Molecular signaling in colorectal carcinogenesis : the roles and relationships of beta-catenin, PPARgamma and COX-2
- Authors: Fredericks, Ernst
- Date: 2013
- Subjects: Colon (Anatomy) -- Cancer , Cyclooxygenase 2 , Peroxisomes
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:10357 , http://hdl.handle.net/10948/d1021014
- Description: Colorectal cancer (CRC) is a common disease with significant morbidity and mortality. In spite of significant advances in understanding the molecular signaling in this disorder, unanswered questions remain. Cyclooxygenase-2 (COX-2) and β-catenin have established roles in colorectal carcinogenesis, with both being upregulated early in the disease course. The role of peroxisome proliferator-activated receptor γ (PPARγ) is less clear, but has been shown to be downregulated in colon cancer models. Butyrate, a short chain fatty acid, produced by colon microbiota and transported into the colonocyte by transporter proteins, appears to be important in early carcinogenesis. The butyrate concentration is reduced in CRC and so are its transporters. Interleukin-17 (IL-17) plays a role in colitis-associated colorectal cancer (CAC), but its function in sporadic CRC is less clear. Similarly, Protein kinase C (PKC) has proven involvement in many solid tumours, including CRC, but its exact mechanistic role is still speculative. AIM: To investigate the role and possible signaling pathways of the major role players, β-catenin, COX-2 and PPARγ in early CRC. Further, to elucidate the mechanistic pathways of butyrate and its transporters, IL-17 and PKC in CRC. METHOD: Informed consent was obtained for all patients. Patients were recruited in various disease categories, including normal, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD) and CRC. Colon biopsy specimens were obtained during colonoscopy and used for immunohistochemistry (IHC) and gene expression analysis of the above genes by quantitative polymerase chain reaction (qPCR). RESULTS: β-catenin mRNA and protein expression was increased in CRC and the IBD groups compared to the normal group, while it was reduced in the IBS groups. COX-2 mRNA expression showed a steady increase from normal, through IBS, IBD and CRC groups to a statistically significant degree. The COX-2 protein expression, however, did not match the mRNA expression with increased COX-2 protein expression in normal and IBS groups and reduced expression in IBD and CRC groups. PPARγ mRNA expression was unchanged in IBD and CRC groups, but significantly increased in the IBS group compared to normal. Butyrate transporter, SLC16A1 mRNA was significantly reduced in CRC, but also in the IBS groups, which was unexpected. In the IBD group, SLC16A1 mRNA was unchanged in Crohn’s disease (CD) but significantly reduced in ulcerative colitis (UC). Similarly, SLC5A8 mRNA expression was significantly reduced in the CRC as well as the IBS groups. In the IBD groups, SLC5A8 was unchanged in UC but significantly increased in CD. IL-17 mRNA expression was significantly reduced in CRC and IBS groups, but unchanged in the IBD groups. PKCε mRNA was significantly increased in CRC as expected. In the IBD groups, PKCε mRNA was unchanged in CD but significantly increased in UC. In the IBS groups, PKCε mRNA in constipation –IBS (C-IBS) was significantly reduced, but unchanged in diarrhoea – IBS (D-IBS). CONCLUSIONS: β-catenin mRNA and protein expression was increased in CRC and the CRC promoting IBD groups. COX-2 protein expression was incongruent with the COX-2 mRNA expression and this may reflect homeostatic control mechanisms. High COX-2 mRNA expression in CRC and CRC promoting IBD groups may be a secondary phenomenon reflecting the inflammatory milieu, rather than a true carcinogenesis-related event. PPARγ does not appear to play a central role in early colon carcinogenesis, in spite of available literature suggesting otherwise. Butyrate transporters showed inconsistent results and for now no firm conclusions can be drawn from this. IL-17 may play a role in CAC as confirmed in this and other studies, but its role in sporadic CRC is tenuous and requires further investigation. Likewise for PKCε, upregulation is associated with increased tumourigenecity as shown in this study, however, the mechanistic pathway(s) involved is still speculative and requires further study.
