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Differentially Methylated Ultra-Conserved Regions Uc160 and Uc283 in Adenomas and Adenocarcinomas Are Associated with Overall Survival of Colorectal Cancer Patients

Deregulation of the transcribed ultra-conserved regions (T-UCRs) Uc160, Uc283, and Uc346 has been reported in colorectal cancer (CRC) recently. Here, we investigated promoter methylation of these T-UCRs during the adenoma–carcinoma sequence and their clinical significance in CRC patients. Methylatio...

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Autores principales: Kottorou, Anastasia E., Dimitrakopoulos, Foteinos-Ioannis D., Antonacopoulou, Anna G., Diamantopoulou, Georgia, Tsoumas, Dimitrios, Koutras, Angelos, Makatsoris, Thomas, Stavropoulos, Michalis, Thomopoulos, Konstantinos C., Hulbert, Alicia, Tzelepi, Vassiliki, Kalofonos, Haralabos P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226527/
https://www.ncbi.nlm.nih.gov/pubmed/32272654
http://dx.doi.org/10.3390/cancers12040895
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author Kottorou, Anastasia E.
Dimitrakopoulos, Foteinos-Ioannis D.
Antonacopoulou, Anna G.
Diamantopoulou, Georgia
Tsoumas, Dimitrios
Koutras, Angelos
Makatsoris, Thomas
Stavropoulos, Michalis
Thomopoulos, Konstantinos C.
Hulbert, Alicia
Tzelepi, Vassiliki
Kalofonos, Haralabos P.
author_facet Kottorou, Anastasia E.
Dimitrakopoulos, Foteinos-Ioannis D.
Antonacopoulou, Anna G.
Diamantopoulou, Georgia
Tsoumas, Dimitrios
Koutras, Angelos
Makatsoris, Thomas
Stavropoulos, Michalis
Thomopoulos, Konstantinos C.
Hulbert, Alicia
Tzelepi, Vassiliki
Kalofonos, Haralabos P.
author_sort Kottorou, Anastasia E.
collection PubMed
description Deregulation of the transcribed ultra-conserved regions (T-UCRs) Uc160, Uc283, and Uc346 has been reported in colorectal cancer (CRC) recently. Here, we investigated promoter methylation of these T-UCRs during the adenoma–carcinoma sequence and their clinical significance in CRC patients. Methylation levels were assessed in CRC, adenomas, infiltrated lymph nodes, and metastatic tissue specimens. In situ hybridization was performed in representative tissue specimens. T-UCRs expression levels were also evaluated in HT-29 colon cancer cells before and after the acquired resistance to 5-fluorouracil (5-FU) and oxaliplatin. A gradual increase in T-UCRs methylation levels from hyperplastic polyps to adenomas and to in situ carcinomas (ISC) and a gradual decrease from ISC to infiltrative and metastatic carcinomas was observed (p < 0.001 for Uc160 and Uc283, p = 0.018 for Uc346). Uc160 and Uc283 methylation was associated with the grade of dysplasia in adenoma specimens (p = 0.034 and p = 0.019, respectively). Furthermore, higher Uc160 methylation, mainly in stage III and IV patients, was related to improved overall survival (OS) in univariate (p = 0.009; HR, 0.366) and multivariate analysis (p = 0.005; HR, 0.240). Similarly, higher methylation of Uc283 was associated with longer OS (p = 0.030). Finally, T-UCRs expression was significantly reduced in HT-29 cells after resistance to chemotherapy. This study suggests that promoter methylation of Uc160, Uc283, and Uc346 is altered during CRC development and that Uc160 and Uc283 methylation may have prognostic significance for CRC patients.
