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Ravi Salgia - One of the best experts on this subject based on the ideXlab platform.
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Role of PAX8 in the regulation of MET and RON receptor tyrosine kinases in non-small cell lung cancer
BMC cancer, 2014Co-Authors: Rajani Kanteti, Aliya N Husain, Everett E. Vokes, Maria Tretiakova, Essam El-hashani, Immanuel Dhanasingh, Sherven Sharma, Jay Sharma, Ravi SalgiaAbstract:Non-small cell lung cancers (NSCLC) are highly heterogeneous at the molecular level and comprise 75% of all lung tumors. We have previously shown that the receptor tyrosine kinase (RTK) MET frequently suffers gain-of-function mutations that significantly promote lung tumorigenesis. Subsequent studies from our lab also revealed that PAX5 transcription factor is preferentially expressed in small cell lung cancer (SCLC) and promotes MET transcription. PAX8, however, is also expressed in NSCLC cell lines. We therefore investigated the role of PAX8 in NSCLC. Using IHC analysis, PAX8 protein expression was determined in archival NSCLC tumor tissues (n = 254). In order to study the effects of PAX8 knockdown on NSCLC cellular functions such as apoptosis and motility, siRNA against PAX8 was used. Confocal fluorescence microscopy was used to monitor the localization of MET, RON and PAX8. The combinatorial effect of PAX8 knockdown and MET inhibition using SU11274 was investigated in NSCLC cell viability assay. Relative levels of PAX8 protein were elevated (≥ + 2 on a scale of 0–3) in adenocarcinoma (58/94), large cell carcinoma (50/85), squamous cell carcinoma (28/47), and metastatic NSCLC (17/28; lymph node). Utilizing early progenitors isolated from NSCLC cell lines and fresh tumor tissues, we observed robust overexpression of PAX8, MET, and RON. PAX8 knockdown A549 cells revealed abrogated PAX8 expression with a concomitant loss in MET and the related RON kinase expression. A dramatic colocalization between the active form of MET (also RON) and PAX8 upon challenging A549 cells with HGF was visualized. A similar colocalization of MET and EGL5 (PAX8 ortholog) proteins was found in embryos of C. elegans. Most importantly, knockdown of PAX8 in A549 cells resulted in enhanced apoptosis (~6 fold) and decreased cell motility (~45%), thereby making PAX8 a potential therapeutic target. However, the combinatorial approach of PAX8 knockdown and treatment with MET inhibitor, SU11274, had marginal additive effect on loss of NSCLC cell viability. PAX8 provides signals for growth and motility of NSCLC cells and is necessary for MET and RON expression. Further investigations are necessary to investigate the therapeutic potential of PA8 in NSCLC.
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abstract lb 119 expression and function of pax5 transcription factor and regulation of c met in sclc potential for novel biomarkers and therapeutics
Cancer Research, 2009Co-Authors: Rajani Kanteti, Soundararajan Krishnaswamy, Leonardo Faoro, Deborah Lang, Sivakumar Loganathan, Everett E. Vokes, Ravi SalgiaAbstract:Lung cancer still remains one of the leading causes of all cancer related deaths. Prognosis in patients with non small cell lung cancer (NSCLC) is better compared to those with small cell lung cancer (SCLC), however the overall survival rate is still very low (17%). A plethora of molecular changes due to various genomic alterations are known to contribute to the development and spread of lung cancers, for instance mutations in p53, RB, Ras, several receptor and non-receptor tyrosine kinases are known to contribute to the variety of phenotypes seen in lung cancer. In this regard, we examined the role of PAX5 transcription factor in SCLC lung cancer. PAX5 is a nuclear transcription factor required for B cell development and its expression was evaluated in upper aerodigestive malignancies and pancreatic cancer by immunoblotting. PAX5 protein expression was relatively high in small cell lung cancer (SCLC, 11/12), however its expression was not detected in non-SCLC (NSCLC, n=13), mesothelioma (n=7), pancreatic (n=6), esophageal (n=6) and head and neck cancer cell lines (n=12). In comparison, PAX8 and PAX3 expression was absent or non-detectable in SCLC cell lines, however PAX8 was expressed in most of the NSCLC cell lines (13/13) tested and also frequently in all the other cell lines . We also detected frequent expression of PAX2 and PAX9 protein in the various cell lines. Utilizing neuroendocrine tumor samples, we found that the frequency as well as the average intensity of expression of PAX5 increased from pulmonary carcinoid (9%, moderate and strong PAX5 expression, n=44), to large cell neuroendocrine carcinoma (LCNC, 27% n=11) to SCLC (33%, n=76). FISH analysis revealed no translocations of PAX5 gene, but polyploidy in some SCLC tumor tissues (6 /37). We determined that PAX5 could regulate the transcription of c-Met using luciferase coupled reporter and ChIP analysis. In addition the phospho-c-Met and PAX5 were both localized to the same intra-nuclear compartment in HGF treated SCLC cells and interacted with each other. Finally, we determined the therapeutic translational potential of PAX5 using PAX5 knockdown SCLC cells in conjunction with Topoisomerase 1 (SN38) and c-Met (SU11274) inhibitors. Loss of endogenous PAX5 significantly decreased the viability of SCLC cells, especially when combined with SN38 or SU11274 and maximum effect was seen when both inhibitors were used. We therefore propose that PAX5 could be an important regulator of c-MET transcription and a potential target for therapy in SCLC. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr LB-119.
