"Suppression of non-small cell lung tumor development by the let-7 microRNA family".

Madhu S. Kumar*, Stefan J. Erkeland ¹, Ryan E. Pester*, Cindy Y. Chen*, Margaret S. Ebert*, Phillip A. Sharp*^{, @}, and Tyler Jacks*^{, 2, @}

*Center for Cancer Research and ² Department of Biology, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139; and
¹ Department of Hematology, Erasmus University Medical Center, 3015 GE, Rotterdam, The Netherlands

^@ To whom correspondence may be addressed. E-mail: sharppa@mit.edu  or  tjacks@mit.edu

Author contributions: M.S.K. and S.J.E. contributed equally to this work; M.S.K., S.J.E., P.A.S., and T.J. designed research; M.S.K., S.J.E., R.E.P., C.Y.C., and M.S.E. performed research; M.S.K. and S.J.E. analyzed data; and M.S.K., S.J.E., P.A.S., and T.J. wrote the paper.
The authors declare no conflict of interest.

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-Ras^G12D-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-Ras^G12D 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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