title: SAP155-mediated c-myc suppressor far-upstream element-binding protein-interacting repressor splicing variants are activated in colon cancer tissues.
abstract: The c-myc transcriptional suppressor, far-upstream element (FUSE)-binding protein (FBP)-interacting repressor (FIR), is alternatively spliced in colorectal cancer tissue (Matsushita et al., Cancer Res 2006). Recently, the knockdown of SAP155 pre-mRNA-splicing factor, a subunit of SF3b, was reported to disturb FIR pre-mRNA splicing and yield FIRΔexon2, an exon 2-spliced variant of FIR, which lacks c-myc repression activity. In the present study, novel splicing variants of FIR, Δ3 and Δ4, were also generated by SAP155 siRNA, and these variants were found to be activated in human colorectal cancer tissue. Furthermore, the expression levels of FIR variant mRNA were examined in the peripheral blood of colorectal cancer patients and healthy volunteers to assess its potency for tumor detection. As expected, circulating FIR variant mRNA in the peripheral blood of cancer patients were significantly overexpressed compared to that in healthy volunteers. In particular, the area under the receiving operating characteristic curve of FIR, FIRΔexon2 or FIRΔexon2/FIR, was greater than those of conventional carcinoembryonic antigen or carbohydrate antigen 19-9. In addition, FIRΔexon2 or FIR mRNA expression in the peripheral blood was significantly reduced after operative removal of colorectal tumors. Thus, circulating FIR and FIRΔexon2 mRNA are potential novel screening markers for colorectal cancer testing with conventional carcinoembryonic antigen and or carbohydrate antigen 19-9. Taken together, our results indicate that overexpression of FIR and its splicing variants in colorectal cancer directs feed-forward or addicted circuit c-myc transcriptional activation. Clinical implications for colorectal cancers of novel FIR splicing variants are also discussed in the present paper.
authors.affiliation: Department of Molecular Diagnosis, Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Toshiko
authors.initials: T
authors.lastname: Kajiwara
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Matsushita
authors.forename: Sakae
authors.initials: S
authors.lastname: Itoga
authors.forename: Mai
authors.initials: M
authors.lastname: Tamura
authors.forename: Nobuko
authors.initials: N
authors.lastname: Tanaka
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tomonaga
authors.forename: Hisahiro
authors.initials: H
authors.lastname: Matsubara
authors.forename: Hideaki
authors.initials: H
authors.lastname: Shimada
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Habara
authors.forename: Masafumi
authors.initials: M
authors.lastname: Matsuo
authors.forename: Fumio
authors.initials: F
authors.lastname: Nomura
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D015295:Antigens, Tumor-Associated, Carbohydrate / Q000235:genetics / Q000378:metabolism; D014408:Biomarkers, Tumor; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism; D005091:Exons / Q000235:genetics; D016147:Genes, Tumor Suppressor; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics* / Q000378:metabolism; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D020033:Protein Isoforms; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D012322:RNA Precursors / Q000235:genetics / Q000378:metabolism; D012326:RNA Splicing; D000072260:RNA Splicing Factors; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D064067:Rho Guanine Nucleotide Exchange Factors; D017413:Ribonucleoprotein, U2 Small Nuclear / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation
chemical_list: D015295:Antigens, Tumor-Associated, Carbohydrate; D014408:Biomarkers, Tumor; C577426:FARP2 protein, human; D020662:Guanine Nucleotide Exchange Factors; D010750:Phosphoproteins; D020033:Protein Isoforms; D016271:Proto-Oncogene Proteins c-myc; D012322:RNA Precursors; D000072260:RNA Splicing Factors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D064067:Rho Guanine Nucleotide Exchange Factors; D017413:Ribonucleoprotein, U2 Small Nuclear; C112491:SF3B1 protein, human; C578959:carbohydrate antigen 199, human