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abstract lb 119 expression and function of pax5 transcription factor and regulation of c met in sclc potential for novel biomarkers and therapeutics
Cancer Research, 2009Co-Authors: Rajani Kanteti, Soundararajan Krishnaswamy, Leonardo Faoro, Deborah Lang, Sivakumar Loganathan, Everett E. Vokes, Ravi SalgiaAbstract:Lung cancer still remains one of the leading causes of all cancer related deaths. Prognosis in patients with non small cell lung cancer (NSCLC) is better compared to those with small cell lung cancer (SCLC), however the overall survival rate is still very low (17%). A plethora of molecular changes due to various genomic alterations are known to contribute to the development and spread of lung cancers, for instance mutations in p53, RB, Ras, several receptor and non-receptor tyrosine kinases are known to contribute to the variety of phenotypes seen in lung cancer. In this regard, we examined the role of PAX5 transcription factor in SCLC lung cancer. PAX5 is a nuclear transcription factor required for B cell development and its expression was evaluated in upper aerodigestive malignancies and pancreatic cancer by immunoblotting. PAX5 protein expression was relatively high in small cell lung cancer (SCLC, 11/12), however its expression was not detected in non-SCLC (NSCLC, n=13), mesothelioma (n=7), pancreatic (n=6), esophageal (n=6) and head and neck cancer cell lines (n=12). In comparison, PAX8 and PAX3 expression was absent or non-detectable in SCLC cell lines, however PAX8 was expressed in most of the NSCLC cell lines (13/13) tested and also frequently in all the other cell lines . We also detected frequent expression of PAX2 and PAX9 protein in the various cell lines. Utilizing neuroendocrine tumor samples, we found that the frequency as well as the average intensity of expression of PAX5 increased from pulmonary carcinoid (9%, moderate and strong PAX5 expression, n=44), to large cell neuroendocrine carcinoma (LCNC, 27% n=11) to SCLC (33%, n=76). FISH analysis revealed no translocations of PAX5 gene, but polyploidy in some SCLC tumor tissues (6 /37). We determined that PAX5 could regulate the transcription of c-Met using luciferase coupled reporter and ChIP analysis. In addition the phospho-c-Met and PAX5 were both localized to the same intra-nuclear compartment in HGF treated SCLC cells and interacted with each other. Finally, we determined the therapeutic translational potential of PAX5 using PAX5 knockdown SCLC cells in conjunction with Topoisomerase 1 (SN38) and c-Met (SU11274) inhibitors. Loss of endogenous PAX5 significantly decreased the viability of SCLC cells, especially when combined with SN38 or SU11274 and maximum effect was seen when both inhibitors were used. We therefore propose that PAX5 could be an important regulator of c-MET transcription and a potential target for therapy in SCLC. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr LB-119.
Rajani Kanteti - One of the best experts on this subject based on the ideXlab platform.
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Role of PAX8 in the regulation of MET and RON receptor tyrosine kinases in non-small cell lung cancer
BMC cancer, 2014Co-Authors: Rajani Kanteti, Aliya N Husain, Everett E. Vokes, Maria Tretiakova, Essam El-hashani, Immanuel Dhanasingh, Sherven Sharma, Jay Sharma, Ravi SalgiaAbstract:Non-small cell lung cancers (NSCLC) are highly heterogeneous at the molecular level and comprise 75% of all lung tumors. We have previously shown that the receptor tyrosine kinase (RTK) MET frequently suffers gain-of-function mutations that significantly promote lung tumorigenesis. Subsequent studies from our lab also revealed that PAX5 transcription factor is preferentially expressed in small cell lung cancer (SCLC) and promotes MET transcription. PAX8, however, is also expressed in NSCLC cell lines. We therefore investigated the role of PAX8 in NSCLC. Using IHC analysis, PAX8 protein expression was determined in archival NSCLC tumor tissues (n = 254). In order to study the effects of PAX8 knockdown on NSCLC cellular functions such as apoptosis and motility, siRNA against PAX8 was used. Confocal fluorescence microscopy was used to monitor the localization of MET, RON and PAX8. The combinatorial effect of PAX8 knockdown and MET inhibition using SU11274 was investigated in NSCLC cell viability assay. Relative levels of PAX8 protein were elevated (≥ + 2 on a scale of 0–3) in adenocarcinoma (58/94), large cell carcinoma (50/85), squamous cell carcinoma (28/47), and metastatic NSCLC (17/28; lymph node). Utilizing early progenitors isolated from NSCLC cell lines and fresh tumor tissues, we observed robust overexpression of PAX8, MET, and RON. PAX8 knockdown A549 cells revealed abrogated PAX8 expression with a concomitant loss in MET and the related RON kinase expression. A dramatic colocalization between the active form of MET (also RON) and PAX8 upon challenging A549 cells with HGF was visualized. A similar colocalization of MET and EGL5 (PAX8 ortholog) proteins was found in embryos of C. elegans. Most importantly, knockdown of PAX8 in A549 cells resulted in enhanced apoptosis (~6 fold) and decreased cell motility (~45%), thereby making PAX8 a potential therapeutic target. However, the combinatorial approach of PAX8 knockdown and treatment with MET inhibitor, SU11274, had marginal additive effect on loss of NSCLC cell viability. PAX8 provides signals for growth and motility of NSCLC cells and is necessary for MET and RON expression. Further investigations are necessary to investigate the therapeutic potential of PA8 in NSCLC.
