Reciprocal regulation of RhoA and RhoC characterizes the EMT and identifies RhoC as a prognostic marker of colon carcinoma
Understanding how RhoC expression and activation are regulated is essential for deciphering its contribution to tumorigenesis. Here, we report that RhoC expression and activation are induced by the epithelial to mesenchymal transition (EMT) of colon carcinoma. Using LIM 1863 colon cancer cells, RhoC...
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| Veröffentlicht in: | Oncogene 2006-11, Vol.25 (52), p.6959-6967 |
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| creator | Bellovin, D I Simpson, K J Danilov, T Maynard, E Rimm, D L Oettgen, P Mercurio, A M |
| description | Understanding how RhoC expression and activation are regulated is essential for deciphering its contribution to tumorigenesis. Here, we report that RhoC expression and activation are induced by the epithelial to mesenchymal transition (EMT) of colon carcinoma. Using LIM 1863 colon cancer cells, RhoC protein expression and subsequent activation were detected coincident with the loss of E-cadherin and acquisition of mesenchymal characteristics. Several Ets-1 binding sites were identified in the RhoC promoter, and evidence was obtained using chromatin immunoprecipitation that Ets-1 can regulate RhoC expression during the EMT. Interestingly, a marked decrease in RhoA activation associated with the EMT was observed that corresponds to the increase in RhoC expression. Use of shRNA established that RhoA inhibits and RhoC promotes post-EMT cell migration, demonstrating functional significance for their coordinate regulation. To assess the importance of RhoC expression in colon cancer, immunohistochemistry was performed on 566 colorectal tumors with known clinical outcome. The level of RhoC ranged from no expression to high expression, and statistical analysis revealed that elevated RhoC expression correlates with poor outcome as well as aberrant expression and localization of E-cadherin. These data provide one mechanism for how RhoC expression is regulated in colon carcinoma and substantiate its utility as a prognostic marker. |
| doi_str_mv | 10.1038/sj.onc.1209682 |
| format | Article |
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Here, we report that RhoC expression and activation are induced by the epithelial to mesenchymal transition (EMT) of colon carcinoma. Using LIM 1863 colon cancer cells, RhoC protein expression and subsequent activation were detected coincident with the loss of E-cadherin and acquisition of mesenchymal characteristics. Several Ets-1 binding sites were identified in the RhoC promoter, and evidence was obtained using chromatin immunoprecipitation that Ets-1 can regulate RhoC expression during the EMT. Interestingly, a marked decrease in RhoA activation associated with the EMT was observed that corresponds to the increase in RhoC expression. Use of shRNA established that RhoA inhibits and RhoC promotes post-EMT cell migration, demonstrating functional significance for their coordinate regulation. To assess the importance of RhoC expression in colon cancer, immunohistochemistry was performed on 566 colorectal tumors with known clinical outcome. The level of RhoC ranged from no expression to high expression, and statistical analysis revealed that elevated RhoC expression correlates with poor outcome as well as aberrant expression and localization of E-cadherin. These data provide one mechanism for how RhoC expression is regulated in colon carcinoma and substantiate its utility as a prognostic marker.</description><identifier>ISSN: 0950-9232</identifier><identifier>EISSN: 1476-5594</identifier><identifier>DOI: 10.1038/sj.onc.1209682</identifier><identifier>PMID: 16715134</identifier><identifier>CODEN: ONCNES</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>Apoptosis ; Binding sites ; Biological and medical sciences ; Biomarkers, Tumor - analysis ; Cadherins - metabolism ; Cell Biology ; Cell Line, Tumor ; Cell migration ; Cell physiology ; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes ; Chromatin ; Clinical outcomes ; Colon cancer ; Colonic Neoplasms - enzymology ; Colonic Neoplasms - pathology ; Colorectal cancer ; E-cadherin ; Enzyme Activation - physiology ; Epithelial Cells - enzymology ; Fundamental and applied biological sciences. Psychology ; Gastroenterology. Liver. Pancreas. Abdomen ; Gene expression ; Human Genetics ; Humans ; Immunohistochemistry ; Immunoprecipitation ; Internal Medicine ; Localization ; Medical prognosis ; Medical sciences ; Medicine ; Medicine & Public Health ; Mesenchyme ; Molecular and cellular biology ; Neoplasm Invasiveness - genetics ; Oncology ; original-article ; Prognosis ; Promoter Regions, Genetic ; Proto-Oncogene Protein c-ets-1 - metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; rho GTP-Binding Proteins - genetics ; rho GTP-Binding Proteins - metabolism ; rhoA GTP-Binding Protein - metabolism ; RhoA protein ; rhoC GTP-Binding Protein ; RNA, Small Interfering ; Statistical analysis ; Stomach. Duodenum. Small intestine. Colon. Rectum. 