title: Alternative splicing of the OCC-1 gene generates three splice variants and a novel exonic microRNA, which regulate the Wnt signaling pathway.
abstract: The Wnt signaling pathway is hyperactivated in most colorectal cancers (CRC). Finding new regulators of this pathway represents the potential for cancer diagnosis or treatment. OCC-1 was initially reported as an up-regulated gene in colon carcinoma, without knowing its mechanism of action. Here, two novel transcript variants and an exonic microRNA that originated from the OCC-1 gene are reported, showing positive effects on Wnt activity. Up-regulation of the known OCC-1 variant (assigned as OCC-1A/B) was limited to CRC, and its overexpression increased survival of CRC-originated SW480 cells (Wnt+), while resulting in apoptosis of Wnt-suppressed SW480 cells or HeLa cells (Wnt-) detected by PI staining. Immunocytochemistry showed that the OCC-1A/B-encoded peptide was localized to the nucleus, where its overexpression resulted in Wnt signaling up-regulation, detected by TOP/FOPflash assay. The noncoding portion of the OCC-1A/B transcript had a suppressive effect on Wnt activity and had a negative correlation with APPL2 neighboring gene expression. Unlike OCC-1A/B, the novel OCC-1C splice variant had no expression alteration in CRC, and it seemed to encode a smaller peptide with cytoplasmic localization. A 60-nucleotide (nt) fragment containing an AUG start codon is spliced out to produce an OCC-1D noncoding RNA variant. The 60-nt RNA was validated as the precursor of a novel microRNA, which we named miR-ex1 Both OCC-1D and miR-ex1 were coordinately up-regulated in CRC. MiR-ex1 functional analysis revealed that it is targeting the APC2 tumor suppressor gene and is an activator of the Wnt signaling pathway. Overall, the OCC-1 gene is now introduced as a novel Wnt signaling regulator and as a potential therapeutic target.
authors.affiliation: Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, 14115-116 Tehran, Iran.
authors.forename: Hadi
authors.initials: H
authors.lastname: Najafi
authors.affiliation: Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, 14115-116 Tehran, Iran.
authors.forename: Bahram M
authors.initials: BM
authors.lastname: Soltani
authors.affiliation: Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, 14115-116 Tehran, Iran.
authors.forename: Sadat
authors.initials: S
authors.lastname: Dokanehiifard
authors.affiliation: Tehran University of Medical Sciences, Shariati Hospital, 1411713135 Tehran, Iran.
authors.forename: Shirzad
authors.initials: S
authors.lastname: Nasiri
authors.affiliation: Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, 14115-116 Tehran, Iran.
authors.forename: Seyed Javad
authors.initials: SJ
authors.lastname: Mowla
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D017398:Alternative Splicing; D017209:Apoptosis; D045744:Cell Line, Tumor; D002470:Cell Survival; D015179:Colorectal Neoplasms / Q000235:genetics*; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics*; D009928:Organ Specificity; D011506:Proteins / Q000235:genetics*; D015854:Up-Regulation; D060449:Wnt Signaling Pathway
chemical_list: C528555:APPL2 protein, human; D048868:Adaptor Proteins, Signal Transducing; C000622319:C12orf75 protein, human; D035683:MicroRNAs; D009363:Neoplasm Proteins; D011506:Proteins
keywords: APPL2; OCC-1; Wnt pathway; alternative splicing; colorectal cancer; microRNA