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Published on: July 28, 2010
Deregulated expression of cryptochrome genes in human colorectal cancer
Gianluigi Mazzoccoli1,2, Tommaso Colangelo3, Anna Panza4
1Division of Internal Medicine and Chronobiology Unit, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza", San Giovanni Rotondo, FG, Italy. g.mazzoccoli@operapadrepio.it.
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.
Insights
Altered expression of cryptochrome genes (CRY1 and CRY2) is linked to colorectal cancer (CRC) development and patient survival. These changes, particularly in elderly females and transverse colon cancers, impact disease progression and chemotherapy response.
Area of Science:
- Oncology
- Molecular Biology
- Chronobiology
Background:
- Circadian disruption and molecular clock dysregulation are implicated in cancer development.
- Cryptochrome genes (CRY1 and CRY2) encode key circadian proteins, but their role in colorectal cancer (CRC) is underexplored.
Purpose of the Study:
- To investigate the expression patterns of CRY1 and CRY2 in human CRC and colon cancer cell lines.
- To determine the correlation between CRY1 and CRY2 expression and clinicopathological features, patient survival, and cellular behavior.
Main Methods:
- Examined CRY1 and CRY2 expression in 50 CRC tissues and four colon cancer cell lines (CaCo2, HCT116, HT29, SW480).
- Analyzed expression levels in relation to patient demographics, tumor location, and survival data.
- Assessed the impact of CRY1 and CRY2 ectopic expression on apoptosis, proliferation, and drug response in cell lines, considering p53 status.
Main Results:
- Significantly altered CRY1 and CRY2 expression was observed in CRC tumors.
- Lower CRY1 levels correlated with older age, female patients, and transverse colon tumors; lower CRY2 levels were associated with transverse colon tumors.
- Elevated CRY1 and CRY2 expression predicted poorer patient survival.
- Cell line studies revealed variable cryptochrome expression, time-dependent mRNA changes, and altered apoptosis and proliferation, influenced by p53 status and other gene expressions (ARNTL, WEE, c-MYC).
Conclusions:
- Cryptochrome gene expression is dysregulated in CRC, particularly in specific patient subgroups and tumor locations, impacting overall survival.
- Altered CRY1 and CRY2 expression, along with genetic interactions, contributes to phenotypic diversity in colon cancer, influencing disease behavior and treatment outcomes.
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