title: An integrative framework identifies alternative splicing events in colorectal cancer development.
abstract: Alternative splicing (AS) is a common mechanism which creates diverse RNA isoforms from a single gene, potentially increasing protein variety. Growing evidence suggests that this mechanism is closely related to cancer progression. In this study, whole transcriptome analysis was performed with GeneChip Human exon 1.0 ST Array from 80 samples comprising 23 normal colon mucosa, 30 primary colorectal cancer and 27 liver metastatic specimens from 46 patients, to identify AS events in colorectal cancer progression. Differentially expressed genes and exons were estimated and AS events were reconstructed by combining exon-level analyses with AltAnalyze algorithms and transcript-level estimations (MMBGX probabilistic method). The number of AS genes in the transition from normal colon mucosa to primary tumor was the most abundant, but fell considerably in the next transition to liver metastasis. 206 genes with probable AS events in colon cancer development and progression were identified, that are involved in processes and pathways relevant to tumor biology, as cell-cell and cell-matrix interactions. Several AS events in VCL, CALD1, B3GNT6 and CTHRC1 genes, differentially expressed during tumor development were validated, at RNA and at protein level. Taken together, these results demonstrate that cancer-specific AS is common in early phases of colorectal cancer natural history.
authors.affiliation: Department of Biology, University of Padova, Padova, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Bisognin
authors.affiliation: Oncology and Immunology Section, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Pizzini
authors.affiliation: Oncology and Immunology Section, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy.
authors.forename: Lisa
authors.initials: L
authors.lastname: Perilli
authors.affiliation: Istituto Oncologico Veneto (IOV), IRCCS, Padova, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Esposito
authors.affiliation: Surgery Section, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Mocellin
authors.affiliation: Surgery Section, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy.
authors.forename: Donato
authors.initials: D
authors.lastname: Nitti
authors.affiliation: Oncology and Immunology Section, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy; Istituto Oncologico Veneto (IOV), IRCCS, Padova, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Zanovello
authors.affiliation: Department of Biology, University of Padova, Padova, Italy. Electronic address: stefania.bortoluzzi@unipd.it.
authors.forename: Stefania
authors.initials: S
authors.lastname: Bortoluzzi
authors.affiliation: Oncology and Immunology Section, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy; Istituto Oncologico Veneto (IOV), IRCCS, Padova, Italy.
authors.forename: Susanna
authors.initials: S
authors.lastname: Mandruzzato
mesh_terms: D000368:Aged; D017398:Alternative Splicing; D003106:Colon / Q000378:metabolism / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D005091:Exons; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D012007:Rectum / Q000378:metabolism / Q000473:pathology
keywords: ASEs; Alternative splicing; Colorectal cancer; Exon arrays; M; N; T; alternatively spliced exons; liver metastasis; ncRNAs; non-coding RNAs; normal colon mucosa; primary colorectal cancer