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abstract lb 119 expression and function of pax5 transcription factor and regulation of c met in sclc potential for novel biomarkers and therapeutics
Cancer Research, 2009Co-Authors: Rajani Kanteti, Soundararajan Krishnaswamy, Leonardo Faoro, Deborah Lang, Sivakumar Loganathan, Everett E. Vokes, Ravi SalgiaAbstract:Lung cancer still remains one of the leading causes of all cancer related deaths. Prognosis in patients with non small cell lung cancer (NSCLC) is better compared to those with small cell lung cancer (SCLC), however the overall survival rate is still very low (17%). A plethora of molecular changes due to various genomic alterations are known to contribute to the development and spread of lung cancers, for instance mutations in p53, RB, Ras, several receptor and non-receptor tyrosine kinases are known to contribute to the variety of phenotypes seen in lung cancer. In this regard, we examined the role of PAX5 transcription factor in SCLC lung cancer. PAX5 is a nuclear transcription factor required for B cell development and its expression was evaluated in upper aerodigestive malignancies and pancreatic cancer by immunoblotting. PAX5 protein expression was relatively high in small cell lung cancer (SCLC, 11/12), however its expression was not detected in non-SCLC (NSCLC, n=13), mesothelioma (n=7), pancreatic (n=6), esophageal (n=6) and head and neck cancer cell lines (n=12). In comparison, PAX8 and PAX3 expression was absent or non-detectable in SCLC cell lines, however PAX8 was expressed in most of the NSCLC cell lines (13/13) tested and also frequently in all the other cell lines . We also detected frequent expression of PAX2 and PAX9 protein in the various cell lines. Utilizing neuroendocrine tumor samples, we found that the frequency as well as the average intensity of expression of PAX5 increased from pulmonary carcinoid (9%, moderate and strong PAX5 expression, n=44), to large cell neuroendocrine carcinoma (LCNC, 27% n=11) to SCLC (33%, n=76). FISH analysis revealed no translocations of PAX5 gene, but polyploidy in some SCLC tumor tissues (6 /37). We determined that PAX5 could regulate the transcription of c-Met using luciferase coupled reporter and ChIP analysis. In addition the phospho-c-Met and PAX5 were both localized to the same intra-nuclear compartment in HGF treated SCLC cells and interacted with each other. Finally, we determined the therapeutic translational potential of PAX5 using PAX5 knockdown SCLC cells in conjunction with Topoisomerase 1 (SN38) and c-Met (SU11274) inhibitors. Loss of endogenous PAX5 significantly decreased the viability of SCLC cells, especially when combined with SN38 or SU11274 and maximum effect was seen when both inhibitors were used. We therefore propose that PAX5 could be an important regulator of c-MET transcription and a potential target for therapy in SCLC. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr LB-119.
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abstract lb 119 expression and function of pax5 transcription factor and regulation of c met in sclc potential for novel biomarkers and therapeutics
Cancer Research, 2009Co-Authors: Rajani Kanteti, Soundararajan Krishnaswamy, Leonardo Faoro, Deborah Lang, Sivakumar Loganathan, Everett E. Vokes, Ravi SalgiaAbstract:Lung cancer still remains one of the leading causes of all cancer related deaths. Prognosis in patients with non small cell lung cancer (NSCLC) is better compared to those with small cell lung cancer (SCLC), however the overall survival rate is still very low (17%). A plethora of molecular changes due to various genomic alterations are known to contribute to the development and spread of lung cancers, for instance mutations in p53, RB, Ras, several receptor and non-receptor tyrosine kinases are known to contribute to the variety of phenotypes seen in lung cancer. In this regard, we examined the role of PAX5 transcription factor in SCLC lung cancer. PAX5 is a nuclear transcription factor required for B cell development and its expression was evaluated in upper aerodigestive malignancies and pancreatic cancer by immunoblotting. PAX5 protein expression was relatively high in small cell lung cancer (SCLC, 11/12), however its expression was not detected in non-SCLC (NSCLC, n=13), mesothelioma (n=7), pancreatic (n=6), esophageal (n=6) and head and neck cancer cell lines (n=12). In comparison, PAX8 and PAX3 expression was absent or non-detectable in SCLC cell lines, however PAX8 was expressed in most of the NSCLC cell lines (13/13) tested and also frequently in all the other cell lines . We also detected frequent expression of PAX2 and PAX9 protein in the various cell lines. Utilizing neuroendocrine tumor samples, we found that the frequency as well as the average intensity of expression of PAX5 increased from pulmonary carcinoid (9%, moderate and strong PAX5 expression, n=44), to large cell neuroendocrine carcinoma (LCNC, 27% n=11) to SCLC (33%, n=76). FISH analysis revealed no translocations of PAX5 gene, but polyploidy in some SCLC tumor tissues (6 /37). We determined that PAX5 could regulate the transcription of c-Met using luciferase coupled reporter and ChIP analysis. In addition the phospho-c-Met and PAX5 were both localized to the same intra-nuclear compartment in HGF treated SCLC cells and interacted with each other. Finally, we determined the therapeutic translational potential of PAX5 using PAX5 knockdown SCLC cells in conjunction with Topoisomerase 1 (SN38) and c-Met (SU11274) inhibitors. Loss of endogenous PAX5 significantly decreased the viability of SCLC cells, especially when combined with SN38 or SU11274 and maximum effect was seen when both inhibitors were used. We therefore propose that PAX5 could be an important regulator of c-MET transcription and a potential target for therapy in SCLC. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr LB-119.
