Suppression of MicroRNA 200 Family Expression by Oncogenic KRAS Activation Promotes Cell Survival and Epithelial-Mesenchymal Transition in KRAS-Driven Cancer

• Published in: Molecular and cellular biology Vol. 36; no. 21; pp. 2742 - 2754
• Main Authors: Zhong, Xiaomin, Zheng, Lan, Shen, Jianfeng, Zhang, Dongmei, Xiong, Minmin, Zhang, Youyou, He, Xinhong, Tanyi, Janos L., Yang, Feng, Montone, Kathleen T., Chen, Xiaojun, Xu, Congjian, Xiang, Andy P., Huang, Qihong, Xu, Xiaowei, Zhang, Lin
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 01.11.2016; American Society for Microbiology
• Subjects: apoptosis; Apoptosis - genetics; Base Sequence; Cell Line, Tumor; Cell Survival - genetics; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - pathology; cell viability; colon; Epithelial-Mesenchymal Transition - genetics; gene expression; Gene Expression Regulation, Neoplastic; genes; Humans; lungs; melanoma; metastasis; microRNA; MicroRNAs - genetics; mutants; Neoplasms - genetics; Oncogenes; Proto-Oncogene Proteins c-jun - metabolism; Proto-Oncogene Proteins p21(ras) - metabolism; Signal Transduction - genetics; Sp1 Transcription Factor
• DOI: 10.1128/MCB.00079-16
• ISSN: 1098-5549; 0270-7306

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.