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Alan Richard Clarke - One of the best experts on this subject based on the ideXlab platform.
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PPARδ status and Mismatch Repair mediated neoplasia in the mouse intestine
BMC Cancer, 2006Co-Authors: Karen Ruth Reed, Owen J. Sansom, Anthony Joseph Hayes, Andreas J. Gescher, Jefferey M. Peters, Alan Richard ClarkeAbstract:Background Therapeutic regulation of PPARδ activity using selective agonists has been proposed for various disorders. However, the consequences of altered peroxisome proliferator-activated receptor delta (PPARδ) activity in the context of intestinal tumourigenesis remain somewhat unclear. Contradictory evidence suggesting PPARδ either attenuates or potentiates intestinal neoplasia. To further investigate the PPARδ dependency of intestinal tumourigenesis, we have analysed the consequences of PPARδ deficiency upon intestinal neoplasia occurring in mice with impaired Mismatch DNA Repair.
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PPARδ status and Mismatch Repair mediated neoplasia in the mouse intestine
BMC Cancer, 2006Co-Authors: Karen Ruth Reed, Owen J. Sansom, Anthony Joseph Hayes, Andreas J. Gescher, Jefferey M. Peters, Alan Richard ClarkeAbstract:Background Therapeutic regulation of PPARδ activity using selective agonists has been proposed for various disorders. However, the consequences of altered peroxisome proliferator-activated receptor delta (PPARδ) activity in the context of intestinal tumourigenesis remain somewhat unclear. Contradictory evidence suggesting PPARδ either attenuates or potentiates intestinal neoplasia. To further investigate the PPARδ dependency of intestinal tumourigenesis, we have analysed the consequences of PPARδ deficiency upon intestinal neoplasia occurring in mice with impaired Mismatch DNA Repair. Methods Mice deficient for both PPARδ and the Mismatch Repair gene Mlh1 were produced and the incidence and severity of intestinal neoplasia recorded. Results No significant differences between the control genotypes and the double mutant genotypes were recorded indicating that deficiency of PPARδ does not modify impaired Mismatch Repair induced neoplasia. Conclusion In contrast with the previously observed acceleration of intestinal neoplasia in the context of the Apc ^ Min /+ mouse, PPARδ deficiency does not alter the phenotype of Mismatch Repair deficiency. This data supports the notion that PPARδ is not required for adenoma formation and indicate that any pro-tumourigenic effect of PPARδ inactivation may be highly context dependent.
Dimitra P. Vageli - One of the best experts on this subject based on the ideXlab platform.
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The Effect of NNK, A Tobacco Smoke Carcinogen, on the miRNA and Mismatch DNA Repair Expression Profiles in Lung and Head and Neck Squamous Cancer Cells
Cells, 2020Co-Authors: Sotirios G. Doukas, Dimitra P. Vageli, George Lazopoulos, Demetrios A. Spandidos, Clarence T. Sasaki, Aristidis TsatsakisAbstract:Tobacco smoking is a common risk factor for lung cancer and head and neck cancer. Molecular changes such as deregulation of miRNA expression have been linked to tobacco smoking in both types of cancer. Dysfunction of the Mismatch DNA Repair (MMR) mechanism has also been associated with a poor prognosis of these cancers, while a cross-talk between specific miRNAs and MMR genes has been previously proposed. We hypothesized that exposure of lung and head and neck squamous cancer cells (NCI and FaDu, respectively) to tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is capable of altering the expression of MSH2 and MLH1, key MMR components, by promoting specific miRNA deregulation. We found that either a low (1 μM) or high (2 μM) dose of NNK induced significant upregulation of "oncomirs" miR-21 and miR-155 and downregulation of "tumor suppressor" miR-422a, as well as the reduction of MMR protein and mRNA expression, in NCI and FaDu, compared to controls. Inhibition of miR-21 restored the NNK-induced reduced MSH2 phenotype in both NCI and FaDu, indicating that miR-21 might contribute to MSH2 regulation. Finally, NNK exposure increased NCI and FaDu survival, promoting cancer cell progression. We provide novel findings that deregulated miR-21, miR-155, and miR-422a and MMR gene expression patterns may be valuable biomarkers for lung and head and neck squamous cell cancer progression in smokers.
