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Deregulated expression of cryptochrome genes in human colorectal cancer

BACKGROUND: Circadian disruption and deranged molecular clockworks are involved in carcinogenesis. The cryptochrome genes (CRY1 and CRY2) encode circadian proteins important for the functioning of biological oscillators. Their expression in human colorectal cancer (CRC) and in colon cancer cell line...

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Autores principales: Mazzoccoli, Gianluigi, Colangelo, Tommaso, Panza, Anna, Rubino, Rosa, De Cata, Angelo, Tiberio, Cristiana, Valvano, Maria Rosa, Pazienza, Valerio, Merla, Giuseppe, Augello, Bartolomeo, Trombetta, Domenico, Storlazzi, Clelia Tiziana, Macchia, Gemma, Gentile, Annamaria, Tavano, Francesca, Vinciguerra, Manlio, Bisceglia, Giovanni, Rosato, Valeria, Colantuoni, Vittorio, Sabatino, Lina, Piepoli, Ada
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4714521/
https://www.ncbi.nlm.nih.gov/pubmed/26768731
http://dx.doi.org/10.1186/s12943-016-0492-8
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author Mazzoccoli, Gianluigi
Colangelo, Tommaso
Panza, Anna
Rubino, Rosa
De Cata, Angelo
Tiberio, Cristiana
Valvano, Maria Rosa
Pazienza, Valerio
Merla, Giuseppe
Augello, Bartolomeo
Trombetta, Domenico
Storlazzi, Clelia Tiziana
Macchia, Gemma
Gentile, Annamaria
Tavano, Francesca
Vinciguerra, Manlio
Bisceglia, Giovanni
Rosato, Valeria
Colantuoni, Vittorio
Sabatino, Lina
Piepoli, Ada
author_facet Mazzoccoli, Gianluigi
Colangelo, Tommaso
Panza, Anna
Rubino, Rosa
De Cata, Angelo
Tiberio, Cristiana
Valvano, Maria Rosa
Pazienza, Valerio
Merla, Giuseppe
Augello, Bartolomeo
Trombetta, Domenico
Storlazzi, Clelia Tiziana
Macchia, Gemma
Gentile, Annamaria
Tavano, Francesca
Vinciguerra, Manlio
Bisceglia, Giovanni
Rosato, Valeria
Colantuoni, Vittorio
Sabatino, Lina
Piepoli, Ada
author_sort Mazzoccoli, Gianluigi
collection PubMed
description BACKGROUND: Circadian disruption and deranged molecular clockworks are involved in carcinogenesis. The cryptochrome genes (CRY1 and CRY2) encode circadian proteins important for the functioning of biological oscillators. Their expression in human colorectal cancer (CRC) and in colon cancer cell lines has not been evaluated so far. METHODS: We investigated CRY1 and CRY2 expression in fifty CRCs and in the CaCo2, HCT116, HT29, SW480 cell lines. RESULTS: CRY1 (p = 0.01) and CRY2 (p < 0.0001) expression was significantly changed in tumour tissue, as confirmed in a large independent CRC dataset. In addition, lower CRY1 mRNA levels were observed in patients in the age range of 62-74 years (p = 0.018), in female patients (p = 0.003) and in cancers located at the transverse colon (p = 0.008). Lower CRY2 levels were also associated with cancer location at the transverse colon (p = 0.007). CRC patients displaying CRY1 (p = 0.042) and CRY2 (p = 0.043) expression levels over the median were hallmarked by a poorer survival rate. Survey of selected colon cancer cell lines evidenced variable levels of cryptochrome genes expression and time-dependent changes in their mRNA levels. Moreover, they showed reduced apoptosis, increased proliferation and different response to 5-fluorouracil and oxaliplatin upon CRY1 and CRY2 ectopic expression. The relationship with p53 status came out as an additional layer of regulation: higher CRY1 and CRY2 protein levels coincided with a wild type p53 as in HCT116 cells and this condition only marginally affected the apoptotic and cell proliferation characteristics of the cells upon CRY ectopic expression. Conversely, lower CRY and CRY2 levels as in HT29 and SW480 cells coincided with a mutated p53 and a more robust apoptosis and proliferation upon CRY transfection. Besides, an heterogeneous pattern of ARNTL, WEE and c-MYC expression hallmarked the chosen colon cancer cell lines and likely influenced their phenotypic changes. CONCLUSION: Cryptochrome gene expression is altered in CRC, particularly in elderly subjects, female patients and cancers located at the transverse colon, affecting overall survival. Altered CRY1 and CRY2 expression patterns and the interplay with the genetic landscape in colon cancer cells may underlie phenotypic divergence that could influence disease behavior as well as CRC patients survival and response to chemotherapy. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12943-016-0492-8) contains supplementary material, which is available to authorized users.
