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Visuttijai, K., Pettersson, J., Mehrbani Azar, Y., van den Bout, I., Örndal, C., Marcickiewicz, J., . . . Behboudi, A. (2016). Lowered Expression of Tumor Suppressor Candidate MYO1CStimulates Cell Proliferation, Suppresses Cell Adhesion and Activates AKT. PLoS ONE, 11(10), Article ID e0164063.
Open this publication in new window or tab >>Lowered Expression of Tumor Suppressor Candidate MYO1CStimulates Cell Proliferation, Suppresses Cell Adhesion and Activates AKT
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2016 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 10, article id 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
Public Library of Science, 2016
Keywords
MYO1C, myosin-1c, tumor suppressor, AKT signaling
National Category
Other Medical Sciences
Research subject
Medical sciences; Bioinformatics
Identifiers
urn:nbn:se:his:diva-13020 (URN)10.1371/journal.pone.0164063 (DOI)000385698100017 ()27716847 (PubMedID)2-s2.0-84991449467 (Scopus ID)
Projects
Cellular, Molecular and Functional Characterization of the Tumor Suppressor Candidate MYO1C
Available from: 2016-10-11 Created: 2016-10-11 Last updated: 2019-11-18
Hedberg Oldfors, C., Garcia Dios, D., Linder, A., Visuttijai, K., Samuelson, E., Karlsson, S., . . . Behboudi, A. (2015). Analysis of an independent tumor suppressor locus telomeric to Tp53 suggested Inpp5k and Myo1c as novel tumor suppressor gene candidates in this region. BMC Genetics, 16(1), Article ID 80.
Open this publication in new window or tab >>Analysis of an independent tumor suppressor locus telomeric to Tp53 suggested Inpp5k and Myo1c as novel tumor suppressor gene candidates in this region
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2015 (English)In: BMC Genetics, ISSN 1471-2156, E-ISSN 1471-2156, Vol. 16, no 1, article id 80Article in journal (Refereed) 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.

Place, publisher, year, edition, pages
Biomed Central, 2015
Keywords
cancer, Myosin-1c, Inpp5k, tumor suppressor
National Category
Basic Medicine
Research subject
Medical sciences
Identifiers
urn:nbn:se:his:diva-12031 (URN)10.1186/s12863-015-0238-4 (DOI)000357852600001 ()26170120 (PubMedID)2-s2.0-84937029410 (Scopus ID)
Funder
Knowledge Foundation, 20120311Åke Wiberg Foundation, 946217602
Available from: 2016-03-14 Created: 2016-03-14 Last updated: 2019-12-02Bibliographically approved
Samuelson, E., Karlsson, S., Partheen, K., Nilsson, S., Szpirer, C. & Behboudi, A. (2012). BAC CGH-array identified specific small-scale genomic imbalances in diploid DMBA-induced rat mammary tumors. BMC Cancer, 12, artikelnummer 352
Open this publication in new window or tab >>BAC CGH-array identified specific small-scale genomic imbalances in diploid DMBA-induced rat mammary tumors
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2012 (English)In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 12, p. artikelnummer 352-Article in journal (Refereed) Published
Abstract [en]

Background: Development of breast cancer is a multistage process influenced by hormonal and environmental factors as well as by genetic background. The search for genes underlying this malignancy has recently been highly productive, but the etiology behind this complex disease is still not understood. In studies using animal cancer models, heterogeneity of the   genetic background and environmental factors is reduced and thus analysis and identification of genetic aberrations in tumors may become easier. To identify chromosomal regions   potentially involved in the initiation and progression of mammary cancer, in the present   work we subjected a subset of experimental mammary tumors to cytogenetic and molecular   genetic analysis.

Methods: Mammary tumors were induced with DMBA (7,12-dimethylbenz[a]anthrazene) in female rats from the susceptible SPRD-Cu3 strain and from crosses and backcrosses between this strain and the resistant WKY strain. We first produced a general overview of chromosomal aberrations in the tumors using conventional kartyotyping (G-banding) and Comparative Genome Hybridization (CGH) analyses. Particular chromosomal changes were then analyzed in more details using an in-house developed BAC (bacterial artificial chromosome) CGH-array platform.

Results: Tumors appeared to be diploid by conventional karyotyping, however several sub-microscopic chromosome gains or losses in the tumor material were identified by BAC CGH-array analysis. An oncogenetic tree analysis based on the BAC CGH-array data suggested gain of rat chromosome (RNO) band 12q11, loss of RNO5q32 or RNO6q21 as the earliest events in the development of these mammary tumors.

Conclusions: Some of the identified changes appear to be more specific for DMBA-induced mammary tumors and some are similar to those previously reported in ACI rat model for estradiol-induced mammary tumors. The later group of changes is more interesting, since they may represent anomalies that involve genes with a critical role in mammary tumor development. Genetic changes identified in this work are at very small scales and thus may provide a more feasible basis for the identification of the target gene(s). Identification of the genes underlying these chromosome changes can provide new insights to the mechanisms   of mammary carcinogenesis.