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Mismatch DNA Repair mRNA expression profiles in oral melanin pigmentation lesion and hamartomatous polyp of a child with Peutz-Jeghers syndrome.
Pediatric Blood & Cancer, 2013Co-Authors: Dimitra P. Vageli, Sotirios G. Doukas, Andreas MarkouAbstract:Mismatch DNA Repair (MMR) mRNA expression analysis was performed on a biopsy of oral mucosa melanin pigmentation lesion, a hamartomatous polyp and peripheral blood derived from a 12-year-old child with Peutz–Jeghers Syndrome (PJS). We present a deficient MMR system, in a PJS patient, which demonstrated low mRNA levels of hMSH6 and hPMS2 and an increasing MMR deficiency from the non-dysplastic lesion to hamartomatous polyp of PJS with a high risk of cancer. Pediatr Blood Cancer 2013;60:E116–E117. © 2013 Wiley Periodicals, Inc.
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Mismatch DNA Repair hMSH2, hMLH1, hMSH6 and hPMS2 mRNA Expression Profiles in Colorectal Carcinomas
Journal of Genetic Syndromes & Gene Therapy, 2013Co-Authors: Dimitra P. Vageli, Roidoula Papamichali, Konstantinos Kambosioras, Christos N Pap, Reou, George K. KoukoulisAbstract:Background: Mismatch Repair (MMR) deficiency has been related with HNPCCs. So far, there is limited information on MMR mRNA profiles in sporadic colorectal carcinomas (CRCs). We previously showed that distinct MMR mRNA phenotypes were related to tumor stage and survival of patients with lung cancer or urinary bladder carcinomas. Aim: The aim of this study was to quantify hMSH2, hMLH1, hMSH6 and hPMS2 mRNA levels, in CRCs and their adjacent normal tissues (ANTs), using accurate methodology, and to correlate MMR mRNA profiles with patient or tumor characteristics. Materials and methods: We analyzed 31 fresh frozen tissue specimens of paired CRCs with their ANTs. We evaluated MMR mRNA profiles by a Q-real-time PCR, using hPBGD gene as reference control and creating a standard curve. The MMR mRNA levels were assigned as ratios MMR/hPBGD mRNAs. Relative expression of each MMR gene was given as ratios of CRCs/ANTs mRNA levels. Results: All CRCs and their ANTs expressed low hPMS2 mRNA levels while a significant proportion of CRCs (73%) and their ANTs (82%) presented low hMSH2 mRNA levels. Analysis of relative expression patterns showed that hMSH6 and hMLH1 exhibited the highest percentages of reduction (53% and 45.5%, respectively). We found a correlation of transcriptional levels between hMSH2 and hMLH1, the crucial components of MMR mechanism and between their counterparts, hMSH6 and hPMS2, in CRCs of early stages, related to gender. On the contrary, CRCs of late stages revealed a correlation between reduced levels of hMSH2 and hMSH6, MutSa components, unrelated to gender but related to lymph node metastasis. Also, reduced hMSH2, hMSH6 and hMLH1 mRNA phenotypes correlated with advanced stage, and rectal localization. Conclusion: In this study we demonstrated that MMR mRNA deficiency is a common event in sporadic CRCs. Specific profiles of MMR deficiency maybe related to tumor progression, especially in male patients.
