title: Suppression of non-small cell lung tumor development by the let-7 microRNA family.
abstract: 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.
authors.affiliation: Center for Cancer Research and Department of Biology, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Madhu S
authors.initials: MS
authors.lastname: Kumar
authors.forename: Stefan J
authors.initials: SJ
authors.lastname: Erkeland
authors.forename: Ryan E
authors.initials: RE
authors.lastname: Pester
authors.forename: Cindy Y
authors.initials: CY
authors.lastname: Chen
authors.forename: Margaret S
authors.initials: MS
authors.lastname: Ebert
authors.forename: Phillip A
authors.initials: PA
authors.lastname: Sharp
authors.forename: Tyler
authors.initials: T
authors.lastname: Jacks
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology*; D016923:Cell Death; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004195:Disease Models, Animal; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology*; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D050505:Mutant Proteins / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
chemical_list: D035683:MicroRNAs; D050505:Mutant Proteins; D018631:ras Proteins