Suppression of MicroRNA 200 Family Expression by Oncogenic KRAS Activation Promotes Cell Survival and Epithelial-Mesenchymal Transition in KRAS-Driven Cancer
Suppression of MicroRNA 200 Family Expression by Oncogenic KRAS Activation Promotes Cell Survival and Epithelial-Mesenchymal Transition in KRAS-Driven Cancer
复制标题
通过致癌 KRAS 激活抑制 MicroRNA 200 家族表达可促进 KRAS 驱动的癌症中的细胞存活和上皮间质转化
DOI：
10.1128/mcb.00079-16
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发表时间：
2016-08
影响因子：
5.3
通讯作者：
Lin Zhang
中科院分区：
文献类型：
--
作者：
Xinhong He;Janos L. Tanyi;Feng Yang;Lin Zhang
摘要致癌的KRAS在肺癌、结肠癌、胰腺癌和黑色素瘤等多种人类癌症的恶性转化、抗细胞凋亡和转移中起重要作用。MicroRNAs(MiRNAs)是一种内源性的18-25个核苷酸的非编码小RNA，通过降解靶mRNAs或抑制蛋白质翻译，以序列特异性的方式调节基因的表达。在本研究中，通过在表达致癌KRAS的IMR90和MCF10A细胞中进行基于阵列的miRNA分析，我们发现microRNA200(mir-200)家族的表达受到KRAS激活的抑制，并且这种抑制除了ZEB1外还受到转录因子Jun和SP1的介导。恢复mir-200的表达可抑制KRAS诱导的体外细胞转化和体内肿瘤形成。此外，我们还发现，通过直接靶向抗凋亡基因BCL2，mir-200的增强表达可以消除KRAS诱导的细胞凋亡抵抗。最后，mir-200能够拮抗突变KRAS驱动的上皮-间充质转化(EMT)。总之，我们的结果表明，抑制内源性mir-200的表达是肿瘤发生和发展过程中对KRAS激活的重要细胞反应之一。
ABSTRACT Oncogenic KRAS contributes to malignant transformation, antiapoptosis, and metastasis in multiple human cancers, such as lung, colon, and pancreatic cancers and melanoma. MicroRNAs (miRNAs) are endogenous 18- to 25-nucleotide noncoding small RNAs that regulate gene expression in a sequence-specific manner via the degradation of target mRNAs or inhibition of protein translation. In the present study, using array-based miRNA profiling in IMR90 and MCF10A cells expressing oncogenic KRAS, we identified that the expression of the microRNA 200 (mir-200) family was suppressed by KRAS activation and that this suppression was mediated by the transcription factors JUN and SP1 in addition to ZEB1. Restoration of mir-200 expression compromised KRAS-induced cellular transformation in vitro and tumor formation in vivo. In addition, we found that enforced expression of mir-200 abrogated KRAS-induced resistance to apoptosis by directly targeting the antiapoptotic gene BCL2. Finally, mir-200 was able to antagonize the epithelial-mesenchymal transition (EMT) driven by mutant KRAS. Collectively, our results suggest that repression of endogenous mir-200 expression is one of the important cellular responses to KRAS activation during tumor initiation and progression.
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影响因子：
56.9
作者：
Lagos-Quintana, M;Rauhut, R;Tuschl, T
通讯作者：
Tuschl, T
影响因子：
11.2
作者：
R. Fenton;J. Hixon;P. Wright;A. Brooks;T. Sayers
通讯作者：
R. Fenton;J. Hixon;P. Wright;A. Brooks;T. Sayers
影响因子：
4.6
作者：
Ungewiss C;Rizvi ZH;Roybal JD;Peng DH;Gold KA;Shin DH;Creighton CJ;Gibbons DL
通讯作者：
Gibbons DL
影响因子：
4.8
作者：
Finco, TS;Westwick, JK;Baldwin, AS
通讯作者：
Baldwin, AS
影响因子：
64.8
作者：
SMEAL, T;BINETRUY, B;KARIN, M
通讯作者：
KARIN, M