疾病类型-胃癌
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科学家确认卵巢癌一对重要致癌基因和抑癌基因
时间:2015-01-30 09:47:42 来源:生物谷 点击:

 卵巢透明细胞癌(OCCC)是卵巢癌种类中恶性程度高的一种,对化疗不敏感,预后不良。近日,美国University of North Carolina医学院的一群研究人员找到了OCCC发生的两个重要基因ARID1A和PIK3CA,当这两种基因同时发生突变,OCCC的发生率是100%。这篇研究发表在最近一期的

根据以前的癌症基因组测序的结果,研究人员已经知道ARID1A是很多肿瘤,包括OCCC的抑癌基因,并且在OCCC中突变率很高。不过最近研究发现,ARID1A单独突变不足以导致OCCC的行成,除非同时有另一个编码磷酸肌醇3-激酶催化亚基(phosphoinositide 3-kinase catalytic subunit)的基因—PIK3CA的超表达。在小鼠上沉默ARID1A同时激活PIK3CA后,小鼠发展出具有高度渗透性的肿瘤,与OCCC病理类型相似,出现血型腹水,最后生存期都未超过7.5周。随后科研人员在小鼠身上试验一种PI3K抑制药物BKM120,发现肿瘤生长得到抑制,小鼠的存活期显著延长。研究人员表示PIK3CA基因突变就如同一个控制细胞生长的催化剂,与ARID1A突变结合,就能使促癌作用加速。

不过为什么要两个突变结合就能发生100%的致癌效果?研究小组发现了一个关键因子,白细胞介素6(IL-6)参与这个过程。ARID1A与PIK3CA突变,导致IL-6生成过度。一般情况下,IL-6主要介导细胞信号参与炎症反应,但对肿瘤是否有作用还不甚清楚。不过研究人员猜测IL-6能促进OCCC的发展,并可能导致死亡。而ARID1A作为抑癌基因,能抑制这种作用。

总结来说,确定ARID1A和PIK3CA突变对OCCC发展的的作用能帮助未来研究新的卵巢癌药物,更可能作为一种新的肿瘤标志物,用于早期OCCC筛查或者预防。

 

DOI:10.1038 / ncomms7118

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.

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