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spelling pubmed-72265272020-05-18 Differentially Methylated Ultra-Conserved Regions Uc160 and Uc283 in Adenomas and Adenocarcinomas Are Associated with Overall Survival of Colorectal Cancer Patients Kottorou, Anastasia E. Dimitrakopoulos, Foteinos-Ioannis D. Antonacopoulou, Anna G. Diamantopoulou, Georgia Tsoumas, Dimitrios Koutras, Angelos Makatsoris, Thomas Stavropoulos, Michalis Thomopoulos, Konstantinos C. Hulbert, Alicia Tzelepi, Vassiliki Kalofonos, Haralabos P. Cancers (Basel) Article Deregulation of the transcribed ultra-conserved regions (T-UCRs) Uc160, Uc283, and Uc346 has been reported in colorectal cancer (CRC) recently. Here, we investigated promoter methylation of these T-UCRs during the adenoma–carcinoma sequence and their clinical significance in CRC patients. Methylation levels were assessed in CRC, adenomas, infiltrated lymph nodes, and metastatic tissue specimens. In situ hybridization was performed in representative tissue specimens. T-UCRs expression levels were also evaluated in HT-29 colon cancer cells before and after the acquired resistance to 5-fluorouracil (5-FU) and oxaliplatin. A gradual increase in T-UCRs methylation levels from hyperplastic polyps to adenomas and to in situ carcinomas (ISC) and a gradual decrease from ISC to infiltrative and metastatic carcinomas was observed (p < 0.001 for Uc160 and Uc283, p = 0.018 for Uc346). Uc160 and Uc283 methylation was associated with the grade of dysplasia in adenoma specimens (p = 0.034 and p = 0.019, respectively). Furthermore, higher Uc160 methylation, mainly in stage III and IV patients, was related to improved overall survival (OS) in univariate (p = 0.009; HR, 0.366) and multivariate analysis (p = 0.005; HR, 0.240). Similarly, higher methylation of Uc283 was associated with longer OS (p = 0.030). Finally, T-UCRs expression was significantly reduced in HT-29 cells after resistance to chemotherapy. This study suggests that promoter methylation of Uc160, Uc283, and Uc346 is altered during CRC development and that Uc160 and Uc283 methylation may have prognostic significance for CRC patients. MDPI 2020-04-07 /pmc/articles/PMC7226527/ /pubmed/32272654 http://dx.doi.org/10.3390/cancers12040895 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Kottorou, Anastasia E.
Dimitrakopoulos, Foteinos-Ioannis D.
Antonacopoulou, Anna G.
Diamantopoulou, Georgia
Tsoumas, Dimitrios
Koutras, Angelos
Makatsoris, Thomas
Stavropoulos, Michalis
Thomopoulos, Konstantinos C.
Hulbert, Alicia
Tzelepi, Vassiliki
Kalofonos, Haralabos P.
Differentially Methylated Ultra-Conserved Regions Uc160 and Uc283 in Adenomas and Adenocarcinomas Are Associated with Overall Survival of Colorectal Cancer Patients
title Differentially Methylated Ultra-Conserved Regions Uc160 and Uc283 in Adenomas and Adenocarcinomas Are Associated with Overall Survival of Colorectal Cancer Patients
title_full Differentially Methylated Ultra-Conserved Regions Uc160 and Uc283 in Adenomas and Adenocarcinomas Are Associated with Overall Survival of Colorectal Cancer Patients
title_fullStr Differentially Methylated Ultra-Conserved Regions Uc160 and Uc283 in Adenomas and Adenocarcinomas Are Associated with Overall Survival of Colorectal Cancer Patients
title_full_unstemmed Differentially Methylated Ultra-Conserved Regions Uc160 and Uc283 in Adenomas and Adenocarcinomas Are Associated with Overall Survival of Colorectal Cancer Patients
title_short Differentially Methylated Ultra-Conserved Regions Uc160 and Uc283 in Adenomas and Adenocarcinomas Are Associated with Overall Survival of Colorectal Cancer Patients
title_sort differentially methylated ultra-conserved regions uc160 and uc283 in adenomas and adenocarcinomas are associated with overall survival of colorectal cancer patients
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226527/
https://www.ncbi.nlm.nih.gov/pubmed/32272654
http://dx.doi.org/10.3390/cancers12040895
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