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Reuben Lotan - One of the best experts on this subject based on the ideXlab platform.
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GPCR5A knockout mouse: A new model for Lung Carcinogenesis.
Cancer Epidemiology and Prevention Biomarkers, 2006Co-Authors: Reuben Lotan, Ludovic Lacroix, Taoyan Men, Junya Fujimoto, Jiong Deng, Li Mao, Carolyn S. Van Pelt, Qingguo TaoAbstract:ED06-02 Lung Carcinogenesis is a multistep process involving progressive genetic and epigenetic changes. Tobacco smoke is the major etiological agent, causing more than 85% of Lung cancers. Non-small cell Lung cancers (NSCLC) are thought to develop via morphologically distinct premalignant lesions by a multistage process. The initiation and progression of these lesions involve both activation of oncogenes and inactivation of tumor-suppressor genes. Mouse models for human cancer, especially those that reproduce genetic changes that underlay the human disease have proven to be valuable tools for understanding the basic tumor biology as well as for the development and validation of new approaches to cancer prevention and therapy. Most mouse strains do not develop or have a low incidence of spontaneous Lung cancer, however, mice of the strain A/J are unique in that the majority (90%) develop Lung adenoma, which may progress infrequently to adenocarcinoma as the mice reach 18 month of age. Such spontaneous Lung tumors uniformly possess a mutant K-ras oncogene. When the mice are exposed to tobacco smoke carcinogens like 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) Lung tumorigenesis is enhanced through promotion of the spontaneously occurring K-ras mutations. Retinoids (e.g., all-trans-retinoic acid, ATRA), play important physiological roles in Lung embryonal development, maintenance of mucociliary epithelial differentiation, and possibly also as endogenous inhibitors of Lung Carcinogenesis. Retinoids possess both chemopreventive and therapeutic effects in animal models of Lung Carcinogenesis. These effects are mediated by activation of nuclear retinoid receptors, which are ligand-dependent enhancers of target gene transcription. We were interested in the identification of retinoic acid target genes because we hypothesized that some of them might mediate the effects of retinoic acid on cell proliferation, survival and chemopreventive potential and might be new targets for intervention. Using differential display, we identified a novel gene, designated GPRC5A (synonyms: RAIG, RAI3, GPCR5A), which was induced by retinoic acid in human head and neck and non-small cell Lung carcinoma (NSCLC) cell lines. The gene encodes a protein with 7 transmembrane domains, which appears to be an orphan G protein coupled receptor. We also cloned the mouse homolog (Gpcr5a), which is similar to the human gene. Both are expressed preferentially in the Lung. Several NSCLC cell lines showed reduced expression that could be restored by retinoic acid. Furthermore, an almost identical retinoic acid response element to which retinoid receptors bind was identified in the promoter region of both the mouse and human genes. The GPCR5A mRNA level was reduced in more than 60% of 18 paired human adjacent normal Lung tissue and non-small cell Lung cancers (both adenocarcinomas and squamous cell carcinomas). Its overexpression in several cell lines suppressed anchorage-independent colony formation. Thus, it seemed that GPCR5A expression is inversely related to Lung cancer and to suppress the transformed phenotype. To better understand the function of the Gprc5a gene and protein, we deleted it (knockout) in mouse using gene-targeting technique. We replaced the Gpcr5a gene with the reporter bacterial beta-galactosidase (Lac Z) gene in mouse embryonal stem cells (ES) and used them to generate mice (strain B6;129F1) deficient in Gpcr5a. The heterozygous or homozygous mice showed no developmental aberrations and were as fertile and gained weight as the wild type littermates. The mice were interbred and followed over a period of up to 2 years for signs of abnormalities. A subset of mice was injected at age 2 months with tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and sacrificed 17 months later. A pathologist analyzed the tissues after HE (+/-); and (-/-) mice was 2% (1/49), 15% (14/93), and 63%(28/44), respectively. A microscopic analysis of histological sections prepared from formalin fixed paraffin-embedded Lungs revealed that 75% of the tumors in the (-/-) mice were (premalignant) Lung adenomas and a few were adenocarcinomas. The few tumors in heterozygotes and wild type mice were all adenomas. Histological sections of some adenomas and adenocarcinomas were analyzed by immunohistochemical techniques for the expression of the differentiation markers CC10 for Clara cells or type I cell, surfactant proteins A, B, and C (SPA, SPB, and pro-SPC) for type II cells. The analysis revealed that most adenomas expressed the type II cell markers and none expressed the Clara cell marker. The NNK treated mice were killed at 17 months after NNK injection and the presence of Lung tumors was assessed. 15/15 (100%) of NNK-treated Gpcr5a(-/-) mice developed Lung tumors, compared to 8/14 (57%) of Gpcr5a(-/-) mice without NNK treatment (p = 0.0063). None of the wild-type littermates, whether treated with NNK (0/15) or not (0/20), had developed Lung tumors in keeping with the expected carcinogen resistance of their parental strains. No Ras mutations were found in any of the tumors tested. Thus, the carcinomas found in Gpcr5a mice appear to develop via a Ras mutation-independent Carcinogenesis process. These results support the conclusion that Gprc5a functions as a tumor suppressor gene in the Lung and as an enhancer of NNK Carcinogenesis. This novel animal model of Lung Carcinogenesis might be useful for improving the understanding of Lung cancer development and for testing new chemopreventive and therapeutic agents.
