RESUMO
RNA splicing is an important biological process associated with cancer initiation and progression. However, the contribution of alternative splicing to pancreatic cancer (PDAC) development is not well understood. Here, we identify an enrichment of RNA binding proteins (RBPs) involved in splicing regulation linked to PDAC progression from a forward genetic screen using Sleeping Beauty insertional mutagenesis in a mouse model of pancreatic cancer. We demonstrate downregulation of RBFOX2, an RBP of the FOX family, promotes pancreatic cancer progression and liver metastasis. Specifically, we show RBFOX2 regulates exon splicing events in transcripts encoding proteins involved in cytoskeletal remodeling programs. These exons are differentially spliced in PDAC patients, with enhanced exon skipping in the classical subtype for several RBFOX2 targets. RBFOX2 mediated splicing of ABI1, encoding the Abelson-interactor 1 adapter protein, controls the abundance and localization of ABI1 protein isoforms in pancreatic cancer cells and promotes the relocalization of ABI1 from the cytoplasm to the periphery of migrating cells. Using splice-switching antisense oligonucleotides (AONs) we demonstrate the ABI1 ∆Ex9 isoform enhances cell migration. Together, our data identify a role for RBFOX2 in promoting PDAC progression through alternative splicing regulation.
Assuntos
Processamento Alternativo , Neoplasias Pancreáticas , Camundongos , Animais , Humanos , Processamento Alternativo/genética , Fatores de Processamento de RNA/genética , Fatores de Processamento de RNA/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Splicing de RNA , Isoformas de Proteínas/genética , Neoplasias Pancreáticas/genética , Proteínas Repressoras/metabolismo , Proteínas do Citoesqueleto/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismoRESUMO
Background/aim: Huntington disease (HD) is a progressive adult-onset neurodegenerative disorder presenting an autosomal dominant inheritance. Since there is no information on the prevalence of HD in northwestern Iran, the aim of the present study was to determine the prevalence of HD and the number of CAG trinucleotide repeats in the population of northwestern Iran.Materials and methods: Genomic DNA was extracted from whole blood by the salting-out method. DNA samples were analyzed to determine the number of CAG trinucleotide repeats of the HD gene. An abnormally large number of CAG repeats, which is a diagnostic factor for the disease, was detected by polymerase chain reaction and agarose gel electrophoresis.Results: Out of 40 cases, we identified 14 nonkindred individuals with one expanded CAG allele at the IT15 gene. The frequency of the HD mutation in our group of patients was 35%. Expanded alleles varied from 36 to 70 CAG repeats, and normal alleles in HD patients varied from 20 to 26 CAG units. Conclusion: We found a significant correlation between age at onset of the disease and length of the expanded CAG tract: the lower the age, the longer the trinucleotide repeats length.