Place, publisher, year, edition, pages
BioMed Central, 2012
National Category
Biological Sciences
Research subject
Natural sciences
Identifiers
urn:nbn:se:his:diva-6545 (URN)10.1186/1471-2407-12-352 (DOI)000310632100001 ()22894538 (PubMedID)2-s2.0-84864931479 (Scopus ID)
Available from: 2012-10-17 Created: 2012-10-17 Last updated: 2017-12-07
Falck, E., Behboudi, A. & Klinga-Levan, K. (2012). The impact of the genetic background on the genome make-up of tumor cells. Genes, Chromosomes and Cancer, 51(5), 438-446
Open this publication in new window or tab >>The impact of the genetic background on the genome make-up of tumor cells
2012 (English)In: Genes, Chromosomes and Cancer, ISSN 1045-2257, E-ISSN 1098-2264, Vol. 51, no 5, p. 438-446Article in journal (Refereed) Published
Abstract [en]

Endometrial adenocarcinoma (EAC) is the most common form of malignancy in the female genital tract, ranking as the fourth leading form of invasive tumors that affect women. The BDII inbred rat strain has been used as a powerful tumor model in studies of the genetic background of EAC. Females from the BDII strain are prone to develop tumors with an incidence of more than 90%. Development of EAC in BDII female rats has similarities in pathogenesis, histopathological, and molecular properties to that of human, and thus represents a unique model for analysis of EAC tumorigenesis and for comparative studies in human EACs. In a previous study, a set of rat EAC cell lines derived from tumors developed in female crossprogenies between BDII and nonsusceptible rat strains were analyzed by spectral karyotyping (SKY). Here we present an analysis with specific focus on the impact of different genetic backgrounds on the rate and occurrence of genetic aberrations in experimental tumors using data presented in the previous report. We could reveal that the ploidy state, and the abundance and type of structural as well as numerical change differed between the two genetic setups. We have also identified chromosomes harboring aberrations independent of genetic input from the nonsusceptible strains, which provide valuable information for the identification of the genes involved in the development of EAC in the BDII model as well as in human endometrial tumors. (C) 2012 Wiley Periodicals, Inc.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2012
National Category
Natural Sciences
Research subject
Natural sciences
Identifiers
urn:nbn:se:his:diva-5665 (URN)10.1002/gcc.21929 (DOI)000301118100003 ()2-s2.0-84857997916 (Scopus ID)
Available from: 2012-04-02 Created: 2012-04-02 Last updated: 2019-09-18Bibliographically approved
Falck, E., Hedberg, C., Klinga-Levan, K. & Behboudi, A. (2011). SKY analysis revealed recurrent numerical and structural chromosome changes in BDII rat endometrial carcinomas. Cancer Cell International, 11, 20
Open this publication in new window or tab >>SKY analysis revealed recurrent numerical and structural chromosome changes in BDII rat endometrial carcinomas
2011 (English)In: Cancer Cell International, ISSN 1475-2867, E-ISSN 1475-2867, Vol. 11, p. 20-Article in journal (Refereed) Published
Abstract [en]

Background: Genomic alterations are common features of cancer cells, and some of these changes are proven to be neoplastic-specific. Such alterations may serve as valuable tools for diagnosis and classification of tumors, prediction of clinical outcome, disease monitoring, and choice of therapy as well as for providing clues to the location of crucial cancer-related genes. Endometrial carcinoma (EC) is the most frequently diagnosed malignancy of the female genital tract, ranking fourth among all invasive tumors affecting women. Cytogenetic studies of human ECs have not produced very conclusive data, since many of these studies are based on karyotyping of limited number of cases and no really specific karyotypic changes have yet been identified. As the majority of the genes are conserved among mammals, the use of inbred animal model systems may serve as a tool for identification of underlying genes and pathways involved in tumorigenesis in humans. In the present work we used spectral karyotyping (SKY) to identify cancer-related aberrations in a well-characterized experimental model for spontaneous endometrial carcinoma in the BDII rat tumor model. Results: Analysis of 21 experimental ECs revealed specific nonrandom numerical and structural chromosomal changes. The most recurrent numerical alterations were gains in rat chromosome 4 (RNO4) and losses in RNO15. The most commonly structural changes were mainly in form of chromosomal translocations and were detected in RNO3, RNO6, RNO10, RNO11, RNO12, and RNO20. Unbalanced chromosomal translocations involving RNO3p was the most commonly observed structural changes in this material followed by RNO11p and RNO10 translocations. Conclusion: The non-random nature of these events, as documented by their high frequencies of incidence, is suggesting for dynamic selection of these changes during experimental EC tumorigenesis and therefore for their potential contribution into development of this malignancy. Comparative molecular analysis of the identified genetic changes in this tumor model with those reported in the human ECs may provide new insights into underlying genetic changes involved in EC development and tumorigenesis.

Place, publisher, year, edition, pages
BioMed Central, 2011
Keywords
SKY, BDII rat, endometrial carcinoma
National Category
Natural Sciences
Research subject
Natural sciences
Identifiers
urn:nbn:se:his:diva-5536 (URN)10.1186/1475-2867-11-20 (DOI)000293340700001 ()2-s2.0-79959571469 (Scopus ID)
Available from: 2012-03-19 Created: 2012-03-01 Last updated: 2017-12-07Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-2525-3752

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