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PAX5 is expressed in small-cell lung cancer and positively regulates c-Met transcription
Laboratory Investigation, 2009Co-Authors: Rajani Kanteti, Vidya Nallasura, Todd Kroll, Soundararajan Krishnaswamy, Leonardo Faoro, Philip Cagle, Sivakumar Loganathan, Aliya N Husain, Maria Tretiakova, Everett E. VokesAbstract:PAX5 is a nuclear transcription factor required for B cell development, and its expression was evaluated in upper aerodigestive malignancies and pancreatic cancer by immunoblotting. The PAX5 protein expression was relatively strong in small-cell lung cancer (SCLC, 11/12); however, its expression was not detected in non-SCLC (NSCLC, n =13), mesothelioma ( n =7), pancreatic ( n =6), esophageal ( n =6) and head and neck cancer cell lines ( n =12). In comparison, PAX8 and PAX3 expressions were absent or non-detectable in SCLC cell lines; however, PAX8 was expressed in most of the tested NSCLC cell lines (13/13) and also frequently in all the other cell lines. We also detected frequent expressions of PAX2 and PAX9 protein in the various cell lines. Utilizing neuroendocrine tumor samples, we found that the frequency as well as the average intensity of the expression of PAX5 increased from pulmonary carcinoid (9%, moderate and strong PAX5 expression, n =44), to large-cell neuroendocrine carcinoma (LCNC, 27%, n =11) to SCLC (33%, n =76). FISH analysis revealed no translocations of the PAX5 gene, but polyploidy in some SCLC tumor tissues (6/37). We determined that PAX5 could regulate the transcription of c-Met using luciferase-coupled reporter and chromatin immunoprecipitation analysis. In addition, the phospho-c-Met (active form) and PAX5 were both localized to the same intra-nuclear compartment in hepatocyte growth factor treated SCLC cells and interacted with each other. Finally, we determined the therapeutic translational potential of PAX5 using PAX5 knockdown SCLC cells in conjunction with Topoisomerase 1 (SN38) and c-Met (SU11274) inhibitors. Loss of endogenous PAX5 significantly decreased the viability of SCLC cells, especially when combined with SN38 or SU11274, and maximum effect was seen when both inhibitors were used. Therefore, we propose that PAX5 could be an important regulator of c-Met transcription and a potential target for therapy in SCLC.
Everett E. Vokes - One of the best experts on this subject based on the ideXlab platform.
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Role of PAX8 in the regulation of MET and RON receptor tyrosine kinases in non-small cell lung cancer
BMC cancer, 2014Co-Authors: Rajani Kanteti, Aliya N Husain, Everett E. Vokes, Maria Tretiakova, Essam El-hashani, Immanuel Dhanasingh, Sherven Sharma, Jay Sharma, Ravi SalgiaAbstract:Non-small cell lung cancers (NSCLC) are highly heterogeneous at the molecular level and comprise 75% of all lung tumors. We have previously shown that the receptor tyrosine kinase (RTK) MET frequently suffers gain-of-function mutations that significantly promote lung tumorigenesis. Subsequent studies from our lab also revealed that PAX5 transcription factor is preferentially expressed in small cell lung cancer (SCLC) and promotes MET transcription. PAX8, however, is also expressed in NSCLC cell lines. We therefore investigated the role of PAX8 in NSCLC. Using IHC analysis, PAX8 protein expression was determined in archival NSCLC tumor tissues (n = 254). In order to study the effects of PAX8 knockdown on NSCLC cellular functions such as apoptosis and motility, siRNA against PAX8 was used. Confocal fluorescence microscopy was used to monitor the localization of MET, RON and PAX8. The combinatorial effect of PAX8 knockdown and MET inhibition using SU11274 was investigated in NSCLC cell viability assay. Relative levels of PAX8 protein were elevated (≥ + 2 on a scale of 0–3) in adenocarcinoma (58/94), large cell carcinoma (50/85), squamous cell carcinoma (28/47), and metastatic NSCLC (17/28; lymph node). Utilizing early progenitors isolated from NSCLC cell lines and fresh tumor tissues, we observed robust overexpression of PAX8, MET, and RON. PAX8 knockdown A549 cells revealed abrogated PAX8 expression with a concomitant loss in MET and the related RON kinase expression. A dramatic colocalization between the active form of MET (also RON) and PAX8 upon challenging A549 cells with HGF was visualized. A similar colocalization of MET and EGL5 (PAX8 ortholog) proteins was found in embryos of C. elegans. Most importantly, knockdown of PAX8 in A549 cells resulted in enhanced apoptosis (~6 fold) and decreased cell motility (~45%), thereby making PAX8 a potential therapeutic target. However, the combinatorial approach of PAX8 knockdown and treatment with MET inhibitor, SU11274, had marginal additive effect on loss of NSCLC cell viability. PAX8 provides signals for growth and motility of NSCLC cells and is necessary for MET and RON expression. Further investigations are necessary to investigate the therapeutic potential of PA8 in NSCLC.
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abstract lb 119 expression and function of pax5 transcription factor and regulation of c met in sclc potential for novel biomarkers and therapeutics
Cancer Research, 2009Co-Authors: Rajani Kanteti, Soundararajan Krishnaswamy, Leonardo Faoro, Deborah Lang, Sivakumar Loganathan, Everett E. Vokes, Ravi SalgiaAbstract:Lung cancer still remains one of the leading causes of all cancer related deaths. Prognosis in patients with non small cell lung cancer (NSCLC) is better compared to those with small cell lung cancer (SCLC), however the overall survival rate is still very low (17%). A plethora of molecular changes due to various genomic alterations are known to contribute to the development and spread of lung cancers, for instance mutations in p53, RB, Ras, several receptor and non-receptor tyrosine kinases are known to contribute to the variety of phenotypes seen in lung cancer. In this regard, we examined the role of PAX5 transcription factor in SCLC lung cancer. PAX5 is a nuclear transcription factor required for B cell development and its expression was evaluated in upper aerodigestive malignancies and pancreatic cancer by immunoblotting. PAX5 protein expression was relatively high in small cell lung cancer (SCLC, 11/12), however its expression was not detected in non-SCLC (NSCLC, n=13), mesothelioma (n=7), pancreatic (n=6), esophageal (n=6) and head and neck cancer cell lines (n=12). In comparison, PAX8 and PAX3 expression was absent or non-detectable in SCLC cell lines, however PAX8 was expressed in most of the NSCLC cell lines (13/13) tested and also frequently in all the other cell lines . We also detected frequent expression of PAX2 and PAX9 protein in the various cell lines. Utilizing neuroendocrine tumor samples, we found that the frequency as well as the average intensity of expression of PAX5 increased from pulmonary carcinoid (9%, moderate and strong PAX5 expression, n=44), to large cell neuroendocrine carcinoma (LCNC, 27% n=11) to SCLC (33%, n=76). FISH analysis revealed no translocations of PAX5 gene, but polyploidy in some SCLC tumor tissues (6 /37). We determined that PAX5 could regulate the transcription of c-Met using luciferase coupled reporter and ChIP analysis. In addition the phospho-c-Met and PAX5 were both localized to the same intra-nuclear compartment in HGF treated SCLC cells and interacted with each other. Finally, we determined the therapeutic translational potential of PAX5 using PAX5 knockdown SCLC cells in conjunction with Topoisomerase 1 (SN38) and c-Met (SU11274) inhibitors. Loss of endogenous PAX5 significantly decreased the viability of SCLC cells, especially when combined with SN38 or SU11274 and maximum effect was seen when both inhibitors were used. We therefore propose that PAX5 could be an important regulator of c-MET transcription and a potential target for therapy in SCLC. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr LB-119.
