Concurrent Targeting of KRAS and AKT by MiR-4689 Is a Novel Treatment Against Mutant KRAS Colorectal Cancer.
Concurrent Targeting of KRAS and AKT by MiR-4689 Is a Novel Treatment Against Mutant KRAS Colorectal Cancer.
复制标题
DOI：
10.1038/mtna.2015.5
复制
发表时间：
2015-03-10
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
KRAS突变是对分子靶向治疗产生耐药性的主要原因。表皮生长因子受体(EGFR)信号的异常可能导致microRNA(MiRNA)和基因调控网络的失调，从而导致肿瘤的发生和发展。为了探讨miRNAs在突变的KRAS癌中的功能相关性，我们将外源KRASG12V导入含有野生型KRAS和BRAF基因的人胚胎肾293和MRC5细胞中，并对调控异常的miRNAs进行了全面的分析。结果表明，成熟miRNA寡核苷酸(MiR)-4689是KRASG12V过表达细胞中显著下调的miRNAs之一，在体外和体内都具有明显的生长抑制和促凋亡作用。与正常粘膜相比，MIR-4689在癌组织中的表达显著下调，在突变的KRAS结直肠癌组织中尤其降低。MIR-4689直接靶向EGFR途径两个主要分支的关键成分v-Ki-ras2 Kirsten鼠肉瘤病毒癌基因同源基因(KRAS)和v-AKT小鼠胸腺瘤病毒癌基因同源基因1(AKT1)，提示KRAS通过抑制miR-4689而过度驱动这一信号通路。总之，这项研究提供了更多的证据表明，突变的KRAS通过抑制miR-4689而发挥EGFR信号级联的广泛调节作用，miR-4689对RAS/丝裂原激活的蛋白激酶(MAPK)和磷脂酰肌醇3-激酶(PI3K)/AKT通路都具有负面调节作用。这些活性表明miR-4689可能是一种有前途的治疗突变的KRAS结直肠癌的药物。
KRAS mutations are a major cause of drug resistance to molecular-targeted therapies. Aberrant epidermal growth factor receptor (EGFR) signaling may cause dysregulation of microRNA (miRNA) and gene regulatory networks, which leads to cancer initiation and progression. To address the functional relevance of miRNAs in mutant KRAS cancers, we transfected exogenous KRASG12V into human embryonic kidney 293 and MRC5 cells with wild-type KRAS and BRAF genes, and we comprehensively profiled the dysregulated miRNAs. The result showed that mature miRNA oligonucleotide (miR)-4689, one of the significantly down-regulated miRNAs in KRASG12V overexpressed cells, was found to exhibit a potent growth-inhibitory and proapoptotic effect both in vitro and in vivo. miR-4689 expression was significantly down-regulated in cancer tissues compared to normal mucosa, and it was particularly decreased in mutant KRAS CRC tissues. miR-4689 directly targets v-ki-ras2 kirsten rat sarcoma viral oncogene homolog (KRAS) and v-akt murine thymoma viral oncogene homolog 1(AKT1), key components of two major branches in EGFR pathway, suggesting KRAS overdrives this signaling pathway through inhibition of miR-4689. Overall, this study provided additional evidence that mutant KRAS functions as a broad regulator of the EGFR signaling cascade by inhibiting miR-4689, which negatively regulates both RAS/mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/AKT pathways. These activities indicated that miR-4689 may be a promising therapeutic agent in mutant KRAS CRC.
登录
查看更多内容
影响因子：
3.7
作者：
Hossain S;Yamamoto H;Chowdhury EH;Wu X;Hirose H;Haque A;Doki Y;Mori M;Akaike T
通讯作者：
Akaike T
影响因子：
11.5
作者：
Hoeflich, Klaus P.;O'Brien, Carol;Lackner, Mark R.
通讯作者：
Lackner, Mark R.
影响因子：
3.8
作者：
Decuzzi, P;Causa, F;Netti, PA
通讯作者：
Netti, PA
影响因子：
3.5
作者：
Chowdhury, E. H.;Maruyama, A.;Akaike, T.
通讯作者：
Akaike, T.
DOI：
10.2174/1875397301004010084
发表时间：
2010-12-21
期刊：
Current chemical genomics
影响因子：
--
作者：
Cheng Z;Garvin D;Paguio A;Stecha P;Wood K;Fan F
通讯作者：
Fan F