Abstract
The Fanconi Anemia (FA) pathway is essential for human cells to maintain genomic integrity following DNA damage. This pathway is involved in repairing damaged DNA through homologous recombination. Cancers with a defective FA pathway are expected to be more sensitive to cross-link based therapy or PARP inhibitors. To evaluate downstream effectors of the FA pathway, we studied the expression of 734 different micro RNAs (miRNA) using NanoString nCounter miRNA array in two FA defective lung cancer cells and matched control cells, along with two lung tumors and matched non-tumor tissue samples that were deficient in the FA pathway. Selected miRNA expression was validated with real-time PCR analysis. Among 734 different miRNAs, a cluster of microRNAs were found to be up-regulated including an important cancer related micro RNA, miR-200C. MiRNA-200C has been reported as a negative regulator of epithelial-mesenchymal transition (EMT) and inhibits cell migration and invasion by promoting the upregulation of E-cadherin through targeting ZEB1 and ZEB2 transcription factors. miRNA-200C was increased in the FA defective lung cancers as compared to controls. AmpliSeq analysis showed significant reduction in ZEB1 and ZEB2 mRNA expression. Our findings indicate the miRNA-200C potentially play a very important role in FA pathway downstream regulation.
Highlights
The Fanconi Anemia (FA) pathway is essential for human cells to maintain genomic integrity following DNA damage
RNA samples isolated from the PD20RV, PD20D2, A549E, A549D2D, H1299E and H1299D2D cells as well as two FANCD2 foci negative human non-small cell lung cancers and matched non-tumor tissues, were used for micro RNAs (miRNA) expression analysis by NanoString nCounter count
MiRNA-200C was upregulated in the FANCD2 foci deficient non-small cell lung cancer cells and tumor tissues
Summary
The Fanconi Anemia (FA) pathway is essential for human cells to maintain genomic integrity following DNA damage. FA is an autosomal recessive disorder (with an exception of the complementation group B, being X-linked) most commonly associated with DNA damage, progressive bone marrow failure (BMF) and escalated risks of c ancer[1,2,3,4,5] This complex heterogeneous disease is linked to mutations in 22 genes[2] identified to date (Fig. 1), referred to as FA subtypes A, B, C, D1/BRCA2, D2, E, F, G, I, J/BRIP1, L, M, N/PALB2, O/RAD51C, P/SLX4, Q/ERCC4, R/RAD51, S/BRCA1, T/UBE2T2,3, U/XRCC24, V/REV75 and W/RFWD36. Any mutation or epigenetic change that disrupts components of the Core Complex abrogates its E3 ligase function, leading to defective FA pathway
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