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Identification of genes expressed differentially in an in vitro human Lung Carcinogenesis model.
Cancer biology & therapy, 2006Co-Authors: Ludovic Lacroix, Gang Feng, Reuben LotanAbstract:Lung cancer is the deadliest among all cancers in the US for both men and women. Early detection of premalignant lesions or tumors appears to be a promising approach to reducing the morbidity and mortality from Lung cancer because the survival of early stage Lung cancer patients is better than that of patients with advanced cancers. We approached the identification of early biomarkers of human Lung Carcinogenesis, by combining the use of cDNA array and an in vitro human Lung Carcinogenesis model that consists of normal (NHBE), immortalized (BEAS-2B and 1799), transformed (1198) and tumorigenic (1170-I) human bronchial epithelial (HBE) cells. We hypothesized that certain genes that are expressed differentially among these cells can serve as both biomarkers for early detection and targets for intervention. Nineteen genes were down-regulated and six were up-regulated in tumorigenic 1170-I HBE cells compared to normal HBE cells (NHBE) using cDNA array. Down- regulated genes encode cell-to-cell and cell-to-mat...
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diminished expression of s100a2 a putative tumor suppressor at early stage of human Lung Carcinogenesis
Cancer Research, 2001Co-Authors: Gang Feng, Emile M Youssef, Reuben LotanAbstract:To identify and understand early events in Lung Carcinogenesis, we used a cDNA array to screen for genes that are expressed differentially in normal human bronchial epithelial (NHBE) cells and a tumorigenic cell line (1170-I) derived from immortalized HBE cells after exposure to cigarette smoke condensate in vivo . Among these genes, we have identified the S100A2 gene, which encodes a nuclear calcium-binding protein, as being down-regulated in the 1170-I cells. Because this gene has been implicated as a tumor suppressor in breast cancer, we examined its potential role as a tumor suppressor in Lung Carcinogenesis. Levels of S100A2 transcript and protein, which were high in NHBE cells, decreased by up to 50% in immortalized HBE cells (BEAS-2B and 1799) and to low to nearly undetectable levels in transformed (1198) and tumorigenic (1170-I) HBE cells. Furthermore, S100A2 mRNA and protein were undetectable in 8 and expressed at a reduced level in 3 of 11 non-small cell Lung cancer (NSCLC) cell lines. Positive immunohistochemical staining of S100A2 was detected in the majority (75–83%) of normal and hyperplastic Lung tissues, whereas it was detected in <10% of metaplastic Lung tissues, squamous cell carcinoma, and adenocarcinoma. Treatment of 1170-I HBE and NSCLC cells with 5-aza-2′-deoxycytidine resulted in partial restoration of S100A2 expression in seven of eight cell lines. Indeed, CpG methylation was detected in the promoter region of the S100A2 gene. Our results suggest that S100A2 expression is suppressed early during Lung Carcinogenesis, possibly by hypermethylation of its promoter, and that its loss may be a contributing factor in Lung cancer development or a biomarker of early changes in this process.