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abstract lb 119 expression and function of pax5 transcription factor and regulation of c met in sclc potential for novel biomarkers and therapeutics
Cancer Research, 2009Co-Authors: Rajani Kanteti, Soundararajan Krishnaswamy, Leonardo Faoro, Deborah Lang, Sivakumar Loganathan, Everett E. Vokes, Ravi SalgiaAbstract:Lung cancer still remains one of the leading causes of all cancer related deaths. Prognosis in patients with non small cell lung cancer (NSCLC) is better compared to those with small cell lung cancer (SCLC), however the overall survival rate is still very low (17%). A plethora of molecular changes due to various genomic alterations are known to contribute to the development and spread of lung cancers, for instance mutations in p53, RB, Ras, several receptor and non-receptor tyrosine kinases are known to contribute to the variety of phenotypes seen in lung cancer. In this regard, we examined the role of PAX5 transcription factor in SCLC lung cancer. PAX5 is a nuclear transcription factor required for B cell development and its expression was evaluated in upper aerodigestive malignancies and pancreatic cancer by immunoblotting. PAX5 protein expression was relatively high in small cell lung cancer (SCLC, 11/12), however its expression was not detected in non-SCLC (NSCLC, n=13), mesothelioma (n=7), pancreatic (n=6), esophageal (n=6) and head and neck cancer cell lines (n=12). In comparison, PAX8 and PAX3 expression was absent or non-detectable in SCLC cell lines, however PAX8 was expressed in most of the NSCLC cell lines (13/13) tested and also frequently in all the other cell lines . We also detected frequent expression of PAX2 and PAX9 protein in the various cell lines. Utilizing neuroendocrine tumor samples, we found that the frequency as well as the average intensity of expression of PAX5 increased from pulmonary carcinoid (9%, moderate and strong PAX5 expression, n=44), to large cell neuroendocrine carcinoma (LCNC, 27% n=11) to SCLC (33%, n=76). FISH analysis revealed no translocations of PAX5 gene, but polyploidy in some SCLC tumor tissues (6 /37). We determined that PAX5 could regulate the transcription of c-Met using luciferase coupled reporter and ChIP analysis. In addition the phospho-c-Met and PAX5 were both localized to the same intra-nuclear compartment in HGF treated SCLC cells and interacted with each other. Finally, we determined the therapeutic translational potential of PAX5 using PAX5 knockdown SCLC cells in conjunction with Topoisomerase 1 (SN38) and c-Met (SU11274) inhibitors. Loss of endogenous PAX5 significantly decreased the viability of SCLC cells, especially when combined with SN38 or SU11274 and maximum effect was seen when both inhibitors were used. We therefore propose that PAX5 could be an important regulator of c-MET transcription and a potential target for therapy in SCLC. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr LB-119.
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PAX5 is expressed in small-cell lung cancer and positively regulates c-Met transcription
Laboratory Investigation, 2009Co-Authors: Rajani Kanteti, Vidya Nallasura, Todd Kroll, Soundararajan Krishnaswamy, Leonardo Faoro, Philip Cagle, Sivakumar Loganathan, Aliya N Husain, Maria Tretiakova, Everett E. VokesAbstract:PAX5 is a nuclear transcription factor required for B cell development, and its expression was evaluated in upper aerodigestive malignancies and pancreatic cancer by immunoblotting. The PAX5 protein expression was relatively strong in small-cell lung cancer (SCLC, 11/12); however, its expression was not detected in non-SCLC (NSCLC, n =13), mesothelioma ( n =7), pancreatic ( n =6), esophageal ( n =6) and head and neck cancer cell lines ( n =12). In comparison, PAX8 and PAX3 expressions were absent or non-detectable in SCLC cell lines; however, PAX8 was expressed in most of the tested NSCLC cell lines (13/13) and also frequently in all the other cell lines. We also detected frequent expressions of PAX2 and PAX9 protein in the various cell lines. Utilizing neuroendocrine tumor samples, we found that the frequency as well as the average intensity of the expression of PAX5 increased from pulmonary carcinoid (9%, moderate and strong PAX5 expression, n =44), to large-cell neuroendocrine carcinoma (LCNC, 27%, n =11) to SCLC (33%, n =76). FISH analysis revealed no translocations of the PAX5 gene, but polyploidy in some SCLC tumor tissues (6/37). We determined that PAX5 could regulate the transcription of c-Met using luciferase-coupled reporter and chromatin immunoprecipitation analysis. In addition, the phospho-c-Met (active form) and PAX5 were both localized to the same intra-nuclear compartment in hepatocyte growth factor treated SCLC cells and interacted with each other. Finally, we determined the therapeutic translational potential of PAX5 using PAX5 knockdown SCLC cells in conjunction with Topoisomerase 1 (SN38) and c-Met (SU11274) inhibitors. Loss of endogenous PAX5 significantly decreased the viability of SCLC cells, especially when combined with SN38 or SU11274, and maximum effect was seen when both inhibitors were used. Therefore, we propose that PAX5 could be an important regulator of c-Met transcription and a potential target for therapy in SCLC.
