Fumagalli Debora, Gacquer David, Rothé Françoise, Lefort Anne, Libert Frederick, Brown David, Kheddoumi Naima, Shlien Adam, Konopka Tomasz, Salgado Roberto, Larsimont Denis, Polyak Kornelia, Willard-Gallo Karen, Desmedt Christine, Piccart Martine, Abramowicz Marc, Campbell Peter J, Sotiriou Christos, Detours Vincent
Breast Cancer Translational Research Laboratory, Jules Bordet Institute, Université Libre de Bruxelles (ULB), Boulevard de Waterloo, 125-1000 Brussels, Belgium.
IRIBHM, Université Libre de Bruxelles (ULB), Route de Lennik, 808-1070 Brussels, Belgium.
Cell Rep. 2015 Oct 13;13(2):277-89. doi: 10.1016/j.celrep.2015.09.032. Epub 2015 Oct 1.
Little is known about how RNA editing operates in cancer. Transcriptome analysis of 68 normal and cancerous breast tissues revealed that the editing enzyme ADAR acts uniformly, on the same loci, across tissues. In controlled ADAR expression experiments, the editing frequency increased at all loci with ADAR expression levels according to the logistic model. Loci-specific "editabilities," i.e., propensities to be edited by ADAR, were quantifiable by fitting the logistic function to dose-response data. The editing frequency was increased in tumor cells in comparison to normal controls. Type I interferon response and ADAR DNA copy number together explained 53% of ADAR expression variance in breast cancers. ADAR silencing using small hairpin RNA lentivirus transduction in breast cancer cell lines led to less cell proliferation and more apoptosis. A-to-I editing is a pervasive, yet reproducible, source of variation that is globally controlled by 1q amplification and inflammation, both of which are highly prevalent among human cancers.
关于RNA编辑在癌症中如何发挥作用，目前所知甚少。对68个正常和癌性乳腺组织进行的转录组分析表明，编辑酶ADAR在不同组织中对相同位点的作用是一致的。在可控的ADAR表达实验中，根据逻辑模型，所有位点的编辑频率均随ADAR表达水平的升高而增加。通过将逻辑函数拟合到剂量反应数据中，可以量化位点特异性的“可编辑性”，即被ADAR编辑的倾向。与正常对照相比，肿瘤细胞中的编辑频率增加。I型干扰素反应和ADAR DNA拷贝数共同解释了乳腺癌中ADAR表达变异的53%。在乳腺癌细胞系中使用小发夹RNA慢病毒转导沉默ADAR，会导致细胞增殖减少和凋亡增加。A到I编辑是一种普遍存在且可重复的变异来源，受1q扩增和炎症的全局控制，这两者在人类癌症中都非常普遍。
