title: miR-1298 Inhibits Mutant KRAS-Driven Tumor Growth by Repressing FAK and LAMB3.
abstract: Global miRNA functional screens can offer a strategy to identify synthetic lethal interactions in cancer cells that might be exploited therapeutically. In this study, we applied this strategy to identify novel gene interactions in KRAS-mutant cancer cells. In this manner, we discovered miR-1298, a novel miRNA that inhibited the growth of KRAS-driven cells both in vitro and in vivo Using miR-TRAP affinity purification technology, we identified the tyrosine kinase FAK and the laminin subunit LAMB3 as functional targets of miR-1298. Silencing of FAK or LAMB3 recapitulated the synthetic lethal effects of miR-1298 expression in KRAS-driven cancer cells, whereas coexpression of both proteins was critical to rescue miR-1298-induced cell death. Expression of LAMB3 but not FAK was upregulated by mutant KRAS. In clinical specimens, elevated LAMB3 expression correlated with poorer survival in lung cancer patients with an oncogenic KRAS gene signature, suggesting a novel candidate biomarker in this disease setting. Our results define a novel regulatory pathway in KRAS-driven cancers, which offers a potential therapeutic target for their eradication. Cancer Res; 76(19); 5777-87. ©2016 AACR.
authors.affiliation: Program for RNA Biology, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Program for RNA Biology, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California. Department of Pediatrics, University of California San Diego, La Jolla, California.
authors.forename: Jason
authors.initials: J
authors.lastname: Dang
authors.affiliation: Program for RNA Biology, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California. Department of Pediatrics, University of California San Diego, La Jolla, California.
authors.forename: Kung-Yen
authors.initials: KY
authors.lastname: Chang
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, University of California San Diego, La Jolla, California. Solid Tumor Therapeutics Program, Moores Cancer Center, University of California, San Diego, La Jolla, California.
authors.forename: Edwin
authors.initials: E
authors.lastname: Yau
authors.affiliation: Program for RNA Biology, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
authors.forename: Pedro
authors.initials: P
authors.lastname: Aza-Blanc
authors.affiliation: Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
authors.forename: Jorge
authors.initials: J
authors.lastname: Moscat
authors.affiliation: Program for RNA Biology, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California. Department of Pediatrics, University of California San Diego, La Jolla, California. Solid Tumor Therapeutics Program, Moores Cancer Center, University of California, San Diego, La Jolla, California. Institute for Genomic Medicine, University of California San Diego, La Jolla, California. trana@ucsd.edu.
authors.forename: Tariq M
authors.initials: TM
authors.lastname: Rana
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000235:genetics*; D045744:Cell Line, Tumor; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D035683:MicroRNAs / Q000032:analysis / Q000502:physiology*; D009154:Mutation; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D000097794:Kalinin
chemical_list: D015815:Cell Adhesion Molecules; D051416:Focal Adhesion Protein-Tyrosine Kinases; D035683:MicroRNAs; D016283:Proto-Oncogene Proteins p21(ras); D000097794:Kalinin; C117307:KRAS protein, human; C000609803:MIRN1298 microRNA, human