Luan D Truong - One of the best experts on this subject based on the ideXlab platform.
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PAX8 Expression in Thyroid Tumors: Comparison with PAX2, TTF-1, and Thyroglobulin
Journal of Interdisciplinary Histopathology, 2017Co-Authors: Ayhan Ozcan, Steven S. Shen, Ashraf Khan, Luan D TruongAbstract:Objective: Diagnostic markers for thyroid differentiation remain in development. Paired box (PAX8) is a member of a transcription factor family instrumental for fetal development and probably neoplastic transformation of the kidney, müllerian organs, and thyroid. Expression of PAX8 in thyroid tissue is evaluated and compared with traditional thyroid markers which are thyroglobulin and thyroid transcription factor-1 (TTF-1). Materials and Methods: Consecutive tissue sections of non-neoplastic thyroid tissue (n = 131), adenomatous nodule (n = 26), follicular neoplasms (n = 25), papillary carcinoma (n = 13), medullary carcinoma (n = 6), poorly differentiated carcinoma (n = 16), undifferentiated carcinoma (n = 6), and benign parathyroid tissue (n = 15) were submitted for PAX8, PAX2, TTF-1, and thyroglobulin immunostain. Staining extent (% of cells stained) and intensity (score 0-3) were evaluated. Results: PAX2 was not seen in any specimens. Strong (intensity score 3) (and diffuse 100% of cells) nuclear staining for PAX8 was noted in every case of non-neoplastic thyroid tissue and differentiated thyroid tumors. Staining for TTF-1 was similar to that of PAX8 in term of frequency, but the extent and intensity were less for some variants of papillary carcinoma or less differentiated follicular neoplasms. Thyroglobulin was noted in every case of non-neoplastic thyroid tissue and differentiated thyroid tumors, but the staining (which is cytoplasmic) was weak and focal in 66 cases of them, and this staining was often masked by strong staining of the adjacent colloid. For undifferentiated carcinoma, PAX8 was the only expressed marker, but in only 1/6 cases. For medullary carcinoma, PAX8 was not seen in any case, but TTF-1 and thyroglobulin were noted in 67% and 33% of cases, respectively. For parathyroid tissue, PAX8 was noted in 80% of cases, but the staining was weak and focal in each; TTF-1 and thyroglobulin were not seen. Conclusions: (1) PAX8 is a very sensitive marker for thyroid differentiation, regardless of diagnoses, (2) PAX8 is the only available marker, albeit of limited sensitivity, for undifferentiated thyroid carcinoma, (3) Both PAX8 and TTF-1 are sensitive markers for thyroid differentiation; with a diagnostic advantage for PAX8; and both are superior to thyroglobulin, (4) PAX8 may be the only marker needed for evaluating thyroid differentiation, and (5) In spite of an ontogenic similarity with PAX8, PAX2 is not expressed by thyroid tissue. [J Interdiscipl Histopathol 2017; 5(2.000): 29-35
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PAX2 and PAX8: useful markers for metastatic effusions.
Acta Cytologica, 2013Co-Authors: Lindsay L. Waters, Suzanne M. Crumley, Dina R. Mody, Luan D Truong, Donna CoffeyAbstract:Objective: It was the aim of this study to determine the utility of PAX2 and PAX8 in cytology effusions with metastatic tumor. Study Design:
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PAX2 and PAX8: useful markers for metastatic effusions.
Acta cytologica, 2013Co-Authors: Lindsay L. Waters, Suzanne M. Crumley, Dina R. Mody, Luan D Truong, Donna CoffeyAbstract:It was the aim of this study to determine the utility of PAX2 and PAX8 in cytology effusions with metastatic tumor. PAX2 and PAX8 immunohistochemical staining was performed on cell blocks of 89 pleural, pericardial and peritoneal effusions with benign diagnoses (18 cases), or secondary to renal cell carcinoma (RCC; 9 cases), müllerian carcinoma (21 cases) or non-müllerian carcinoma (41 cases). PAX2 stained 0% (0/18) of controls, 100% (8/8) of RCCs, 35% (7/20) of müllerian carcinomas, and 2% (1/41) of non-müllerian carcinomas. PAX8 stained 6% (1/18) of control cases, 100% (9/9) of RCC cases, 100% (20/20) of müllerian carcinomas, and 5% (2/41) of non-müllerian carcinomas. PAX2 was 35% sensitive and 95% specific for müllerian carcinoma and 100% sensitive and 95% specific for RCC. PAX8 was 100% sensitive and 95% specific for müllerian carcinoma and 100% sensitive and 95% specific for RCC. PAX8 is more sensitive than PAX2 for metastatic effusions from müllerian carcinomas (100 vs. 35%), while also having a higher intensity of staining than PAX2. However, PAX2 and PAX8 are both highly sensitive and specific for RCCs. PAX2 and PAX8 are valuable diagnostic markers for metastatic müllerian carcinomas and RCCs in effusion cytology. PAX8 is superior for carcinomas of müllerian origin. © 2013 S. Karger AG, Basel.
