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Molecular Cancer
Published in: Molecular Cancer 1/2016

Open Access 01-12-2016 | Research

Deregulated expression of cryptochrome genes in human colorectal cancer

Authors: Gianluigi Mazzoccoli, Tommaso Colangelo, Anna Panza, Rosa Rubino, Angelo De Cata, Cristiana Tiberio, Maria Rosa Valvano, Valerio Pazienza, Giuseppe Merla, Bartolomeo Augello, Domenico Trombetta, Clelia Tiziana Storlazzi, Gemma Macchia, Annamaria Gentile, Francesca Tavano, Manlio Vinciguerra, Giovanni Bisceglia, Valeria Rosato, Vittorio Colantuoni, Lina Sabatino, Ada Piepoli

Published in: Molecular Cancer | Issue 1/2016

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Abstract

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.
Appendix
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Metadata
Title
Deregulated expression of cryptochrome genes in human colorectal cancer
Authors
Gianluigi Mazzoccoli
Tommaso Colangelo
Anna Panza
Rosa Rubino
Angelo De Cata
Cristiana Tiberio
Maria Rosa Valvano
Valerio Pazienza
Giuseppe Merla
Bartolomeo Augello
Domenico Trombetta
Clelia Tiziana Storlazzi
Gemma Macchia
Annamaria Gentile
Francesca Tavano
Manlio Vinciguerra
Giovanni Bisceglia
Valeria Rosato
Vittorio Colantuoni
Lina Sabatino
Ada Piepoli
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2016
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/s12943-016-0492-8

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