- Full Text:
- Date Issued: 2013
- Authors: Fredericks, Ernst
- Date: 2013
- Subjects: Colon (Anatomy) -- Cancer , Cyclooxygenase 2 , Peroxisomes
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:10357 , http://hdl.handle.net/10948/d1021014
- Description: Colorectal cancer (CRC) is a common disease with significant morbidity and mortality. In spite of significant advances in understanding the molecular signaling in this disorder, unanswered questions remain. Cyclooxygenase-2 (COX-2) and β-catenin have established roles in colorectal carcinogenesis, with both being upregulated early in the disease course. The role of peroxisome proliferator-activated receptor γ (PPARγ) is less clear, but has been shown to be downregulated in colon cancer models. Butyrate, a short chain fatty acid, produced by colon microbiota and transported into the colonocyte by transporter proteins, appears to be important in early carcinogenesis. The butyrate concentration is reduced in CRC and so are its transporters. Interleukin-17 (IL-17) plays a role in colitis-associated colorectal cancer (CAC), but its function in sporadic CRC is less clear. Similarly, Protein kinase C (PKC) has proven involvement in many solid tumours, including CRC, but its exact mechanistic role is still speculative. AIM: To investigate the role and possible signaling pathways of the major role players, β-catenin, COX-2 and PPARγ in early CRC. Further, to elucidate the mechanistic pathways of butyrate and its transporters, IL-17 and PKC in CRC. METHOD: Informed consent was obtained for all patients. Patients were recruited in various disease categories, including normal, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD) and CRC. Colon biopsy specimens were obtained during colonoscopy and used for immunohistochemistry (IHC) and gene expression analysis of the above genes by quantitative polymerase chain reaction (qPCR). RESULTS: β-catenin mRNA and protein expression was increased in CRC and the IBD groups compared to the normal group, while it was reduced in the IBS groups. COX-2 mRNA expression showed a steady increase from normal, through IBS, IBD and CRC groups to a statistically significant degree. The COX-2 protein expression, however, did not match the mRNA expression with increased COX-2 protein expression in normal and IBS groups and reduced expression in IBD and CRC groups. PPARγ mRNA expression was unchanged in IBD and CRC groups, but significantly increased in the IBS group compared to normal. Butyrate transporter, SLC16A1 mRNA was significantly reduced in CRC, but also in the IBS groups, which was unexpected. In the IBD group, SLC16A1 mRNA was unchanged in Crohn’s disease (CD) but significantly reduced in ulcerative colitis (UC). Similarly, SLC5A8 mRNA expression was significantly reduced in the CRC as well as the IBS groups. In the IBD groups, SLC5A8 was unchanged in UC but significantly increased in CD. IL-17 mRNA expression was significantly reduced in CRC and IBS groups, but unchanged in the IBD groups. PKCε mRNA was significantly increased in CRC as expected. In the IBD groups, PKCε mRNA was unchanged in CD but significantly increased in UC. In the IBS groups, PKCε mRNA in constipation –IBS (C-IBS) was significantly reduced, but unchanged in diarrhoea – IBS (D-IBS). CONCLUSIONS: β-catenin mRNA and protein expression was increased in CRC and the CRC promoting IBD groups. COX-2 protein expression was incongruent with the COX-2 mRNA expression and this may reflect homeostatic control mechanisms. High COX-2 mRNA expression in CRC and CRC promoting IBD groups may be a secondary phenomenon reflecting the inflammatory milieu, rather than a true carcinogenesis-related event. PPARγ does not appear to play a central role in early colon carcinogenesis, in spite of available literature suggesting otherwise. Butyrate transporters showed inconsistent results and for now no firm conclusions can be drawn from this. IL-17 may play a role in CAC as confirmed in this and other studies, but its role in sporadic CRC is tenuous and requires further investigation. Likewise for PKCε, upregulation is associated with increased tumourigenecity as shown in this study, however, the mechanistic pathway(s) involved is still speculative and requires further study.