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flat pattern of nephrogenic adenoma previously unrecognized pattern unveiled using pax2 and PAX8 immunohistochemistry
Modern Pathology, 2013Co-Authors: Sergio Pinaoviedo, Alberto G Ayala, Steven S. Shen, Jae Y Ro, Luan D TruongAbstract:Flat pattern of nephrogenic adenoma: previously unrecognized pattern unveiled using PAX2 and PAX8 immunohistochemistry
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flat pattern of nephrogenic adenoma previously unrecognized pattern unveiled using pax2 and PAX8 immunohistochemistry
Modern Pathology, 2013Co-Authors: Sergio Pinaoviedo, Alberto G Ayala, Steven S. Shen, Luan D TruongAbstract:Nephrogenic adenoma is a benign lesion of the urinary tract, particularly the urinary bladder. It is a gross and microscopic mimicker of urothelial neoplasm or metastatic carcinoma. Several histological patterns (tubular, tubulocystic, polypoid, papillary, fibromyxoid) have been recognized, but a flat pattern has not been described. Histologically, nephrogenic adenoma consists of tubules, cysts or papillae lined by flat to polygonal cells with frequent hobnail appearance. The stroma is often edematous or has a granulation tissue-like appearance with acute or chronic inflammation. By immunohistochemistry, nephrogenic adenomas are positive for renal epithelial markers CK7, CD10 and alpha-methylacyl-coenzyme A racemase, and negative for bladder urothelium or prostate markers. Recent studies have shown that nephrogenic adenomas are positive for PAX2 and PAX8. We encountered an interesting case of tubular nephrogenic adenoma with adjacent areas suspicious of flat urothelial atypia. Immunohistochemistry for PAX2 and PAX8 were positive in these areas, unveiling a flat pattern of nephrogenic adenoma. This case prompted us to study 15 cases of nephrogenic adenoma to determine additional instances of flat pattern and to assess the value of PAX2 and PAX8 immunoreactivity to diagnose nephrogenic adenoma. PAX2 and PAX8 immunostaining was positive in 14/15 and 15/15 cases, respectively. The flat pattern was present at least focally adjacent to tubular, polypoid and papillary areas, in 8/15 cases of nephrogenic adenoma. In conclusion, the flat pattern is a common finding in nephrogenic adenomas, but easily under recognized by morphologic examination and may be confused with flat urothelial lesions with atypia. Immunostains for PAX2 and PAX8 are useful in the detection of nephrogenic adenomas and particularly unveil those nephrogenic adenomas with flat pattern.
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PAX8 Expression in Thyroid Tumors: Comparison with PAX2, TTF-1, and Thyroglobulin
Journal of Interdisciplinary Histopathology, 2017Co-Authors: Ayhan Ozcan, Steven S. Shen, Ashraf Khan, Luan D TruongAbstract:Objective: Diagnostic markers for thyroid differentiation remain in development. Paired box (PAX8) is a member of a transcription factor family instrumental for fetal development and probably neoplastic transformation of the kidney, müllerian organs, and thyroid. Expression of PAX8 in thyroid tissue is evaluated and compared with traditional thyroid markers which are thyroglobulin and thyroid transcription factor-1 (TTF-1). Materials and Methods: Consecutive tissue sections of non-neoplastic thyroid tissue (n = 131), adenomatous nodule (n = 26), follicular neoplasms (n = 25), papillary carcinoma (n = 13), medullary carcinoma (n = 6), poorly differentiated carcinoma (n = 16), undifferentiated carcinoma (n = 6), and benign parathyroid tissue (n = 15) were submitted for PAX8, PAX2, TTF-1, and thyroglobulin immunostain. Staining extent (% of cells stained) and intensity (score 0-3) were evaluated. Results: PAX2 was not seen in any specimens. Strong (intensity score 3) (and diffuse 100% of cells) nuclear staining for PAX8 was noted in every case of non-neoplastic thyroid tissue and differentiated thyroid tumors. Staining for TTF-1 was similar to that of PAX8 in term of frequency, but the extent and intensity were less for some variants of papillary carcinoma or less differentiated follicular neoplasms. Thyroglobulin was noted in every case of non-neoplastic thyroid tissue and differentiated thyroid tumors, but the staining (which is cytoplasmic) was weak and focal in 66 cases of them, and this staining was often masked by strong staining of the adjacent colloid. For undifferentiated carcinoma, PAX8 was the only expressed marker, but in only 1/6 cases. For medullary carcinoma, PAX8 was not seen in any case, but TTF-1 and thyroglobulin were noted in 67% and 33% of cases, respectively. For parathyroid tissue, PAX8 was noted in 80% of cases, but the staining was weak and focal in each; TTF-1 and thyroglobulin were not seen. Conclusions: (1) PAX8 is a very sensitive marker for thyroid differentiation, regardless of diagnoses, (2) PAX8 is the only available marker, albeit of limited sensitivity, for undifferentiated thyroid carcinoma, (3) Both PAX8 and TTF-1 are sensitive markers for thyroid differentiation; with a diagnostic advantage for PAX8; and both are superior to thyroglobulin, (4) PAX8 may be the only marker needed for evaluating thyroid differentiation, and (5) In spite of an ontogenic similarity with PAX8, PAX2 is not expressed by thyroid tissue. [J Interdiscipl Histopathol 2017; 5(2.000): 29-35
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flat pattern of nephrogenic adenoma previously unrecognized pattern unveiled using pax2 and PAX8 immunohistochemistry