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Here, we report that RhoC expression and activation are induced by the epithelial to mesenchymal transition (EMT) of colon carcinoma. Using LIM 1863 colon cancer cells, RhoC protein expression and subsequent activation were detected coincident with the loss of E-cadherin and acquisition of mesenchymal characteristics. Several Ets-1 binding sites were identified in the RhoC promoter, and evidence was obtained using chromatin immunoprecipitation that Ets-1 can regulate RhoC expression during the EMT. Interestingly, a marked decrease in RhoA activation associated with the EMT was observed that corresponds to the increase in RhoC expression. Use of shRNA established that RhoA inhibits and RhoC promotes post-EMT cell migration, demonstrating functional significance for their coordinate regulation. To assess the importance of RhoC expression in colon cancer, immunohistochemistry was performed on 566 colorectal tumors with known clinical outcome. 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Here, we report that RhoC expression and activation are induced by the epithelial to mesenchymal transition (EMT) of colon carcinoma. Using LIM 1863 colon cancer cells, RhoC protein expression and subsequent activation were detected coincident with the loss of E-cadherin and acquisition of mesenchymal characteristics. Several Ets-1 binding sites were identified in the RhoC promoter, and evidence was obtained using chromatin immunoprecipitation that Ets-1 can regulate RhoC expression during the EMT. Interestingly, a marked decrease in RhoA activation associated with the EMT was observed that corresponds to the increase in RhoC expression. Use of shRNA established that RhoA inhibits and RhoC promotes post-EMT cell migration, demonstrating functional significance for their coordinate regulation. To assess the importance of RhoC expression in colon cancer, immunohistochemistry was performed on 566 colorectal tumors with known clinical outcome. The level of RhoC ranged from no expression to high expression, and statistical analysis revealed that elevated RhoC expression correlates with poor outcome as well as aberrant expression and localization of E-cadherin. These data provide one mechanism for how RhoC expression is regulated in colon carcinoma and substantiate its utility as a prognostic marker.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>16715134</pmid><doi>10.1038/sj.onc.1209682</doi><tpages>9</tpages></addata></record> |
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| ispartof | Oncogene, 2006-11, Vol.25 (52), p.6959-6967 |
| issn | 0950-9232 1476-5594 |
| language | eng |
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| source | MEDLINE; Springer Nature - Complete Springer Journals; Nature Journals Online; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | Apoptosis Binding sites Biological and medical sciences Biomarkers, Tumor - analysis Cadherins - metabolism Cell Biology Cell Line, Tumor Cell migration Cell physiology Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes Chromatin Clinical outcomes Colon cancer Colonic Neoplasms - enzymology Colonic Neoplasms - pathology Colorectal cancer E-cadherin Enzyme Activation - physiology Epithelial Cells - enzymology Fundamental and applied biological sciences. Psychology Gastroenterology. Liver. Pancreas. Abdomen Gene expression Human Genetics Humans Immunohistochemistry Immunoprecipitation Internal Medicine Localization Medical prognosis Medical sciences Medicine Medicine & Public Health Mesenchyme Molecular and cellular biology Neoplasm Invasiveness - genetics Oncology original-article Prognosis Promoter Regions, Genetic Proto-Oncogene Protein c-ets-1 - metabolism Reverse Transcriptase Polymerase Chain Reaction rho GTP-Binding Proteins - genetics rho GTP-Binding Proteins - metabolism rhoA GTP-Binding Protein - metabolism RhoA protein rhoC GTP-Binding Protein RNA, Small Interfering Statistical analysis Stomach. Duodenum. Small intestine. Colon. Rectum. Anus Transcription, Genetic Tumorigenesis Tumors |
| title | Reciprocal regulation of RhoA and RhoC characterizes the EMT and identifies RhoC as a prognostic marker of colon carcinoma |
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