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Lowered Expression of Tumor Suppressor Candidate MYO1CStimulates Cell Proliferation, Suppresses Cell Adhesion and Activates AKT
University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Department of Medical and Clinical Genetics, Sahlgrenska Academy, University of Gothenburg. (Tumor Biology Research Group)ORCID iD: 0000-0002-4800-8533
Department of Medical and Clinical Genetics, Sahlgrenska Academy, University of Gothenburg, Gothenburg.
University of Skövde, School of Bioscience.
Department of physiology, Faculty of Health Sciences, University of Pretoria, South Africa.
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2016 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 10, e0164063Article in journal (Refereed) Published
Abstract [en]

Myosin-1C (MYO1C) is a tumor suppressor candidate located in a region of recurrent losses distal to TP53. Myo1c can tightly and specifically bind to PIP2, the substrate of Phosphoinositide 3-kinase (PI3K), and to Rictor, suggesting a role for MYO1C in the PI3K pathway. This study was designed to examine MYO1C expression status in a panel of well-stratified endometrial carcinomas as well as to assess the biological significance of MYO1C as a tumor suppressor in vitro. We found a significant correlation between the tumor stage and lowered expression of MYO1C in endometrial carcinoma samples. In cell transfection experiments, we found a negative correlation between MYO1C expression and cell proliferation, and MYO1C silencing resulted in diminished cell migration and adhesion. Cells expressing excess of MYO1C had low basal level of phosphorylated protein kinase B (PKB, a.k.a. AKT) and cells with knocked down MYO1C expression showed a quicker phosphorylated AKT (pAKT) response in reaction to serum stimulation. Taken together the present study gives further evidence for tumor suppressor activity of MYO1C and suggests MYO1C mediates its tumor suppressor function through inhibition of PI3K pathway and its involvement in loss of contact inhibition.

Place, publisher, year, edition, pages
2016. Vol. 11, no 10, e0164063
Keyword [en]
MYO1C, myosin-1c, tumor suppressor, AKT signaling
National Category
Other Medical Sciences
Research subject
Medical sciences
Identifiers
URN: urn:nbn:se:his:diva-13020DOI: 10.1371/journal.pone.0164063ISI: 000385698100017PubMedID: 27716847Scopus ID: 2-s2.0-84991449467OAI: oai:DiVA.org:his-13020DiVA: diva2:1034166
Projects
Cellular, Molecular and Functional Characterization of the Tumor Suppressor Candidate MYO1C
Available from: 2016-10-11 Created: 2016-10-11 Last updated: 2017-01-20
In thesis
1. Cellular, Molecular and Functional Characterization of the Tumor Suppressor Candidate MYO1C
Open this publication in new window or tab >>Cellular, Molecular and Functional Characterization of the Tumor Suppressor Candidate MYO1C
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
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. 

Place, publisher, year, edition, pages
Gothenburg: Ineko AB, 2016. 36 p.
Keyword
MYO1C, myosin IC, tumor suppressor gene, cancer, tumor, PI3K/AKT signaling
National Category
Other Medical Sciences
Research subject
Medical sciences
Identifiers
urn:nbn:se:his:diva-13021 (URN)978-91-628-9736-9 (ISBN)
Public defence
2016-04-18, Arvid Carlsson, Medicinaregatan 3, Gothenburg, 09:00 (English)
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Projects
Cellular, Molecular and Functional Characterization of the Tumor Suppressor Candidate MYO1C
Available from: 2016-10-11 Created: 2016-10-11 Last updated: 2016-10-13Bibliographically approved

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