Many microRNAs (miRNAs) target mRNAs involved in processes aberrant in tumorigenesis, such as proliferation, survival, and differentiation. In particular, the let-7 miRNA family has been proposed to function in tumor suppression, because reduced expression of let-7 family members is common in non-small cell lung cancer (NSCLC). Here, we show that let-7 functionally inhibits non-small cell tumor development. Ectopic expression of let-7g in K-RasG12D-expressing murine lung cancer cells induced both cell cycle arrest and cell death. In tumor xenografts, we observed significant growth reduction of both murine and human non-small cell lung tumors when overexpression of let-7g was induced from lentiviral vectors. In let-7g expressing tumors, reductions in Ras family and HMGA2 protein levels were detected. Importantly, let-7g-mediated tumor suppression was more potent in lung cancer cell lines harboring oncogenic K-Ras mutations than in lines with other mutations. Ectopic expression of K-RasG12D largely rescued let-7g mediated tumor suppression, whereas ectopic expression of HMGA2 was less effective. Finally, in an autochthonous model of NSCLC in the mouse, let-7g expression substantially reduced lung tumor burden.

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Keywords K-Ras, Lung cancer
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Journal Proceedings of the National Academy of Sciences of the United States of America
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Kumar, M.S, Erkeland, S.J, Pester, R.E, Chen, C.Y, Ebert, M.S, Sharp, P.A, & Jacks, T. (2008). Suppression of non-small cell lung tumor development by the let-7 microRNA family. Proceedings of the National Academy of Sciences of the United States of America, 105(10), 3903–3908. doi:10.1073/pnas.0712321105