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Diminished Expression of S100A2, a Putative Tumor Suppressor, at Early Stage of Human Lung Carcinogenesis
Cancer research, 2001Co-Authors: Gang Feng, Emile M Youssef, Reuben LotanAbstract:To identify and understand early events in Lung Carcinogenesis, we used a cDNA array to screen for genes that are expressed differentially in normal human bronchial epithelial (NHBE) cells and a tumorigenic cell line (1170-I) derived from immortalized HBE cells after exposure to cigarette smoke condensate in vivo . Among these genes, we have identified the S100A2 gene, which encodes a nuclear calcium-binding protein, as being down-regulated in the 1170-I cells. Because this gene has been implicated as a tumor suppressor in breast cancer, we examined its potential role as a tumor suppressor in Lung Carcinogenesis. Levels of S100A2 transcript and protein, which were high in NHBE cells, decreased by up to 50% in immortalized HBE cells (BEAS-2B and 1799) and to low to nearly undetectable levels in transformed (1198) and tumorigenic (1170-I) HBE cells. Furthermore, S100A2 mRNA and protein were undetectable in 8 and expressed at a reduced level in 3 of 11 non-small cell Lung cancer (NSCLC) cell lines. Positive immunohistochemical staining of S100A2 was detected in the majority (75–83%) of normal and hyperplastic Lung tissues, whereas it was detected in
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Retinoid Refractoriness Occurs during Lung Carcinogenesis Despite Functional Retinoid Receptors
Cancer research, 1995Co-Authors: Yeul Hong Kim, David F. Dohi, Gil Ro Han, Chang Ping Zou, Nobuhiko Oridate, Garrett L. Walsh, Jonathan C. Nesbitt, Waun Ki Hong, Reuben LotanAbstract:Retinoids have demonstrated activity in the prevention of second primary tumors in patients with non-small cell Lung cancer (NSCLC). They also contribute to the normal growth and differentiation of human bronchial epithelial (HBE) cells. Because retinoids mediate their actions through retinoid nuclear receptors (RARs and RXRs), aberrant signaling through retinoid receptors could contribute to Lung Carcinogenesis. Using a Lung Carcinogenesis model consisting of normal, premalignant, and malignant HBE cells, we exmined all- trans retinoic acid (t-RA)-induced changes in cellular growth. These studies revealed that t-RA treatment inhibited the growth of normal HBE cells, but premalignant and malignant HBE cells were relatively resistant to t-RA. Coincident with the development of retinoid refractoriness, basal expression of the retinoic acid nuclear receptor β (RAR-β) increased. Analysis of receptor function by gel shift and transient transfection assays of normal, premalignant, and malignant HBE cells demonstrated that receptor-DNA binding and transcriptional activation properties were intact in the t-RA-refractory malignant HBE cells. To compare these findings to NSCLCs in patients, we investigated retinoid receptor expression in NSCLC biopsies. A subset of the tumors expressed RAR-β, reflecting the RAR-β expression observed in the malignant HBE cells in culture. These findings demonstrate that retinoid receptor function was intact in the t-RA-refractory malignant HBE cell line, suggesting that the defect in retinoid signaling in this Lung Carcinogenesis model is not intrinsic to the retinoid receptors.
Yeul Hong Kim - One of the best experts on this subject based on the ideXlab platform.
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Abstract 3130: Discovery of tumor suppressor microRNA using smoking-related Lung Carcinogenesis cell model
Molecular and Cellular Biology, 2015Co-Authors: Jae Sook Sung, Jong Won Lee, Yeul Hong KimAbstract:Cigarette smoking is an important risk factor for Lung cancer and induces DNA hypermethylation. Hypermethylation can silence tumor suppressor miRNAs. However, it is less known regarding the role of miRNA methylation in Lung Carcinogenesis, especially smoking-related Lung cancer. We are now to discover the smoking-induced altered tumor suppressor miRNA in human Lung Carcinogenesis cell model. First, we examined miRNA expression profiles using Affymetrix GeneChip miRNA4.0 in human Lung Carcinogenesis cell model; NHBE, BEAS2B, 1799, 1198, 1170I cells (PNAS. 89:6693-97. 1992, Cancer Biol Ther. 5:665-73. 2006). And we have validated candidate tumor suppressor miRNAs by TaqMan real time PCR. We first discovered 6 candidate tumor suppressor miRNAs (miR-4448, miR-3180-3p, miR-584-5p, miR-3658, miR-8064, miR-371b) and we confirmed known decreased expression of several miRNAs in Lung Carcinogenesis cell model. Next, we tested methylation of candidate tumor suppressor miRNAs promoter CpG site by pyrosequencing. Increase of methylation was observed for 4 of the 6 candidate tumor suppressor miRNAs in human Lung Carcinogenesis cell model. Furthermore, methylation of miR-584-5p, miR-3658, miR-8064, miR-371b were greater in 1198 and 1170I cells exposed to cigarette smoking condensate (CSC). In the further study, we will confirm the role of tumor suppressor miRNA in smoking-related Lung Carcinogenesis by functional study. These finding suggest that tumor suppressor miRNAs are miRNA silenced by epigenetic mechanisms during smoking-induced Lung Carcinogenesis. This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (NRF-2013R1A1A2062146) and the Korea Health Technology RD 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3130. doi:10.1158/1538-7445.AM2015-3130
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Wnt5a Is Associated with Cigarette Smoke-Related Lung Carcinogenesis via Protein Kinase C
PloS one, 2013Co-Authors: Young Mi Whang, Jae Sook Sung, Jong Won Lee, Hyun-kyung Kim, Kyong Hwa Park, In Song Koh, Yeul Hong KimAbstract:Wnt5a is overexpressed during the progression of human non-small cell Lung cancer. However, the roles of Wnt5a during smoking-related Lung Carcinogenesis have not been clearly elucidated. We investigated the associations between Wnt5a and the early development of cigarette smoke related Lung cancer using human bronchial epithelial (HBE) cells (NHBE, BEAS-2B, 1799, 1198 and 1170I) at different malignant stages established by exposure to cigarette smoke condensate (CSC). Abnormal up-regulation of Wnt5a mRNA and proteins was detected in CSC-exposed transformed 1198 and tumorigenic 1170I cells as compared with other non-CSC exposed HBE cells. Tumor tissues obtained from smokers showed higher Wnt5a expressions than matched normal tissues. In non-CSC exposed 1799 cells, treatment of recombinant Wnt5a caused the activations of PKC and Akt, and the blockage of Wnt5a and PKC significantly decreased the viabilities of CSC-transformed 1198 cells expressing high levels of Wnt5a. This reduced cell survival rate was associated with increased apoptosis via the down-regulation of Bcl2 and the induction of cleaved poly ADP-ribose polymerase. Moreover, CSC-treated 1799 cells showed induction of Wnt5a expression and enhanced colony-forming capacity. The CSC-induced colony forming efficiency was suppressed by the co-incubation with a PKC inhibitor. In conclusion, these results suggest that cigarette smoke induces Wnt5a-coupled PKC activity during Lung Carcinogenesis, which causes Akt activity and anti-apoptosis in Lung cancer. Therefore, current study provides novel clues for the crucial role of Wnt5a in the smoking-related Lung Carcinogenesis.
