Analysis of an independent tumor suppressor locus telomeric to Tp53 suggested Inpp5k and Myo1c as novel tumor suppressor gene candidates in this region

Abstract

BackgroundSeveral 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.ResultsReal-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.ConclusionInnp5k 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 materialThe online version of this article (doi:10.1186/s12863-015-0238-4) contains supplementary material, which is available to authorized users.

Personalized Proteome Profiles of Healthy and Tumor Human Colon Organoids Reveal Both Individual Diversity and Basic Features of Colorectal Cancer

“…Among the 305 significantly changing proteins found in our dataset, several have already been related to CRC. MYO1C was found downregulated in the tumor organoids, and it has been recently suggested as a tumor suppressor gene candidate related to Tp53 (Hedberg Oldfors et al, 2015). Desmocollin-2 has been previously reported as being decreased or absent in CRC studies (Funakoshi et al, 2008;Khan et al, 2006) and was also downregulated in our dataset.…”

Exosomes derived from embryonal and alveolar rhabdomyosarcoma carry differential miRNA cargo and promote invasion of recipient fibroblasts

“…Significantly represented networks featured proteins previously implicated in ARMS biology (GSK3b, MDM2, CDKN1A, CDKN2A, IGF1R)4344454647, proteins involved in immune evasion and tumor metastasis (CXCL8, CSF1, IFNAR1, CCR2, CASR)4849505152, stemness (SOX2, POU5F1)5354, tumor cell proliferation and invasion (YBX1)41, or have been associated with other tumor types with a possible role in tumor biology (PRKACA, MYO1C, BRINP3)555657. The finding of the miRNA networks targeting proteins involved in stemness, immune evasion and metastasis, enriched in ARMS but not ERMS exosomes, suggests that paracrine signaling via exosomes may have differential effects on mediating the known aggressive behavior of ARMS.…”

Lowered Expression of Tumor Suppressor Candidate MYO1C Stimulates Cell Proliferation, Suppresses Cell Adhesion and Activates AKT

“…In the year 2000, Hanahan and Weinberg proposed six hallmarks of cancer (revised later to eight hallmarks); eight traits that are required for a cell to evolve from normal to tumor: ability to sustain proliferative signaling, ability to evade growth suppressors, ability to avoid apoptosis, ability to induce angiogenesis, ability to replicate immortally, ability to avoid immune destruction, ability to deregulate cellular energetics, and ability to invade and metastasize [ 37 , 38 ]. In the present work, by using clinical samples along with cell culture-based functional assays, we aimed to examine the original hypothesis of MYO1C acting as a tumor suppressor gene [ 6 ] in relation to some of Hanahan and Weinberg’s proposed tumorigenesis abilities.…”

“…Deletions at the homologous position on human chromosome 17 (17p13.3) unassociated with TP53 mutation have been reported in several types of human tumors [ 2 – 5 ], suggesting a tumor suppressor activity in this chromosomal region. In deletion mapping, combined with gene expression, sequencing and epigenetic silencing, the candidate region was delimited and Myo1c was identified as one of the most likely candidates for the proposed tumor suppressor activity [ 6 ].…”