title: Epigenetic inactivation of the novel candidate tumor suppressor gene ITIH5 in colon cancer predicts unfavorable overall survival in the CpG island methylator phenotype.
abstract: Inter-α-trypsin inhibitor heavy chain 5 (ITIH5) is supposed to be involved in extracellular matrix stability and thus may play a key role in the inhibition of tumor progression. The current study is the first to analyze in depth ITIH5 expression as well as its potential clinical and functional impact in colon cancer. Based on 30 tumor and 30 adjacent normal tissues we examined ITIH5 mRNA expression and promoter methylation, whose significance was further validated by independent data sets from The Cancer Genome Atlas (TCGA) platform. In addition, ITIH5 protein expression was evaluated using immunohistochemistry. ITIH5 mRNA expression loss was significantly associated (P<0.001) with hypermethylation of the ITIH5 promoter in primary colon tumors. In addition, treatment of tumor cell lines with demethylating (DAC) and histone acetylating (TSA) agents induced ITIH5 expression. In line, independent TCGA data revealed a significant expression loss of ITIH5, particularly in the MSI-high and CIMP-positive phenotype concordant with an increased ITIH5 hypermethylation in CIMP-positive colon tumors (P<0.001). In proximal, i.e., right-sided tumors, abundant ITIH5 expression was associated with longer overall survival (OS, P = 0.049) and the CIMP-positive (P = 0.032) subgroup. Functionally, ITIH5 re-expression mediated a reduced proliferation in HCT116 and CaCo2 cells. In conclusion, our results indicate that ITIH5 is a novel putative tumor suppressor gene in colon cancer with a potential impact in the CIMP-related pathway. ITIH5 may serve as a novel epigenetic-based diagnostic biomarker with further clinical impact for risk stratification of CIMP-positive colon cancer patients.
authors.affiliation: Molecular Oncology Group; Institute of Pathology; Medical Faculty of the RWTH Aachen University; Aachen, Germany.
authors.forename: Vera
authors.initials: V
authors.lastname: Kloten
authors.affiliation: Molecular Oncology Group; Institute of Pathology; Medical Faculty of the RWTH Aachen University; Aachen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Rose
authors.affiliation: Molecular Oncology Group; Institute of Pathology; Medical Faculty of the RWTH Aachen University; Aachen, Germany.
authors.forename: Sophie
authors.initials: S
authors.lastname: Kaspar
authors.affiliation: Molecular Oncology Group; Institute of Pathology; Medical Faculty of the RWTH Aachen University; Aachen, Germany.
authors.forename: Saskia
authors.initials: S
authors.lastname: von Stillfried
authors.affiliation: Molecular Oncology Group; Institute of Pathology; Medical Faculty of the RWTH Aachen University; Aachen, Germany.
authors.forename: Ruth
authors.initials: R
authors.lastname: Knüchel
authors.affiliation: Molecular Oncology Group; Institute of Pathology; Medical Faculty of the RWTH Aachen University; Aachen, Germany.
authors.forename: Edgar
authors.initials: E
authors.lastname: Dahl
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D018938:Caco-2 Cells; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D016147:Genes, Tumor Suppressor; D045325:HCT116 Cells; D006801:Humans; D009367:Neoplasm Staging; D010641:Phenotype; D011401:Promoter Regions, Genetic; D053491:Proteinase Inhibitory Proteins, Secretory / Q000235:genetics / Q000378:metabolism*; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor; C482680:ITIH5 protein, human; D053491:Proteinase Inhibitory Proteins, Secretory
keywords: CpG island methylator phenotype; DNA methylation; ITIH5; microsatellite instability; proximal colon; tumor suppressor gene
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