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spelling pubmed-47145212016-01-16 Deregulated expression of cryptochrome genes in human colorectal cancer Mazzoccoli, Gianluigi Colangelo, Tommaso Panza, Anna Rubino, Rosa De Cata, Angelo Tiberio, Cristiana Valvano, Maria Rosa Pazienza, Valerio Merla, Giuseppe Augello, Bartolomeo Trombetta, Domenico Storlazzi, Clelia Tiziana Macchia, Gemma Gentile, Annamaria Tavano, Francesca Vinciguerra, Manlio Bisceglia, Giovanni Rosato, Valeria Colantuoni, Vittorio Sabatino, Lina Piepoli, Ada Mol Cancer Research BACKGROUND: Circadian disruption and deranged molecular clockworks are involved in carcinogenesis. The cryptochrome genes (CRY1 and CRY2) encode circadian proteins important for the functioning of biological oscillators. Their expression in human colorectal cancer (CRC) and in colon cancer cell lines has not been evaluated so far. METHODS: We investigated CRY1 and CRY2 expression in fifty CRCs and in the CaCo2, HCT116, HT29, SW480 cell lines. RESULTS: CRY1 (p = 0.01) and CRY2 (p < 0.0001) expression was significantly changed in tumour tissue, as confirmed in a large independent CRC dataset. In addition, lower CRY1 mRNA levels were observed in patients in the age range of 62-74 years (p = 0.018), in female patients (p = 0.003) and in cancers located at the transverse colon (p = 0.008). Lower CRY2 levels were also associated with cancer location at the transverse colon (p = 0.007). CRC patients displaying CRY1 (p = 0.042) and CRY2 (p = 0.043) expression levels over the median were hallmarked by a poorer survival rate. Survey of selected colon cancer cell lines evidenced variable levels of cryptochrome genes expression and time-dependent changes in their mRNA levels. Moreover, they showed reduced apoptosis, increased proliferation and different response to 5-fluorouracil and oxaliplatin upon CRY1 and CRY2 ectopic expression. The relationship with p53 status came out as an additional layer of regulation: higher CRY1 and CRY2 protein levels coincided with a wild type p53 as in HCT116 cells and this condition only marginally affected the apoptotic and cell proliferation characteristics of the cells upon CRY ectopic expression. Conversely, lower CRY and CRY2 levels as in HT29 and SW480 cells coincided with a mutated p53 and a more robust apoptosis and proliferation upon CRY transfection. Besides, an heterogeneous pattern of ARNTL, WEE and c-MYC expression hallmarked the chosen colon cancer cell lines and likely influenced their phenotypic changes. CONCLUSION: Cryptochrome gene expression is altered in CRC, particularly in elderly subjects, female patients and cancers located at the transverse colon, affecting overall survival. Altered CRY1 and CRY2 expression patterns and the interplay with the genetic landscape in colon cancer cells may underlie phenotypic divergence that could influence disease behavior as well as CRC patients survival and response to chemotherapy. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12943-016-0492-8) contains supplementary material, which is available to authorized users. BioMed Central 2016-01-15 /pmc/articles/PMC4714521/ /pubmed/26768731 http://dx.doi.org/10.1186/s12943-016-0492-8 Text en © Mazzoccoli et al. 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Mazzoccoli, Gianluigi
Colangelo, Tommaso
Panza, Anna
Rubino, Rosa
De Cata, Angelo
Tiberio, Cristiana
Valvano, Maria Rosa
Pazienza, Valerio
Merla, Giuseppe
Augello, Bartolomeo
Trombetta, Domenico
Storlazzi, Clelia Tiziana
Macchia, Gemma
Gentile, Annamaria
Tavano, Francesca
Vinciguerra, Manlio
Bisceglia, Giovanni
Rosato, Valeria
Colantuoni, Vittorio
Sabatino, Lina
Piepoli, Ada
Deregulated expression of cryptochrome genes in human colorectal cancer
title Deregulated expression of cryptochrome genes in human colorectal cancer
title_full Deregulated expression of cryptochrome genes in human colorectal cancer
title_fullStr Deregulated expression of cryptochrome genes in human colorectal cancer
title_full_unstemmed Deregulated expression of cryptochrome genes in human colorectal cancer
title_short Deregulated expression of cryptochrome genes in human colorectal cancer
title_sort deregulated expression of cryptochrome genes in human colorectal cancer
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4714521/
https://www.ncbi.nlm.nih.gov/pubmed/26768731
http://dx.doi.org/10.1186/s12943-016-0492-8
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