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

TitleSuppression of non-small cell lung tumor development by the let-7 microRNA family.
Publication TypeJournal Article
Year of Publication2008
AuthorsKumar, MS, Erkeland, SJ, Pester, RE, Chen, CY, Ebert, MS, Sharp, PA, Jacks, T
JournalProc Natl Acad Sci U S A
Date Published2008 Mar 11
KeywordsAnimals, Carcinoma, Non-Small-Cell Lung, Cell Death, Cell Line, Cell Line, Tumor, Cell Proliferation, Disease Models, Animal, Humans, Lung Neoplasms, Male, Mice, MicroRNAs, Mutant Proteins, ras Proteins

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.

Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID18308936
PubMed Central IDPMC2268826
Grant List2-PO1-CA42063-21 / CA / NCI NIH HHS / United States
P30-CA14051 / CA / NCI NIH HHS / United States
R01-GM34277 / GM / NIGMS NIH HHS / United States
U54 CA112967 / CA / NCI NIH HHS / United States
/ / Howard Hughes Medical Institute / United States