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Study finds loss of RBFOX2 protein promotes pancreatic cancer metastasis through effects on cytoskeletal remodeling

Deregulation of alternative RNA splicing promotes pancreatic cancer progression and metastasis
RBFOX2 is differentially expressed and alternatively spliced in pancreatic cancer. RBFOX2 expression analysis using microarray data from GEO dataset GSE28735 27 showed a significant increase in RBFOX2 expression in tumors (n = 45) compared to normal pancreas (n = 45) (a FDR adj. P = 0.006, two-sided t-test). Gene expression analysis of CPTAC RNA-seq data34 generated from normal pancreas and resected pancreatic cancer specimens showed RBFOX2 gene expression is significantly higher in tumors of the basal subtype (n = 54) compared to normal pancreas (n = 19) (b adj. P < 0.0001, ordinary one-way ANOVA with Tukey’s multiple comparisons, DF = 138) and no difference between normal pancreas and the classical subtype (n = 70) (adj. P = 0.2135, two-sided t-test). RBFOX2 expression is significantly increased in basal (n = 48) compared to classical (n = 56) PDAC in RNA-seq data from E-MTAB-683035 (c Wilcoxon Rank-sum test, P = 0.00023). The canonical full length RBFOX2 transcript includes two N-terminal two exons encode an N-terminal nuclear localization signal, while downstream exon 10 (ENSG00000100320:015) encodes an internal NLS (d). RBFOX2 transcripts in the pancreas utilize an internal start codon present in exon 3 and lack the N-terminal exons. RBFOX2 transcripts show alternative splicing of exon 10 in mature transcripts. The RBFOX2 recognition sequence UCGAUG is present upstream of exon 10 (e). RBFOX2 binding at this site is predicted to facilitate skipping of exon 10 in mature transcripts. Analysis of percent spliced-in (PSI), a measure of exon inclusion, for alternatively spliced RBFOX2 exon 10 in RBFOX2transcripts shows a significant increase in the inclusion of exon 10 in normal pancreas (n = 20) compared to PDAC (n = 136), (f CPTAC, P < 0.0001, 2-tailed t-test, t = 4.700, df=159). RBFOX2 exon 10 PSI was significantly different between classical and basal PDAC tumors (g CPTAC34, P = 0.0365, 2-tailed t-test, t = 2.115, df=117). Samples ±2 SD from the population mean were removed prior to statistical analysis. Data are presented as mean values +/- SD. The box plots define the 25th and 75th percentiles (box), median (solid line) and the minima and maxima (whiskers). Statistical analysis was performed using PRISM and the P-values reported for the indicated statistical tests are shown. Source data are provided as a Source data file. Credit: Nature Communications (2023). DOI: 10.1038/s41467-023-44126-w

Pancreatic cancer presents a challenging prognosis, marked by a five-year overall survival rate of merely 12.5%. Diagnosis frequently occurs at an advanced stage, characterized by metastasis to distant sites. The intricate molecular mechanisms governing pancreatic cancer metastasis remain a subject of ongoing research and exploration.

In a recent article published in Nature Communications, Moffitt Cancer Center researchers, in collaboration with The Tisch Cancer Institute; St. Jude Children's Research Hospital; the Agency for Science, Technology and Research in Singapore; and the University of Otago in New Zealand, demonstrate that deregulation of a protein called RBFOX2, involved in RNA splicing, contributes to the progression and metastasis of .

RNA is a nucleic acid that promotes the synthesis of proteins. While the nucleotide sequence of RNA is encoded by the DNA of the genome, RNA molecules undergo several modifications before eventually entering the ribosome to make protein. An important process that modifies RNA sequences is , whereby specific sequences within the RNA molecule may be rearranged, included or excluded.

This process results in different versions of RNA molecules generated from a single DNA sequence that will produce protein variants with potentially different activities. Alternative RNA splicing is critical for many ; however, the involvement of alternative RNA splicing in cancer development is not entirely understood.

The research team wanted to assess whether alternative RNA splicing is involved in the development and progression of pancreatic cancer. Through molecular-based laboratory experiments and mouse models, they discovered that RNA-binding proteins involved in splicing regulation were involved in pancreatic cancer progression. One of the key proteins they identified is RBFOX2.

Results showed RBFOX2 protein levels were lower in pancreatic cancer cells that had metastasized to other sites. These observations suggest that RBFOX2 may be a tumor suppressor protein that normally functions to inhibit cancer metastasis. The researchers confirmed this hypothesis by demonstrating that loss of RBFOX2 in pancreatic cell lines and mouse models increased , invasion, tumor development and metastasis.

The researchers performed additional experiments to determine the downstream pathways impacted by RBFOX2 that lead to pancreatic cancer progression.

They found that RBFOX2 regulates the splicing of RNA molecules that code for proteins involved in cytoskeletal remodeling, with one of the critical molecules being RNA that codes for the protein ABI1. In cells without RBFOX2, the location of ABI1 is redistributed to the cell periphery, where it impacts the cell cytoskeleton and promotes cell migration.

These combined observations demonstrate the importance of alternative RNA splicing to pancreatic cancer progression and suggest the need for additional studies to understand the mechanisms regulating RBFOX2 splicing activity fully.

"While analyses to date have identified few splicing regulators with prognostic implications in pancreatic cancer, the incidence of exon splicing events conserved across pancreatic tumors and other cancers suggests the processes regulated by alternatively spliced transcripts are integral to progression," said Karen Mann, Ph.D., assistant member of the Department of Molecular Oncology at Moffitt.

More information: Michelle Maurin et al, RBFOX2 deregulation promotes pancreatic cancer progression and metastasis through alternative splicing, Nature Communications (2023). DOI: 10.1038/s41467-023-44126-w

Journal information: Nature Communications
Citation: Study finds loss of RBFOX2 protein promotes pancreatic cancer metastasis through effects on cytoskeletal remodeling (2024, January 11) retrieved 22 April 2024 from
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