Lung cancer is the leading cause of cancer death worldwide, largely due to its highly metastatic nature. Hence, elucidating the molecular mechanisms for tumor metastasis remains one of the most pressing challenges in lung cancer research. To date, most studies on cancer metastasis have focused on protein-coding genes, yet it has become increasingly clear that non-coding RNAs, particularly, microRNAs (miRNAs), are integral components of the molecular network for cancer metastasis, Using a Kras-driven, p53 deficient lung adenocarcinoma mouse model, we compared the miRNA expression profiles between primary and metastatic lung tumors, and identified miR-200 miRNAs as the most downregulated miRNAs in lung cancer metastases. The miR-200 family consists of five homologous miRNAs located at two genomic loci: mir- 200b/200a/429 and mir-200c/141. To characterize miR-200 functions in lung cancer metastasis, we generated KrasLSL-G12D/+;p53fl/fl; mir-200c/141-/- (KP200cKO) mice, which exhibited a significant increase of tumor metastases within a short latency. Interestingly, all metastatic KP200cKO tumors examined exhibited a complete silencing of all miR-200 miRNAs, suggesting that a complete loss of miR-200 redundancy was essential for developing cancer metastasis in this model. Based on these preliminary findings, we hypothesize that miR-200 miRNAs are key repressors of cancer metastasis in Kras-driven, p53 deficient lung adenocarcinomas. Using mouse genetics, CRISPR genome editing, cell and molecular approaches, we propose to comprehensively characterize the importance of miR-200 miRNAs during lung cancer metastasis, and will elucidate the underlying molecular and cellular mechanisms that govern the biological functions and transcriptional regulation of miR-200 miRNAs. Our proposed studies will provide important insights into a highly robust mechanism to repress lung cancer metastasis.

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Using a combined approach of mouse genetics, CRISPR genome editing, cell biology and molecular biology, our proposed studies aim to characterize the functional importance of the miR200 family miRNAs in repressing lung cancer metastasis. These studies will not only generate important insights into the molecular regulation of lung cancer metastasis, but also contribute to the development of novel diagnostic markers and therapeutic targets for metastatic lung cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Cancer Molecular Pathobiology Study Section (CAMP)
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Ault, Grace S
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University of California Berkeley
Schools of Arts and Sciences
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Modzelewski, Andrew J; Chen, Sean; Willis, Brandon J et al. (2018) Efficient mouse genome engineering by CRISPR-EZ technology. Nat Protoc 13:1253-1274
Li, Meng Amy; Amaral, Paulo P; Cheung, Priscilla et al. (2017) A lncRNA fine tunes the dynamics of a cell state transition involving Lin28, let-7 and de novo DNA methylation. Elife 6:
Choi, Yong Jin; Lin, Chao-Po; Risso, Davide et al. (2017) Deficiency of microRNA miR-34a expands cell fate potential in pluripotent stem cells. Science 355:
Chen, Sean; Lee, Benjamin; Lee, Angus Yiu-Fai et al. (2016) Highly Efficient Mouse Genome Editing by CRISPR Ribonucleoprotein Electroporation of Zygotes. J Biol Chem 291:14457-67
Olive, Virginie; Minella, Alex C; He, Lin (2015) Outside the coding genome, mammalian microRNAs confer structural and functional complexity. Sci Signal 8:re2
Mor, Eyal; He, Lin; Torchinsky, Arkady et al. (2014) MicroRNA-34a is dispensable for p53 function as teratogenesis inducer. Arch Toxicol 88:1749-63
Song, Rui; Walentek, Peter; Sponer, Nicole et al. (2014) miR-34/449 miRNAs are required for motile ciliogenesis by repressing cp110. Nature 510:115-20
Krzeszinski, Jing Y; Wei, Wei; Huynh, HoangDinh et al. (2014) miR-34a blocks osteoporosis and bone metastasis by inhibiting osteoclastogenesis and Tgif2. Nature 512:431-5
Xue, Bin; He, Lin (2014) An expanding universe of the non-coding genome in cancer biology. Carcinogenesis 35:1209-16
Okada, Nobuhiro; Lin, Chao-Po; Ribeiro, Marcelo C et al. (2014) A positive feedback between p53 and miR-34 miRNAs mediates tumor suppression. Genes Dev 28:438-50

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