Modern Pathology, 2013Co-Authors: Sergio Pinaoviedo, Alberto G Ayala, Steven S. Shen, Jae Y Ro, Luan D TruongAbstract:Flat pattern of nephrogenic adenoma: previously unrecognized pattern unveiled using PAX2 and PAX8 immunohistochemistry
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flat pattern of nephrogenic adenoma previously unrecognized pattern unveiled using pax2 and PAX8 immunohistochemistry
Modern Pathology, 2013Co-Authors: Sergio Pinaoviedo, Alberto G Ayala, Steven S. Shen, Luan D TruongAbstract:Nephrogenic adenoma is a benign lesion of the urinary tract, particularly the urinary bladder. It is a gross and microscopic mimicker of urothelial neoplasm or metastatic carcinoma. Several histological patterns (tubular, tubulocystic, polypoid, papillary, fibromyxoid) have been recognized, but a flat pattern has not been described. Histologically, nephrogenic adenoma consists of tubules, cysts or papillae lined by flat to polygonal cells with frequent hobnail appearance. The stroma is often edematous or has a granulation tissue-like appearance with acute or chronic inflammation. By immunohistochemistry, nephrogenic adenomas are positive for renal epithelial markers CK7, CD10 and alpha-methylacyl-coenzyme A racemase, and negative for bladder urothelium or prostate markers. Recent studies have shown that nephrogenic adenomas are positive for PAX2 and PAX8. We encountered an interesting case of tubular nephrogenic adenoma with adjacent areas suspicious of flat urothelial atypia. Immunohistochemistry for PAX2 and PAX8 were positive in these areas, unveiling a flat pattern of nephrogenic adenoma. This case prompted us to study 15 cases of nephrogenic adenoma to determine additional instances of flat pattern and to assess the value of PAX2 and PAX8 immunoreactivity to diagnose nephrogenic adenoma. PAX2 and PAX8 immunostaining was positive in 14/15 and 15/15 cases, respectively. The flat pattern was present at least focally adjacent to tubular, polypoid and papillary areas, in 8/15 cases of nephrogenic adenoma. In conclusion, the flat pattern is a common finding in nephrogenic adenomas, but easily under recognized by morphologic examination and may be confused with flat urothelial lesions with atypia. Immunostains for PAX2 and PAX8 are useful in the detection of nephrogenic adenomas and particularly unveil those nephrogenic adenomas with flat pattern.
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PAX2 and PAX8 expression in primary and metastatic renal tumors, A comprehensive comparison
Archives of pathology & laboratory medicine, 2012Co-Authors: Ayhan Ozcan, Gustavo De La Roza, Steven S. Shen, Luan D TruongAbstract:The diagnosis of renal cell carcinoma (RCC) remains problematic, especially in the context of metastasis or small-needle biopsies. PAX2 and PAX8 transcription factors are known to be expressed by several histologic types of renal neoplasms. To evaluate the diagnostic utility of PAX2 and PAX8 relative to one another, which has not been studied. Consecutive tissue sections from the archival samples of 243 primary and 99 metastatic renal neoplasms were submitted to PAX2 and PAX8 immunostain. Within the primary neoplasms, PAX2 versus PAX8 expression was noted in 90 of 95 (95%) versus 92 of 95 (97%) for clear cell RCC, 29 of 38 (76%) versus 38 of 38 (100%) for papillary RCC, 14 of 25 (56%) versus 22 of 25 (88%) for chromophobe RCC, 3 of 7 (43%) versus 5 of 7 (71%) for collecting duct RCC, 6 of 8 (75%) versus 8 of 8 (100%) for acquired cystic kidney disease-related RCC, and 7 of 13 (54%) versus 11 of 13 (85%) for oncocytoma. Regardless of histologic subtype, PAX8 staining was noted in more cells and with more intense staining than PAX2. Within the metastatic RCCs, PAX8 expression was more frequently positive than PAX2 expression (88 of 99 cases; 89%; versus 75 of 99 cases; 76%). Both PAX2 and PAX8 are diagnostically useful markers for both primary and metastatic renal neoplasms of a large variety of histologic types. However, PAX8 appears to be more sensitive than PAX2 in both primary and metastatic settings. PAX8 can be included in any immunohistochemical panel for the diagnosis of primary renal neoplasms. Adding PAX2 should be optional, but this would gain limited further diagnostic yield. In a metastatic setting, both PAX8 and PAX2 can be included in a panel because a small subset of metastatic RCCs are stained only with PAX2.
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pax2 and PAX8 expression in primary and metastatic renal tumors a comprehensive comparison
Archives of Pathology & Laboratory Medicine, 2012Co-Authors: Ayhan Ozcan, Gustavo De La Roza, Steven S. Shen, Jae Y Ro, Luan D TruongAbstract:Context.—The diagnosis of renal cell carcinoma (RCC) remains problematic, especially in the context of metastasis or small-needle biopsies. PAX2 and PAX8 transcription factors are known to be expressed by several histologic types of renal neoplasms. Objective.—To evaluate the diagnostic utility of PAX2 and PAX8 relative to one another, which has not been studied. Design.—Consecutive tissue sections from the archival samples of 243 primary and 99 metastatic renal neoplasms were submitted to PAX2 and PAX8 immunostain. Results.—Within the primary neoplasms, PAX2 versus PAX8 expression was noted in 90 of 95 (95%) versus 92 of 95 (97%) for clear cell RCC, 29 of 38 (76%) versus 38 of 38 (100%) for papillary RCC, 14 of 25 (56%) versus 22 of 25 (88%) for chromophobe RCC, 3 of 7 (43%) versus 5 of 7 (71%) for collecting duct RCC, 6 of 8 (75%) versus 8 of 8 (100%) for acquired cystic kidney disease–related RCC, and 7 of 13 (54%) versus 11 of 13 (85%) for oncocytoma. Regardless of histologic subtype, PAX8 staining wa...
