的基因失常與一條特異性的功能信號(hào)TGF-β信號(hào)途徑有關(guān),。”
TGF-β信號(hào)是細(xì)胞內(nèi)一條非常重要的信號(hào)途徑,，參與調(diào)控細(xì)胞生長和分化。在正常情況下它主要起抑制腫瘤生長的作用,，而當(dāng)TGF-β信號(hào)發(fā)生異常時(shí)就會(huì)促進(jìn)腫瘤發(fā)生,。在新研究中研究人員發(fā)現(xiàn)卵巢癌細(xì)胞中的TGF-β超家族基因發(fā)生了甲基化，從而導(dǎo)致了TGF-β信號(hào)抑制,。Murphy和同事們還證實(shí)隨著患者年齡增大TGF-β超家族基因甲基化程度亦增高,，這表明基因特異性的甲基化可隨著時(shí)間而發(fā)生累積,。
Murphy說：“在新研究我們篩查出了多個(gè)甲基化的基因。在下一步的研究工作中我們研究焦點(diǎn)就是揭示這些基因在卵巢癌中的特異性作用,，并基于我們的研究發(fā)現(xiàn)設(shè)計(jì)出卵巢癌的靶向性治療策略,。”（生物谷Bioon.com）
生物谷推薦原文出處：
Genome Research doi:10.1101/gr.108803.110
Epigenetic suppression of the TGF-beta pathway revealed by transcriptome profiling in ovarian cancer
Noriomi Matsumura1,2,7, Zhiqing Huang1,7, Seiichi Mori3,8, Tsukasa Baba1,2, Shingo Fujii4, Ikuo Konishi2, Edwin S. Iversen5, Andrew Berchuck1 and Susan K. Murphy1,6,9
1Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Duke University Medical Center, Durham, North Carolina 27710, USA;
2Department of Gynecology and Obstetrics, Kyoto University, Kyoto 606-8507, Japan;
3Institute for Genome Sciences and Policy, Duke University, Durham, North Carolina 27710, USA;
4National Hospital Organization Kyoto Medical Center, Kyoto 612-8555, Japan;
5Department of Statistical Sciences, Duke University, Durham, North Carolina 27708, USA;
6Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, USA
?8 Present address: Genomic Oncology Program, Cancer Science Institute Singapore, National University of Singapore, Singapore 117456, Singapore.
Abstract
Epithelial ovarian cancer is the leading cause of death among gynecologic malignancies. Diagnosis usually occurs after metastatic spread, largely reflecting vague symptoms of early disease combined with lack of an effective screening strategy. Epigenetic mechanisms of gene regulation, including DNA methylation, are fundamental to normal cellular function and also play a major role in carcinogenesis. To elucidate the biological and clinical relevance of DNA methylation in ovarian cancer, we conducted expression microarray analysis of 39 cell lines and 17 primary culture specimens grown in the presence or absence of DNA methyltransferase (DNMT) inhibitors. Two parameters, induction of expression and standard deviation among untreated samples, identified 378 candidate methylated genes, many relevant to TGF-beta signaling. We analyzed 43 of these genes and they all exhibited methylation. Treatment with DNMT inhibitors increased TGF-beta pathway activity. Hierarchical clustering of ovarian cancers using the 378 genes reproducibly generated a distinct gene cluster strongly correlated with TGF-beta pathway activity that discriminates patients based on age. These data suggest that accumulation of age-related epigenetic modifications leads to suppression of TGF-beta signaling and contributes to ovarian carcinogenesis.
