Abstract 4442: micoRNA in FA defective tumor

Abstract

Abstract The Fanconi Anemia (FA) pathway is essential for human cells to maintain integrity following DNA damage. This pathway is involved in the endogenous repair of double stranded DNA breaks and homologous recombination as well as repair of DNA cross-linking caused by exogenous agents. Cancers with defective FA pathway are expected to be more sensitive to cross-link based therapy, or to treatments in which additional repair mechanisms are targeted. We have recently reported the detection of up to 20% of NSCLC to be FA functionally inactive (lack of FANCD2 foci formation in the nucleus of proliferating cells by triple stain immunofluorescence, FATSI negative). MicroRNAs (miRs, miRNA) are small, 19-25 nucleotide, single stranded, non-coding RNA molecules that have regulatory roles in humans by targeting mRNAs via cleaved or translational repression which can affect the output of protein coding genes and cause various changes in developmental and physiological processes including cancer. It has been published that some miRNAs are tumor suppressors, and others are oncogenes. However, microRNAs and the FA pathway in relationship to lung cancer progression remain unknown. In order to elucidate the role of FA related miRs in human lung cancer development or treatment, we analyzed miR expression in lung cancer cells and patient lung tumors. Several cell lines were generated using RNAi technology with FANCD2 deficiency and confirmed via reduction in FANCD2 protein expression. Using Nanostring counter technology, microRNA array analysis was performed on FANCD2 foci positive and foci negative tumors as well as matching normal lung tissues. A cluster of microRNAs (mir-431, 377, 376c, 200c, 26a, 135a, and let-7e) were found to be up-regulated, and miR-494,205, 630, 145,671 were found to be down-regulated in the foci negative tumors samples compared to matching non-tumor lung tissue. The same group of miRs were upregulated and its corresponding group were down-regulated in the foci negative tumors as compared to foci positive tumors. These findings indicate that the FA pathway may regulate downstream genes through regulation of microRNAs in lung cancer. In order to validate this hypothesis, specific miRs were be analyzed with Real-Time Quantitative PCR via foci positive and foci negative samples (cell and patient tissue) in hopes of finding significant and consistent regulation. This study contributes to further understanding in miRNA and cancer pathology that may be applicable to futuristic lung cancer treatment. Citation Format: Shirley Tang, Li Gao, Kathleen Kathleen, Andrew Fink, Arjun Kalvala, Brittany Aguila, Gregory Otterson, Miguel Villalona-Calero, Wenrui Duan. micoRNA in FA defective tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4442. doi:10.1158/1538-7445.AM2017-4442