卵巢透明細(xì)胞癌（OCCC）是卵巢癌種類中惡性程度高的一種，對化療不敏感，預(yù)后不良。近日，美國University of North Carolina醫(yī)學(xué)院的一群研究人員找到了OCCC發(fā)生的兩個重要基因ARID1A和PIK3CA，當(dāng)這兩種基因同時發(fā)生突變，OCCC的發(fā)生率是100%。這篇研究發(fā)表在最近一期的
根據(jù)以前的癌癥基因組測序的結(jié)果，研究人員已經(jīng)知道ARID1A是很多腫瘤，包括OCCC的抑癌基因，并且在OCCC中突變率很高。不過最近研究發(fā)現(xiàn)，ARID1A單獨(dú)突變不足以導(dǎo)致OCCC的行成，除非同時有另一個編碼磷酸肌醇3-激酶催化亞基（phosphoinositide 3-kinase catalytic subunit）的基因—PIK3CA的超表達(dá)。在小鼠上沉默ARID1A同時激活PIK3CA后，小鼠發(fā)展出具有高度滲透性的腫瘤，與OCCC病理類型相似，出現(xiàn)血型腹水，最后生存期都未超過7.5周。隨后科研人員在小鼠身上試驗(yàn)一種PI3K抑制藥物BKM120，發(fā)現(xiàn)腫瘤生長得到抑制，小鼠的存活期顯著延長。研究人員表示PIK3CA基因突變就如同一個控制細(xì)胞生長的催化劑，與ARID1A突變結(jié)合，就能使促癌作用加速。
不過為什么要兩個突變結(jié)合就能發(fā)生100%的致癌效果？研究小組發(fā)現(xiàn)了一個關(guān)鍵因子，白細(xì)胞介素6（IL-6）參與這個過程。ARID1A與PIK3CA突變，導(dǎo)致IL-6生成過度。一般情況下，IL-6主要介導(dǎo)細(xì)胞信號參與炎癥反應(yīng)，但對腫瘤是否有作用還不甚清楚。不過研究人員猜測IL-6能促進(jìn)OCCC的發(fā)展，并可能導(dǎo)致死亡。而ARID1A作為抑癌基因，能抑制這種作用。
總結(jié)來說，確定ARID1A和PIK3CA突變對OCCC發(fā)展的的作用能幫助未來研究新的卵巢癌藥物，更可能作為一種新的腫瘤標(biāo)志物，用于早期OCCC篩查或者預(yù)防。
Coexistent ARID1A–PIK3CA mutations promote ovarian clear-cell tumorigenesis through pro-tumorigenic inflammatory cytokine signalling
Ronald L. Chandler, Jeffrey S. Damrauer, Jesse R. Raab, Jonathan C. Schisler, Matthew D. Wilkerson, John P. Didion, Joshua Starmer, Daniel Serber, Della Yee, Jessie Xiong, David B. Darr, Fernando Pardo-Manuel de Villena, William Y. Kim, Terry Magnuson.
Abstract
Ovarian clear-cell carcinoma (OCCC) is an aggressive form of ovarian cancer with high ARID1A mutation rates. Here we present a mutant mouse model of OCCC. We find that ARID1A inactivation is not sufficient for tumour formation, but requires concurrent activation of the phosphoinositide 3-kinase catalytic subunit, PIK3CA. Remarkably, the mice develop highly penetrant tumours with OCCC-like histopathology, culminating in haemorrhagic ascites and a median survival period of 7.5 weeks. Therapeutic treatment with the pan-PI3K inhibitor, BKM120, prolongs mouse survival by inhibiting the tumour cell growth. Cross-species gene expression comparisons support a role for IL-6 inflammatory cytokine signalling in OCCC pathogenesis. We further show that ARID1A and PIK3CA mutations cooperate to promote tumour growth through sustained IL-6 overproduction. Our findings establish an epistatic relationship between SWI/SNF chromatin remodelling and PI3K pathway mutations in OCCC and demonstrate that these pathways converge on pro-tumorigenic cytokine signalling. We propose that ARID1A protects against inflammation-driven tumorigenesis.
