MacKenzie Douglas J, Robertson Neil A, Rather Iqbal, Reid Claire, Sendzikaite Gintare, Cruickshanks Hazel, McBryan Tony, Hodges Andrew, Pritchard Catrin, Blyth Karen, Adams Peter D
Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
iScience. 2020 Feb 21;23(2):100838. doi: 10.1016/j.isci.2020.100838. Epub 2020 Jan 14.
Approximately 10% of human colorectal cancer (CRC) are associated with activated BRAFV600E mutation, typically in absence of APC mutation and often associated with a CpG island methylator (CIMP) phenotype. To protect from cancer, normal intestinal epithelial cells respond to oncogenic BRAFV600E by activation of intrinsic p53 and p16-dependent tumor suppressor mechanisms, such as cellular senescence. Conversely, CIMP is thought to contribute to bypass of these tumor suppressor mechanisms, e.g. via epigenetic silencing of tumor suppressor genes, such as p16. It has been repeatedly proposed that DNMT3B is responsible for BRAFV600E-induced CIMP in human CRC. Here we set out to test this by in silico, in vitro, and in vivo approaches. We conclude that although both BRAFV600E and DNMT3B harbor oncogenic potential in vitro and in vivo and show some evidence of cooperation in tumor promotion, they do not frequently cooperate to promote CIMP and human intestinal cancer.
大约10%的人类结直肠癌（CRC）与激活的BRAFV600E突变相关，通常不存在APC突变，且常与CpG岛甲基化表型（CIMP）相关。为了预防癌症，正常肠上皮细胞通过激活内在的p53和p16依赖性肿瘤抑制机制（如细胞衰老）来应对致癌性BRAFV600E。相反，CIMP被认为有助于绕过这些肿瘤抑制机制，例如通过肿瘤抑制基因（如p16）的表观遗传沉默。人们一再提出，DNMT3B负责BRAFV600E诱导的人类CRC中的CIMP。在这里，我们通过计算机模拟、体外和体内方法来验证这一点。我们得出的结论是，尽管BRAFV600E和DNMT3B在体外和体内都具有致癌潜力，并显示出一些在肿瘤促进方面的合作证据，但它们并不经常合作来促进CIMP和人类肠道癌。