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Retinoid Refractoriness Occurs during Lung Carcinogenesis Despite Functional Retinoid Receptors
Cancer research, 1995Co-Authors: Yeul Hong Kim, David F. Dohi, Gil Ro Han, Chang Ping Zou, Nobuhiko Oridate, Garrett L. Walsh, Jonathan C. Nesbitt, Waun Ki Hong, Reuben LotanAbstract:Retinoids have demonstrated activity in the prevention of second primary tumors in patients with non-small cell Lung cancer (NSCLC). They also contribute to the normal growth and differentiation of human bronchial epithelial (HBE) cells. Because retinoids mediate their actions through retinoid nuclear receptors (RARs and RXRs), aberrant signaling through retinoid receptors could contribute to Lung Carcinogenesis. Using a Lung Carcinogenesis model consisting of normal, premalignant, and malignant HBE cells, we exmined all- trans retinoic acid (t-RA)-induced changes in cellular growth. These studies revealed that t-RA treatment inhibited the growth of normal HBE cells, but premalignant and malignant HBE cells were relatively resistant to t-RA. Coincident with the development of retinoid refractoriness, basal expression of the retinoic acid nuclear receptor β (RAR-β) increased. Analysis of receptor function by gel shift and transient transfection assays of normal, premalignant, and malignant HBE cells demonstrated that receptor-DNA binding and transcriptional activation properties were intact in the t-RA-refractory malignant HBE cells. To compare these findings to NSCLCs in patients, we investigated retinoid receptor expression in NSCLC biopsies. A subset of the tumors expressed RAR-β, reflecting the RAR-β expression observed in the malignant HBE cells in culture. These findings demonstrate that retinoid receptor function was intact in the t-RA-refractory malignant HBE cell line, suggesting that the defect in retinoid signaling in this Lung Carcinogenesis model is not intrinsic to the retinoid receptors.
Luis M Montuenga - One of the best experts on this subject based on the ideXlab platform.
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Altered expression of adhesion molecules and epithelial–mesenchymal transition in silica-induced rat Lung Carcinogenesis
Laboratory Investigation, 2004Co-Authors: David Blanco, Eider Elizegi, Irene Pino, Fernando Lecanda, Silvestre Vicent, Mario F. Fraga, Umberto Saffiotti, Manel Esteller, Luis M MontuengaAbstract:Loss of the epithelial phenotype and disruption of adhesion molecules is a hallmark in the epithelial–mesenchymal transition (EMT) reported in several types of cancer. Most of the studies about the relevance of adhesion and junction molecules in Lung cancer have been performed using established tumors or in vitro models. The sequential molecular events leading to EMT during Lung cancer progression are still not well understood. We have used a rat model for multistep Lung Carcinogenesis to study the status of adherens and tight junction proteins and mesenchymal markers during EMT. After silica-induced chronic inflammation, rats sequentially develop epithelial hyperplasia, preneoplastic lesions, and tumors such as adenocarcinomas and squamous cell carcinomas. In comparison with normal and hyperplastic bronchiolar epithelium and with hyperplastic alveolar type II cells, the expression levels of E-cadherin, α -catenin and β -catenin were significantly reduced in adenomatoid preneoplastic lesions and in late tumors. The loss of E-cadherin in tumors was associated with its promoter hypermethylation. α - and β -catenin dysregulation lead to cytoplasmic accumulation in some carcinomas. No nuclear β -catenin localization was found at any stage of any preneoplastic or neoplastic lesion. Zonula occludens protein-1 was markedly decreased in 66% of adenocarcinomas and in 100% squamous cell carcinomas. The mesenchymal-associated proteins N-cadherin and vimentin were analyzed as markers for EMT. N-cadherin was de novo expressed in 32% of adenocarcinomas and 33% of squamous cell carcinomas. Vimentin-positive tumor cells were found in 35% of adenocarcinomas and 88% of squamous cell carcinomas. Mesenchymal markers were absent in precursor lesions, both hyperplastic and adenomatoid. The present results show that silica-induced rat Lung Carcinogenesis is a good model to study EMT in vivo , and also provide in vivo evidence suggesting that the changes in cell–cell adhesion molecules are an early event in Lung Carcinogenesis, while EMT occurs at a later stage.