- Full Text:
- Date Issued: 2013
The relationship between authentic leadership, psychological capital, psychological climate, team commitment and the intention to quit in a South African manufacturing organisation
- Authors: Munyaka, Sharon Audley
- Date: 2012
- Subjects: Leadership -- South Africa , Organizational commitment -- South Africa , Work environment -- South Africa , Employees -- Resignation -- South Africa , Tire industry workers -- South Africa
- Language: English
- Type: Thesis , Doctoral , DCom
- Identifier: vital:9418 , http://hdl.handle.net/10948/d1021088
- Description: Grounded in the positive psychology paradigm the recently recognised core construct of psychological capital was focussed in a South African study. A non-experimental, correlational study (n=204) examined the relationship between authentic leadership, psychological capital, psychological climate, team commitment and intention to quit. The present study was exploratory in nature and the pattern of relationships being investigated had not been previously tested in a South African context. A self-administered composite questionnaire consisting of five psychological scales were distributed to employees in the junior to senior management level at a global tyre manufacturing organisation based in Port Elizabeth, South Africa. The five scales were the Authentic Leadership Questionnaire by Walumbwa, Psychological Capital Questionnaire by Luthans, Psychological Climate by Koys and DeCotiis, Team Commitment by Bennett and the Intention to Quit Scale by Cohen. All the measures applied on the South African sample were developed outside South Africa and model equivalence had to be established. The content and structure of the measures were investigated through confirmatory factor analysis and exploratory factor analysis. With the exception of the Cohen scale of intention to quit, all other measures changed their factorial structures to suit the present data. The propositions in the study were tested through descriptive statistics, t-tests, ANOVA, post hoc tests, Cohen’s d, Pearson product-moment correlation and multiple regressions. Structural equation models were built to test the relationships between the scales and sub scales of authentic leadership, psychological capital, psychological climate, team commitment and intention to quit. Results of the analyses carried out, show significantly strong relationships between the variables. Of note is the marked relationship between authentic leadership and psychological climate. Most of the propositions were accepted in light of the relationships that emerged. The proposition indicating structural equation models was rejected because none of the models built in the study successfully produced an adequate fit on the data. Contributions of the study were in terms of the portability of the measurement instruments applied in the study as well as the relationships that emerged. Re-validation of the measures is required to enable clarity on how the variables in the study are interpreted across cultural contexts. Directions for future research include extending the study to other samples and other cultures. Measuring social desirability of the instruments could possibly provide clarity on how the different samples respond to the measures. Studies that compare the reading ability as well as the ability to comprehend the items in the measures would provide valuable information.
- Full Text:
- Date Issued: 2012
- Authors: Munyaka, Sharon Audley
- Date: 2012
- Subjects: Leadership -- South Africa , Organizational commitment -- South Africa , Work environment -- South Africa , Employees -- Resignation -- South Africa , Tire industry workers -- South Africa
- Language: English
- Type: Thesis , Doctoral , DCom
- Identifier: vital:9418 , http://hdl.handle.net/10948/d1021088
- Description: Grounded in the positive psychology paradigm the recently recognised core construct of psychological capital was focussed in a South African study. A non-experimental, correlational study (n=204) examined the relationship between authentic leadership, psychological capital, psychological climate, team commitment and intention to quit. The present study was exploratory in nature and the pattern of relationships being investigated had not been previously tested in a South African context. A self-administered composite questionnaire consisting of five psychological scales were distributed to employees in the junior to senior management level at a global tyre manufacturing organisation based in Port Elizabeth, South Africa. The five scales were the Authentic Leadership Questionnaire by Walumbwa, Psychological Capital Questionnaire by Luthans, Psychological Climate by Koys and DeCotiis, Team Commitment by Bennett and the Intention to Quit Scale by Cohen. All the measures applied on the South African sample were developed outside South Africa and model equivalence had to be established. The content and structure of the measures were investigated through confirmatory factor analysis and exploratory factor analysis. With the exception of the Cohen scale of intention to quit, all other measures changed their factorial structures to suit the present data. The propositions in the study were tested through descriptive statistics, t-tests, ANOVA, post hoc tests, Cohen’s d, Pearson product-moment correlation and multiple regressions. Structural equation models were built to test the relationships between the scales and sub scales of authentic leadership, psychological capital, psychological climate, team commitment and intention to quit. Results of the analyses carried out, show significantly strong relationships between the variables. Of note is the marked relationship between authentic leadership and psychological climate. Most of the propositions were accepted in light of the relationships that emerged. The proposition indicating structural equation models was rejected because none of the models built in the study successfully produced an adequate fit on the data. Contributions of the study were in terms of the portability of the measurement instruments applied in the study as well as the relationships that emerged. Re-validation of the measures is required to enable clarity on how the variables in the study are interpreted across cultural contexts. Directions for future research include extending the study to other samples and other cultures. Measuring social desirability of the instruments could possibly provide clarity on how the different samples respond to the measures. Studies that compare the reading ability as well as the ability to comprehend the items in the measures would provide valuable information.
- Full Text:
- Date Issued: 2012
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