The primary objective of this proposal is to determine if microRNAs participate in the regulation of critical genes implicated in lung cancer drug sensitivity. We have developed a computational method to predict interactions between miRNAs and mRNAs. Based on this method, we predict that a number of oncogenes, tumor suppressor genes, and genes relevant to drug resistance are regulated by miRNAs. We have confirmed several of these predictions using miRNA expression profiling data on a small number of cell lines, including small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC) and immortalized human bronchial epithelial (HBEC) cell lines. We will use a combination of in silico and in vitro approaches to address the following questions: Are specific microRNA expression profiles correlated with differential drug sensitivity in lung cancer cell lines? Do microRNAs play a functional role in drug sensitivity/resistance of lung cancer cells? Can microRNA expression levels be manipulated to increase drug sensitivity of lung cancer cells in cell culture? Study design: We will use microRNA microarray to identify miRNAs that are differentially expressed across a panel of lung cancer cell lines. We will then predict the mRNA targets of the regulated miRNAs using both our own bioinformatics tools as well as those developed by other investigators. We will perform studies in cultured cells using a reporter assay system to determine if expression of the miRNA is associated with repressed translation of the predicted target mRNA in cultured cells. Finally, we will determine if over-expression or silencing of the microRNAs affects mRNA translation of the target gene(s) and results in specific changes in sensitivity to widely-used anti-cancer drugs. Cancer relevance: Identifying aberrant miRNA expression consistent with the models of miRNA involvement in cancer can provide new insight into lung cancer disease mechanisms, and a new set of diagnostic markers and therapeutic targets which could play a significant role in the treatment of human disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA129632-05
Application #
8115167
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Arya, Suresh
Project Start
2007-09-25
Project End
2011-08-31
Budget Start
2011-08-01
Budget End
2011-08-31
Support Year
5
Fiscal Year
2011
Total Cost
$14,099
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Borkowski, Robert; Du, Liqin; Zhao, Zhenze et al. (2015) Genetic mutation of p53 and suppression of the miR-17?92 cluster are synthetic lethal in non-small cell lung cancer due to upregulation of vitamin D Signaling. Cancer Res 75:666-75
Du, L; Zhao, Z; Ma, X et al. (2014) miR-93-directed downregulation of DAB2 defines a novel oncogenic pathway in lung cancer. Oncogene 33:4307-15
Du, Liqin; Borkowski, Robert; Zhao, Zhenze et al. (2013) A high-throughput screen identifies miRNA inhibitors regulating lung cancer cell survival and response to paclitaxel. RNA Biol 10:1700-13
Ahn, Young-Ho; Gibbons, Don L; Chakravarti, Deepavali et al. (2012) ZEB1 drives prometastatic actin cytoskeletal remodeling by downregulating miR-34a expression. J Clin Invest 122:3170-83
Du, Liqin; Subauste, Maria C; DeSevo, Christopher et al. (2012) miR-337-3p and its targets STAT3 and RAP1A modulate taxane sensitivity in non-small cell lung cancers. PLoS One 7:e39167
Du, Liqin; Pertsemlidis, Alexander (2012) microRNA regulation of cell viability and drug sensitivity in lung cancer. Expert Opin Biol Ther 12:1221-39
Du, Liqin; Pertsemlidis, Alexander (2011) Cancer and neurodegenerative disorders: pathogenic convergence through microRNA regulation. J Mol Cell Biol 3:176-80
Du, Liqin; Schageman, Jeoffrey J; Irnov et al. (2010) MicroRNA expression distinguishes SCLC from NSCLC lung tumor cells and suggests a possible pathological relationship between SCLCs and NSCLCs. J Exp Clin Cancer Res 29:75
Kozlitina, Julia; Xing, Chao; Pertsemlidis, Alexander et al. (2010) Power of genetic association studies with fixed and random genotype frequencies. Ann Hum Genet 74:429-38
Du, Liqin; Pertsemlidis, Alexander (2010) microRNAs and lung cancer: tumors and 22-mers. Cancer Metastasis Rev 29:109-22

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