Analysis of an independent tumor suppressor locus telomeric to Tp53 suggested Inpp5k and Myo1c as novel tumor suppressor gene candidates in this region
| Autor: | Anna Linder, Diego Garcia Dios, Afrouz Behboudi, Kittichate Visuttijai, Emma Samuelson, Carola Hedberg Oldfors, Staffan Nilsson, Sandra Karlsson |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Tumor suppressor gene
Medicinska och farmaceutiska grundvetenskaper tumor suppressor Locus (genetics) Endometrial carcinoma Biology Hydroxamic Acids Inpp5k Myosin Type I Skip Gene expression Genetics Animals Humans Gene family cancer Genetics(clinical) Genes Tumor Suppressor Gene Genetics (clinical) Regulation of gene expression Myosin-1c Inositol Polyphosphate 5-Phosphatases Basic Medicine DNA Methylation Hic1 Molecular biology Phosphoric Monoester Hydrolases Rats Myo1c Gene Expression Regulation Genetic Loci DNA methylation Chromosomal region Azacitidine 17p13.3 Female RNO10q24-q25 Tp53 Tumor Suppressor Protein p53 Research Article |
| Zdroj: | BMC Genetics |
| Popis: | Background Several reports indicate a commonly deleted chromosomal region independent from, and distal to the TP53 locus in a variety of human tumors. In a previous study, we reported a similar finding in a rat tumor model for endometrial carcinoma (EC) and through developing a deletion map, narrowed the candidate region to 700 kb, harboring 19 genes. In the present work real-time qPCR analysis, Western blot, semi-quantitative qPCR, sequencing, promoter methylation analysis, and epigenetic gene expression restoration analyses (5-aza-2´-deoxycytidine and/or trichostatin A treatments) were used to analyze the 19 genes located within the candidate region in a panel of experimental tumors compared to control samples. Results Real-time qPCR analysis suggested Hic1 (hypermethylated in cancer 1), Inpp5k (inositol polyphosphate-5-phosphatase K; a.k.a. Skip, skeletal muscle and kidney enriched inositol phosphatase) and Myo1c (myosin 1c) as the best targets for the observed deletions. No mutation in coding sequences of these genes was detected, hence the observed low expression levels suggest a haploinsufficient mode of function for these potential tumor suppressor genes. Both Inpp5k and Myo1c were down regulated at mRNA and/or protein levels, which could be rescued in gene expression restoration assays. This could not be shown for Hic1. Conclusion Innp5k and Myo1c were identified as the best targets for the deletions in the region. INPP5K and MYO1C are located adjacent to each other within the reported independent region of tumor suppressor activity located at chromosome arm 17p distal to TP53 in human tumors. There is no earlier report on the potential tumor suppressor activity of INPP5K and MYO1C, however, overlapping roles in phosphoinositide (PI) 3-kinase/Akt signaling, known to be vital for the cell growth and survival, are reported for both. Moreover, there are reports on tumor suppressor activity of other members of the gene families that INPP5K and MYO1C belong to. Functional significance of these two candidate tumor suppressor genes in cancerogenesis pathways remains to be investigated. Electronic supplementary material The online version of this article (doi:10.1186/s12863-015-0238-4) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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