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altered expression of adhesion molecules and epithelial mesenchymal transition in silica induced rat Lung Carcinogenesis
Laboratory Investigation, 2004Co-Authors: David Blanco, Eider Elizegi, Irene Pino, Fernando Lecanda, Silvestre Vicent, Mario F. Fraga, Umberto Saffiotti, Manel Esteller, Luis M MontuengaAbstract:Loss of the epithelial phenotype and disruption of adhesion molecules is a hallmark in the epithelial– mesenchymal transition (EMT) reported in several types of cancer. Most of the studies about the relevance of adhesion and junction molecules in Lung cancer have been performed using established tumors or in vitro models. The sequential molecular events leading to EMT during Lung cancer progression are still not well understood. We have used a rat model for multistep Lung Carcinogenesis to study the status of adherens and tight junction proteins and mesenchymal markers during EMT. After silica-induced chronic inflammation, rats sequentially develop epithelial hyperplasia, preneoplastic lesions, and tumors such as adenocarcinomas and squamous cell carcinomas. In comparison with normal and hyperplastic bronchiolar epithelium and with hyperplastic alveolar type II cells, the expression levels of E-cadherin, a-catenin and b-catenin were significantly reduced in adenomatoid preneoplastic lesions and in late tumors. The loss of E-cadherin in tumors was associated with its promoter hypermethylation. a- and b-catenin dysregulation lead to cytoplasmic accumulation in some carcinomas. No nuclear b-catenin localization was found at any stage of any preneoplastic or neoplastic lesion. Zonula occludens protein-1 was markedly decreased in 66% of adenocarcinomas and in 100% squamous cell carcinomas. The mesenchymal-associated proteins N-cadherin and vimentin were analyzed as markers for EMT. N-cadherin was de novo expressed in 32% of adenocarcinomas and 33% of squamous cell carcinomas. Vimentin-positive tumor cells were found in 35% of adenocarcinomas and 88% of squamous cell carcinomas. Mesenchymal markers were absent in precursor lesions, both hyperplastic and adenomatoid. The present results show that silica-induced rat Lung Carcinogenesis is a good model to study EMT in vivo, and also provide in vivo evidence suggesting that the changes in cell–cell adhesion molecules are an early event in Lung Carcinogenesis, while EMT occurs at a later stage. Laboratory Investigation (2004) 84, 999–1012, advance online publication, 14 June 2004; doi:10.1038/labinvest.3700129
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Altered expression of adhesion molecules and epithelial–mesenchymal transition in silica-induced rat Lung Carcinogenesis
Laboratory investigation; a journal of technical methods and pathology, 2004Co-Authors: David Blanco, Eider Elizegi, Irene Pino, Fernando Lecanda, Silvestre Vicent, Mario F. Fraga, Umberto Saffiotti, Manel Esteller, Luis M MontuengaAbstract:Loss of the epithelial phenotype and disruption of adhesion molecules is a hallmark in the epithelial– mesenchymal transition (EMT) reported in several types of cancer. Most of the studies about the relevance of adhesion and junction molecules in Lung cancer have been performed using established tumors or in vitro models. The sequential molecular events leading to EMT during Lung cancer progression are still not well understood. We have used a rat model for multistep Lung Carcinogenesis to study the status of adherens and tight junction proteins and mesenchymal markers during EMT. After silica-induced chronic inflammation, rats sequentially develop epithelial hyperplasia, preneoplastic lesions, and tumors such as adenocarcinomas and squamous cell carcinomas. In comparison with normal and hyperplastic bronchiolar epithelium and with hyperplastic alveolar type II cells, the expression levels of E-cadherin, a-catenin and b-catenin were significantly reduced in adenomatoid preneoplastic lesions and in late tumors. The loss of E-cadherin in tumors was associated with its promoter hypermethylation. a- and b-catenin dysregulation lead to cytoplasmic accumulation in some carcinomas. No nuclear b-catenin localization was found at any stage of any preneoplastic or neoplastic lesion. Zonula occludens protein-1 was markedly decreased in 66% of adenocarcinomas and in 100% squamous cell carcinomas. The mesenchymal-associated proteins N-cadherin and vimentin were analyzed as markers for EMT. N-cadherin was de novo expressed in 32% of adenocarcinomas and 33% of squamous cell carcinomas. Vimentin-positive tumor cells were found in 35% of adenocarcinomas and 88% of squamous cell carcinomas. Mesenchymal markers were absent in precursor lesions, both hyperplastic and adenomatoid. The present results show that silica-induced rat Lung Carcinogenesis is a good model to study EMT in vivo, and also provide in vivo evidence suggesting that the changes in cell–cell adhesion molecules are an early event in Lung Carcinogenesis, while EMT occurs at a later stage. Laboratory Investigation (2004) 84, 999–1012, advance online publication, 14 June 2004; doi:10.1038/labinvest.3700129
Dhanapal Sakthisekaran - One of the best experts on this subject based on the ideXlab platform.
