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Analysis of an independent tumor suppressor locus telomeric to Tp53 suggested Inpp5k and Myo1c as novel tumor suppressor gene candidates in this region
Sahlgrenska Academy, University of Gothenburg.
Sahlgrenska Academy, University of Gothenburg.
Sahlgrenska Academy, University of Gothenburg.
Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi. Sahlgrenska Academy, University of Gothenburg. (Tumörbiologi, Tumor Biology)ORCID-id: 0000-0002-4800-8533
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2015 (Engelska)Ingår i: BMC Genetics, ISSN 1471-2156, E-ISSN 1471-2156, Vol. 16, nr 1, artikel-id 80Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

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.

Ort, förlag, år, upplaga, sidor
2015. Vol. 16, nr 1, artikel-id 80
Nyckelord [en]
cancer, Myosin-1c, Inpp5k, tumor suppressor
Nationell ämneskategori
Medicinska och farmaceutiska grundvetenskaper
Forskningsämne
Medicin
Identifikatorer
URN: urn:nbn:se:his:diva-12031DOI: 10.1186/s12863-015-0238-4ISI: 000357852600001PubMedID: 26170120Scopus ID: 2-s2.0-84937029410OAI: oai:DiVA.org:his-12031DiVA, id: diva2:911606
Forskningsfinansiär
KK-stiftelsen, 20120311Åke Wibergs Stiftelse, 946217602Tillgänglig från: 2016-03-14 Skapad: 2016-03-14 Senast uppdaterad: 2018-01-10Bibliografiskt granskad
Ingår i avhandling
1. Cellular, Molecular and Functional Characterization of the Tumor Suppressor Candidate MYO1C
Öppna denna publikation i ny flik eller fönster >>Cellular, Molecular and Functional Characterization of the Tumor Suppressor Candidate MYO1C
2016 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Tumor suppressor genes play a role as a growth regulator and a gatekeeper of a cell. Their inactivation is often detected in malignant tumors. Identification of novel tumor suppressor gene candidates may help to further understand tumorigenesis and aid in the discovery of a new treatment leading toward cure of cancer.

This PhD research project aimed to understand functional significance of a novel tumor suppressor gene candidate, myosin IC (MYO1C) and to identify potential interaction(s) of the MYO1C protein with key components of the signaling pathways involving in cancer development.

In an experimental rat model for endometrial carcinoma (EC), detailed molecular genetic analysis of a candidate tumor suppressor region located distal to the tumor protein 53 (Tp53) suggested the myosin IC gene (Myo1c) as the best potential target for deletion of the genetic material. The question arising was whether and how MYO1C could function as a tumor suppressor gene. By using qPCR, Western blot or immunohistochemistry analyses, we examined MYO1C protein level in panels of well-stratified human colorectal cancer (CRC) and EC respectively. We found that MYO1C was significantly down-regulated in these cancer materials and that for the EC panel, the observed down-regulation of MYO1C correlated with tumor stage, where tumors at more advanced stages had less expression of MYO1C. In cell transfection experiments, we found that over-expression of MYO1C significantly decreased cell proliferation, and silencing MYO1C with siRNA increased cell viability. Additionally, knockdown of MYO1C impaired the ability of cells to migrate, spread and adhere to the surface. Recent published studies suggested a potential interplay between MYO1C and the phosphoinositide 3-kinase (PI3K)/AKT pathway. To examine this hypothesis, we analyzed the expression and/or activation of components of the PI3K/AKT and RAS/ERK signaling pathways in vivo in CRC samples, and in vitro in cells transfected with the MYO1C gene expression construct or MYO1C-targeted siRNA. To identify other potential pathways/ mechanisms through which MYO1C may exert its tumor suppressor activity, we additionally performed new sets of MYO1C-siRNA knockdown experiments. At different time points post transfection, we performed microarray global gene expression experiments followed by bioinformatics analysis of the data. Altogether, the results suggested an early PI3K/AKT response to altered MYO1C expression. We additionally identified several cancer-related genes/pathways with late response to MYO1C knockdown. All things considered, the identification of MYO1C-expression impact on cell proliferation, migration, and adhesion in combination with its interplay between several cancer-related genes and signaling pathways provide further evidence for the initial hypothesis of a tumor suppressor activity of MYO1C. 

Ort, förlag, år, upplaga, sidor
Gothenburg: Ineko AB, 2016. s. 36
Nyckelord
MYO1C, myosin IC, tumor suppressor gene, cancer, tumor, PI3K/AKT signaling
Nationell ämneskategori
Annan medicin och hälsovetenskap
Forskningsämne
Medicin
Identifikatorer
urn:nbn:se:his:diva-13021 (URN)978-91-628-9736-9 (ISBN)
Disputation
2016-04-18, Arvid Carlsson, Medicinaregatan 3, Gothenburg, 09:00 (Engelska)
Opponent
Handledare
Projekt
Cellular, Molecular and Functional Characterization of the Tumor Suppressor Candidate MYO1C
Tillgänglig från: 2016-10-11 Skapad: 2016-10-11 Senast uppdaterad: 2017-11-27Bibliografiskt granskad

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