COMBINATION THERAPY OF MICRORNAS LET-7, MIR-34A, AND MIR-30 MAY REDUCE TUMOR GROWTH IN NON-SMALL CELL LUNG CANCER (NSCLC)

Abstract

MicroRNAs (miRNAs or miRs) are evolutionarily conserved non-protein coding molecules that play a central role in the regulation of post-transcriptional eukaryotic gene expression by affecting the translation and stability of mRNAs. Alterations in miRNA functions have been associated with various diseases, including different types of cancers such as lung, breast or kidney. Signatures of various miRNAs can help in identifying and defining the type of tumor, expression of miRNAs levels, prognosis and response to treatment. Notably the oncogenic miRNAs miR-17-92 and mi R-155 have the potential to cause cancerous growths and are evident due to their high quantities or mutated states. Decreased expression of miRNAs such as lei-7, miR-30, and miR-34a have been detected in lung cancer tissues compared to the normal tissues. Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths and its gene signatures have depicted typical protein-coding gene mutations as well as subsets of microRNAs that are aberrantly expressed. The current study focuses on over expressing these three tumor suppressive miRNAs (let-7, miR-34a, and miR- 30) to show that they play a significant role in tumor suppression. Let-7 is a tumor suppressor and its family members have been shown to suppress genes including c-MYC, KI?AS, HMGA2, and LEN28 isoforms..MiR-34a acts as a tumor-suppressor gene by targeting many oncogenes, (c-MYC, MET, BCL-2, sum., FIDAC, SNAIL", FOX1131, and CTNNB1) related to proliferation, apoptosis, and invasion while miR-30 over-expression promotes myogenic differentiation while its inhibition hinders myoblast differentiation. The reduction in let-7, miR-34a, and miR 30 are particularly relevant to the NSCLC oncogenic phenotype as these miRNAs target key oncogenes involved in multiple stages of the tumorigenic process and in the maintenance of oncogene addiction such as /?AS, 13(12, MET, and MYC'. In viiro studies will be done using human lung cancer cell lines to show decreased tumorigenesis when all three miRNAs are over-expressed simultaneously. Additionally, the KICISLSL G 121Y+ ; p5 .3'fl vfix NSCLC mouse model will be used for the in vivo studies to determine the antitumor activities of the three miRNAs when increasing over expression. The results should show that over-expressing let-7, miR 34a, and miR-30 simultaneously results in an even broader repression of key oncogenes and enhanced efficacy in aggressive NSCLC compared to treatment with one or two miRNAs.