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ORAL ADMINISTRATION OF THYMOQUINONE ATTENUATES BENZO (A) PYRENE INDUCED Lung Carcinogenesis IN MALE SWISS ALBINO MICE
International Journal of Pharmacy and Pharmaceutical Sciences, 2014Co-Authors: Gajendran Nithya, Revathi Mani, Dhanapal SakthisekaranAbstract:Objective: The present study has been designed to unravel the anticancer potential of thymoquinone against Benzo(a)pyrene induced Lung cancer in male swiss albino mice. Thymoquinone (C 10 H 12 O 2 0 )is a bioactive compound derived from the medicinal plant Nigella sativa. Thymoquinone (TQ) has been shown to exert anticancer effect on various cancer cell lines and there is no study on the efficacy of TQ on Benzo(a)pyrene [B(a)P] induced Lung Carcinogenesis in male swiss albino mice. Methods: The changes in heme indices ( RBC, Hb, WBC, monocytes, lymphocytes and neutrophils), membrane bound ATPases (Na + /K + ATPase, Mg 2+ ATPase and Ca 2+ ATPase) in control and experimental animals were analysed in serum and Lung tissue homogenate. Results: Lung cancer induced animals showed a considerably altered levels of heme indices with concomitant decreased levels of membrane bound ATPases in the Lung tissue and erythrocyte membrane. Oral administration of TQ at a dose of 20mg/kg b.w brought back the levels of the biochemical parameters to near normal. Conclusion: TQ supplementation restored the detrimental effects induced by B (a) P, indicating its anticancer potential in the treatment of experimental Lung Carcinogenesis. Keywords: Benzo(a)pyrene,Lung cancer, Thymoquinone, Heme indices, Membrane bound ATPases.
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Protective role of Solanum trilobatum (Solanaeace) against benzo(a)pyrene-induced Lung Carcinogenesis in Swiss albino mice
Biomedicine & Preventive Nutrition, 2014Co-Authors: R. Venugopal, Ganapathy Ekambaram, V. Mahesh, A. Aadithya, Dhanapal SakthisekaranAbstract:Abstract Objective To investigate the protective effect of leaf extract of Solanum trilobatum (ELEST) against benzo( a )pyrene (BP) induced Lung Carcinogenesis. Methods Experiment was designed with the treatment regimen of ELEST [200 mg/kg body weight dissolved in dimethyl sulphoxide(DMSO)] for 4 weeks before (pre-initiation) and from 12th week after B( a )P (50 mg/kg body weight) induced Lung carcinoma(post-initation). Results Administration of BP (50 mg/kg body weight) resulted in increased lipid peroxidation (LPO) and marker enzymes, such as arylhydrocarbon hydroxylase (AHH), gamma-glutamyl transpeptidase (γGT), 5′-nucleotidase (5′ND) and lactate dehydrogenase (LDH) along with decrease in the levels of tissue antioxidants, like superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), reduced glutathione (GSH), vitamin E and vitamin C in mice. Significantly, ELEST modulated these alterations suggest the efficacy of ELEST in the chemotherapeutics of Lung cancer. The histopathological studies also evidenced the protective efficiency of the extract against Lung Carcinogenesis. Further, significant increase in the levels of Cytochrome P 450 , Cytochrome b 5 , NADPH Cyt c reductase and decrease in UDP-glucuronyl transferase and quinone reductase was observed in microsomal fraction of Lung and liver of BP-induced mice, whereas the treatment with ELEST resulted in reversal of modulations observed in the activities of detoxification enzymes. Conclusions Collectively, the present observations indicate that the treatment with ELEST exhibited protective and antioxidant effect against BP-induced Lung Carcinogenesis.