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Mismatch Repair hMSH2, hMLH1, hMSH6 and hPMS2 mRNA expression profiles in precancerous and cancerous urothelium
Oncology Letters, 2012Co-Authors: Dimitra P. Vageli, Sotirios G. Doukas, George K. Koukoulis, Stavros Giannopoulos, Christos Kalaitzis, Stilianos Giannakopoulos, Alexandra Giatromanolaki, Stavros TouloupidisAbstract:Changes in the expression of the Mismatch Repair (MMR) genes hMSH2, hMLH1, hMSH6 and hPMS2 reflect dysfunction of the DNA Repair system that may allow the malignant transformation of tissue cells. The aim of the present study was to address the mRNA expression profiles of the Mismatch DNA Repair system in cancerous and precancerous urothelium. This is the first study to quantify MMR mRNA expression by applying quantitative real-time PCR (qPCR) and translate the results to mRNA phenotypic profiles (r, reduced; R, regular or elevated) in bladder tumors [24 urothelial cell carcinomas (UCCs) and 1 papillary urothelial neoplasm of low malignant potential (PUNLMP)] paired with their adjacent normal tissues (ANTs). Genetic instability analysis was applied at polymorphic sites distal or close to the hMSH2 and hMLH1 locus. Presenting our data, reduced hMSH2, hMSH6 and hPMS2 mRNA expression profiles were observed in cancerous and precancerous urothelia. Significantly, the ANTs of UCCs revealed the highest percentages of reduced hMSH2 (r2), hMSH6 (r6) and hPMS2 (p2) mRNA phenotypes relative to their tumors (P
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Phenotypic Mismatch Repair hMSH2 and hMLH1 gene expression profiles in primary non-small cell lung carcinomas.
Lung Cancer, 2009Co-Authors: Dimitra P. Vageli, Zoe Daniil, Jubrail Dahabreh, Eleni Karagianni, Dimitra N. Vamvakopoulou, Maria Ioannou, Karin Scarpinato, Nikos C. Vamvakopoulos, Konstantinos I. Gourgoulianis, George K. KoukoulisAbstract:Abstract Background Defects in the human DNA Mismatch Repair genes (MMR) hMSH2 and hMLH1 are responsible for the development of sporadic and hereditary colorectal cancers. The role of MMR genes in the pathogenesis of lung cancer has not been elucidated. The aim of this study was to address the phenotypic mRNA expression profiles of Mismatch DNA Repair system in lung cancer. Materials and methods We evaluated the mRNA levels of the hMSH2 and hMLH1 components of the Mismatch DNA Repair (MMR) system in 29 unselected frozen pairs of primary non-small cell lung carcinomas (NSCLCs) and their adjacent normal tissue (ANTs) specimens by quantitative real-time PCR analysis relative to housekeeping Porphobilinogen deaminase ( hPBGD ) mRNA. To simplify and potentially improve the analysis of data, we defined for each individual MMR mRNA two possible phenotypes: a regular (R 2 : hMSH2/hPBGD mRNAs≥1 and R 1 : hMLH1/hPBGD mRNAs≥1) and a reduced (r 2 : hMSH2/hPBGD mRNAs 1 : hMLH1/hPBGD mRNAs Results Phenotyping defined four distinct MMR system expression profiles, R 2 R 1 , r 2 R 1 , R 2 r 1 and r 2 r 1 by ascending tumor progression rate and identified a previously unrecognized disease-associated phenotypic entity (r 2 r 1 ). The phenotype-based biological aspects of the MMR system suggested that its two components: (1) function independently and (2) are not directly involved in the onset of the transformation process, since healthy lung tissue was devoid of r 2 r 1 phenotypes. Conclusion These findings link MMR mRNA levels of paired lung tissue specimens to patients' clinical condition and suggest that phenotypic translation of molecular MMR data refines the biology of the MMR system with consequent diagnostic implications in the clinical assessment of lung cancer patients.
Karen Ruth Reed - One of the best experts on this subject based on the ideXlab platform.