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Cytoprotective Effect of Mangiferin on Benzo(a)pyrene‐Induced Lung Carcinogenesis in Swiss Albino Mice
Basic & clinical pharmacology & toxicology, 2008Co-Authors: Peramaiyan Rajendran, Ganapathy Ekambaram, Dhanapal SakthisekaranAbstract:Antioxidants are one of the key players in tumourigenesis, and several natural and synthetic antioxidants have been shown to have anticancer effects. In the present investigation, the efficacy of mangiferin on the antioxidant status of benzo(a)pyrene-induced Lung Carcinogenesis in Swiss albino mice was assessed. The animals were divided into five groups. The animals in groups I and V were normal control and mangiferin control, respectively. Groups II, III and IV were administered with benzo(a)pyrene (50 mg/kg body weight, orally) for 4 weeks (twice a week) to induced Lung Carcinogenesis. Starting 1 week prior to benzo(a)pyrene administration, group III animals were treated with mangiferin (100 mg/kg body weight) in the diet for 18 weeks; 12 weeks after benzo(a)pyrene administration, group III animals were treated with mangiferin that continued until the end of the experiment period (18 weeks). At the end of the experiment period, the reactive oxygen species, glutathione and the activities of antioxidant enzymes were assessed in both Lung and liver tissues. The levels of glutathione, superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, vitamin E and vitamin C were decreased in group II animals. However, in the mangiferin + benzo(a)pyrene-treated groups III and IV, the levels of GSH and the activities of antioxidant enzymes in both Lung and liver were improved when compared with benzo(a)pyrene-induced group II animals. In addition, the finding that mangiferin decreased reactive oxygen species levels and enhanced antioxidant status suggests that this polyphenol might also be of value in the prevention of benzo(a)pyrene-induced Lung Carcinogenesis.
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Modulatory effect of Piperine on mitochondrial antioxidant system in Benzo(a)pyrene-induced experimental Lung Carcinogenesis.
Phytomedicine : international journal of phytotherapy and phytopharmacology, 2004Co-Authors: Karuppaiyah Selvendiran, Palaniyandi Senthilnathan, Venkatraman Magesh, Dhanapal SakthisekaranAbstract:Chemoprevention has emerged as a very effective preventive measure against Carcinogenesis. Many bioactive compounds present in edible as well in herbal plants have revealed their cancer chemopreventive potential. In the present study, our goal was to investigate the impact of piperine, a principle ingredient of pepper, on alterations of mitochondrial antioxidant system and lipid peroxidation in Benzo(a)pyrene (B(a)P) induced experimental Lung Carcinogenesis. Oral supplementation of piperine (50 mg/kg body weight) effectively suppressed Lung Carcinogenesis in B(a)p induced mice as revealed by the decrease in the extent of mitochondrial lipid peroxidation and concomitant increase in the activities of enzymatic antioxidants (superoxide dismutase, catalase and glutathione peroxidase) and non enzymatic antioxidant (reduced glutathione, vitamin E and vitamin C) levels when compared to Lung Carcinogenesis bearing animals. Our data suggests that piperine may extent its chemopreventive effect by modulating lipid peroxidation and augmenting antioxidant defense system.
David Blanco - One of the best experts on this subject based on the ideXlab platform.
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Altered expression of adhesion molecules and epithelial–mesenchymal transition in silica-induced rat Lung Carcinogenesis
Laboratory Investigation, 2004Co-Authors: David Blanco, Eider Elizegi, Irene Pino, Fernando Lecanda, Silvestre Vicent, Mario F. Fraga, Umberto Saffiotti, Manel Esteller, Luis M MontuengaAbstract:Loss of the epithelial phenotype and disruption of adhesion molecules is a hallmark in the epithelial–mesenchymal transition (EMT) reported in several types of cancer. Most of the studies about the relevance of adhesion and junction molecules in Lung cancer have been performed using established tumors or in vitro models. The sequential molecular events leading to EMT during Lung cancer progression are still not well understood. We have used a rat model for multistep Lung Carcinogenesis to study the status of adherens and tight junction proteins and mesenchymal markers during EMT. After silica-induced chronic inflammation, rats sequentially develop epithelial hyperplasia, preneoplastic lesions, and tumors such as adenocarcinomas and squamous cell carcinomas. In comparison with normal and hyperplastic bronchiolar epithelium and with hyperplastic alveolar type II cells, the expression levels of E-cadherin, α -catenin and β -catenin were significantly reduced in adenomatoid preneoplastic lesions and in late tumors. The loss of E-cadherin in tumors was associated with its promoter hypermethylation. α - and β -catenin dysregulation lead to cytoplasmic accumulation in some carcinomas. No nuclear β -catenin localization was found at any stage of any preneoplastic or neoplastic lesion. Zonula occludens protein-1 was markedly decreased in 66% of adenocarcinomas and in 100% squamous cell carcinomas. The mesenchymal-associated proteins N-cadherin and vimentin were analyzed as markers for EMT. N-cadherin was de novo expressed in 32% of adenocarcinomas and 33% of squamous cell carcinomas. Vimentin-positive tumor cells were found in 35% of adenocarcinomas and 88% of squamous cell carcinomas. Mesenchymal markers were absent in precursor lesions, both hyperplastic and adenomatoid. The present results show that silica-induced rat Lung Carcinogenesis is a good model to study EMT in vivo , and also provide in vivo evidence suggesting that the changes in cell–cell adhesion molecules are an early event in Lung Carcinogenesis, while EMT occurs at a later stage.
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altered expression of adhesion molecules and epithelial mesenchymal transition in silica induced rat Lung Carcinogenesis
Laboratory Investigation, 2004Co-Authors: David Blanco, Eider Elizegi, Irene Pino, Fernando Lecanda, Silvestre Vicent, Mario F. Fraga, Umberto Saffiotti, Manel Esteller, Luis M MontuengaAbstract:Loss of the epithelial phenotype and disruption of adhesion molecules is a hallmark in the epithelial– mesenchymal transition (EMT) reported in several types of cancer. Most of the studies about the relevance of adhesion and junction molecules in Lung cancer have been performed using established tumors or in vitro models. The sequential molecular events leading to EMT during Lung cancer progression are still not well understood. We have used a rat model for multistep Lung Carcinogenesis to study the status of adherens and tight junction proteins and mesenchymal markers during EMT. After silica-induced chronic inflammation, rats sequentially develop epithelial hyperplasia, preneoplastic lesions, and tumors such as adenocarcinomas and squamous cell carcinomas. In comparison with normal and hyperplastic bronchiolar epithelium and with hyperplastic alveolar type II cells, the expression levels of E-cadherin, a-catenin and b-catenin were significantly reduced in adenomatoid preneoplastic lesions and in late tumors. The loss of E-cadherin in tumors was associated with its promoter hypermethylation. a- and b-catenin dysregulation lead to cytoplasmic accumulation in some carcinomas. No nuclear b-catenin localization was found at any stage of any preneoplastic or neoplastic lesion. Zonula occludens protein-1 was markedly decreased in 66% of adenocarcinomas and in 100% squamous cell carcinomas. The mesenchymal-associated proteins N-cadherin and vimentin were analyzed as markers for EMT. N-cadherin was de novo expressed in 32% of adenocarcinomas and 33% of squamous cell carcinomas. Vimentin-positive tumor cells were found in 35% of adenocarcinomas and 88% of squamous cell carcinomas. Mesenchymal markers were absent in precursor lesions, both hyperplastic and adenomatoid. The present results show that silica-induced rat Lung Carcinogenesis is a good model to study EMT in vivo, and also provide in vivo evidence suggesting that the changes in cell–cell adhesion molecules are an early event in Lung Carcinogenesis, while EMT occurs at a later stage. Laboratory Investigation (2004) 84, 999–1012, advance online publication, 14 June 2004; doi:10.1038/labinvest.3700129
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Altered expression of adhesion molecules and epithelial–mesenchymal transition in silica-induced rat Lung Carcinogenesis
Laboratory investigation; a journal of technical methods and pathology, 2004Co-Authors: David Blanco, Eider Elizegi, Irene Pino, Fernando Lecanda, Silvestre Vicent, Mario F. Fraga, Umberto Saffiotti, Manel Esteller, Luis M MontuengaAbstract:Loss of the epithelial phenotype and disruption of adhesion molecules is a hallmark in the epithelial– mesenchymal transition (EMT) reported in several types of cancer. Most of the studies about the relevance of adhesion and junction molecules in Lung cancer have been performed using established tumors or in vitro models. The sequential molecular events leading to EMT during Lung cancer progression are still not well understood. We have used a rat model for multistep Lung Carcinogenesis to study the status of adherens and tight junction proteins and mesenchymal markers during EMT. After silica-induced chronic inflammation, rats sequentially develop epithelial hyperplasia, preneoplastic lesions, and tumors such as adenocarcinomas and squamous cell carcinomas. In comparison with normal and hyperplastic bronchiolar epithelium and with hyperplastic alveolar type II cells, the expression levels of E-cadherin, a-catenin and b-catenin were significantly reduced in adenomatoid preneoplastic lesions and in late tumors. The loss of E-cadherin in tumors was associated with its promoter hypermethylation. a- and b-catenin dysregulation lead to cytoplasmic accumulation in some carcinomas. No nuclear b-catenin localization was found at any stage of any preneoplastic or neoplastic lesion. Zonula occludens protein-1 was markedly decreased in 66% of adenocarcinomas and in 100% squamous cell carcinomas. The mesenchymal-associated proteins N-cadherin and vimentin were analyzed as markers for EMT. N-cadherin was de novo expressed in 32% of adenocarcinomas and 33% of squamous cell carcinomas. Vimentin-positive tumor cells were found in 35% of adenocarcinomas and 88% of squamous cell carcinomas. Mesenchymal markers were absent in precursor lesions, both hyperplastic and adenomatoid. The present results show that silica-induced rat Lung Carcinogenesis is a good model to study EMT in vivo, and also provide in vivo evidence suggesting that the changes in cell–cell adhesion molecules are an early event in Lung Carcinogenesis, while EMT occurs at a later stage. Laboratory Investigation (2004) 84, 999–1012, advance online publication, 14 June 2004; doi:10.1038/labinvest.3700129