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PPARδ status and Mismatch Repair mediated neoplasia in the mouse intestine
BMC Cancer, 2006Co-Authors: Karen Ruth Reed, Owen J. Sansom, Anthony Joseph Hayes, Andreas J. Gescher, Jefferey M. Peters, Alan Richard ClarkeAbstract:Background Therapeutic regulation of PPARδ activity using selective agonists has been proposed for various disorders. However, the consequences of altered peroxisome proliferator-activated receptor delta (PPARδ) activity in the context of intestinal tumourigenesis remain somewhat unclear. Contradictory evidence suggesting PPARδ either attenuates or potentiates intestinal neoplasia. To further investigate the PPARδ dependency of intestinal tumourigenesis, we have analysed the consequences of PPARδ deficiency upon intestinal neoplasia occurring in mice with impaired Mismatch DNA Repair.
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PPARδ status and Mismatch Repair mediated neoplasia in the mouse intestine
BMC Cancer, 2006Co-Authors: Karen Ruth Reed, Owen J. Sansom, Anthony Joseph Hayes, Andreas J. Gescher, Jefferey M. Peters, Alan Richard ClarkeAbstract:Background Therapeutic regulation of PPARδ activity using selective agonists has been proposed for various disorders. However, the consequences of altered peroxisome proliferator-activated receptor delta (PPARδ) activity in the context of intestinal tumourigenesis remain somewhat unclear. Contradictory evidence suggesting PPARδ either attenuates or potentiates intestinal neoplasia. To further investigate the PPARδ dependency of intestinal tumourigenesis, we have analysed the consequences of PPARδ deficiency upon intestinal neoplasia occurring in mice with impaired Mismatch DNA Repair. Methods Mice deficient for both PPARδ and the Mismatch Repair gene Mlh1 were produced and the incidence and severity of intestinal neoplasia recorded. Results No significant differences between the control genotypes and the double mutant genotypes were recorded indicating that deficiency of PPARδ does not modify impaired Mismatch Repair induced neoplasia. Conclusion In contrast with the previously observed acceleration of intestinal neoplasia in the context of the Apc ^ Min /+ mouse, PPARδ deficiency does not alter the phenotype of Mismatch Repair deficiency. This data supports the notion that PPARδ is not required for adenoma formation and indicate that any pro-tumourigenic effect of PPARδ inactivation may be highly context dependent.
Jean-claude Scimeca - One of the best experts on this subject based on the ideXlab platform.
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Family of SRY/Sox proteins is involved in the regulation of the mouseMsh4 (MutS homolog 4) gene expression
Molecular Reproduction and Development, 2001Co-Authors: V Santucci-darmanin, V. Vidal, C Scimeca, Claude Turc-carel, V�ronique Paquis-flucklinger, Sabine Santucci-darmanin, Fr�d�rique Vidal, Jean-claude ScimecaAbstract:The eukaryotic MutHLS-like system plays a crucial role in both mitosis and meiosis. Until now, a number of works have focused on the function of MutS and MutL homologs during Mismatch DNA Repair. Nevertheless, little is known about the role of these proteins during meiosis. MSH4 is a meiosis specific protein that is necessary for meiotic recombination in Saccharomyces cerevisiae. The human MSH4 protein is only found in testis and ovary. It is involved first in synapsis and second during recombination together with MLH1 (MutL Homolog 1). Here, we report the identification of the mouse Msh4 gene that is located on chromosome 3. We examined the expression of mMsh4 in testes of increasing developmental age and in elutriated germ cells. The pattern of expression during spermatogenesis is consistent with a role for MSH4 both during zygonema and pachynema. We demonstrated a promoter activity of the mMsh4 5'-flanking region by cell transfection experiments with a luciferase reporter gene. We found several SRY/Sox binding sites in this region and co-transfection experiments showed that SRY could down regulate mMsh4 promoter transcriptional activity. We propose that the regulation of mMsh4 expression could be one of the reasons for the persistence of SRY and/or SRY-related proteins in adult testis.
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Family of SRY/Sox proteins is involved in the regulation of the mouse Msh4 (MutS Homolog 4) gene expression
Molecular Reproduction and Development, 2001Co-Authors: Sabine Santucci-darmanin, Claude Turc-carel, Jean-claude Scimeca, Frédérique Vidal, V�ronique Paquis-flucklingerAbstract:The eukaryotic MutHLS-like system plays a crucial role in both mitosis and meiosis. Until now, a number of works have focused on the function of MutS and MutL homologs during Mismatch DNA Repair. Nevertheless, little is known about the role of these proteins during meiosis. MSH4 is a meiosis specific protein that is necessary for meiotic recombination in Saccharomyces cerevisiae. The human MSH4 protein is only found in testis and ovary. It is involved first in synapsis and second during recombination together with MLH1 (MutL Homolog 1). Here, we report the identification of the mouse Msh4 gene that is located on chromosome 3. We examined the expression of mMsh4 in testes of increasing developmental age and in elutriated germ cells. The pattern of expression during spermatogenesis is consistent with a role for MSH4 both during zygonema and pachynema. We demonstrated a promoter activity of the mMsh4 5'-flanking region by cell transfection experiments with a luciferase reporter gene. We found several SRY/Sox binding sites in this region and co-transfection experiments showed that SRY could down regulate mMsh4 promoter transcriptional activity. We propose that the regulation of mMsh4 expression could be one of the reasons for the persistence of SRY and/or SRY-related proteins in adult testis.
Jefferey M. Peters - One of the best experts on this subject based on the ideXlab platform.
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PPARδ status and Mismatch Repair mediated neoplasia in the mouse intestine
BMC Cancer, 2006Co-Authors: Karen Ruth Reed, Owen J. Sansom, Anthony Joseph Hayes, Andreas J. Gescher, Jefferey M. Peters, Alan Richard ClarkeAbstract:Background Therapeutic regulation of PPARδ activity using selective agonists has been proposed for various disorders. However, the consequences of altered peroxisome proliferator-activated receptor delta (PPARδ) activity in the context of intestinal tumourigenesis remain somewhat unclear. Contradictory evidence suggesting PPARδ either attenuates or potentiates intestinal neoplasia. To further investigate the PPARδ dependency of intestinal tumourigenesis, we have analysed the consequences of PPARδ deficiency upon intestinal neoplasia occurring in mice with impaired Mismatch DNA Repair.
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PPARδ status and Mismatch Repair mediated neoplasia in the mouse intestine
BMC Cancer, 2006Co-Authors: Karen Ruth Reed, Owen J. Sansom, Anthony Joseph Hayes, Andreas J. Gescher, Jefferey M. Peters, Alan Richard ClarkeAbstract:Background Therapeutic regulation of PPARδ activity using selective agonists has been proposed for various disorders. However, the consequences of altered peroxisome proliferator-activated receptor delta (PPARδ) activity in the context of intestinal tumourigenesis remain somewhat unclear. Contradictory evidence suggesting PPARδ either attenuates or potentiates intestinal neoplasia. To further investigate the PPARδ dependency of intestinal tumourigenesis, we have analysed the consequences of PPARδ deficiency upon intestinal neoplasia occurring in mice with impaired Mismatch DNA Repair. Methods Mice deficient for both PPARδ and the Mismatch Repair gene Mlh1 were produced and the incidence and severity of intestinal neoplasia recorded. Results No significant differences between the control genotypes and the double mutant genotypes were recorded indicating that deficiency of PPARδ does not modify impaired Mismatch Repair induced neoplasia. Conclusion In contrast with the previously observed acceleration of intestinal neoplasia in the context of the Apc ^ Min /+ mouse, PPARδ deficiency does not alter the phenotype of Mismatch Repair deficiency. This data supports the notion that PPARδ is not required for adenoma formation and indicate that any pro-tumourigenic effect of PPARδ inactivation may be highly context dependent.