Deregulated expression of cryptochrome genes in human colorectal cancer

Mazzoccoli, Gianluigi; Colangelo, Tommaso; Panza, Anna; Rubino, Rosa; Cata, Angelo De; Tiberio, C.; 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

doi:10.1186/s12943-016-0492-8

Cited by 38 publications

(31 citation statements)

References 49 publications

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“…Cell number and density of viable cells were determined using CAsy Cell Counter (Innovatis, Sittingbourne, UK) as previously reported [57]. Briefly, each sample (cell suspension) was prepared three times in CAsyTon (Innovatis) buffer, followed by triplicate measurements of 200 μl sample volume.…”

Section: Methodsmentioning

confidence: 99%

Analysis of clock gene-miRNA correlation networks reveals candidate drivers in colorectal cancer

et al. 2016

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Altered functioning of the biological clock is involved in cancer onset and progression. MicroRNAs (miRNAs) interact with the clock genes modulating the function of genetically encoded molecular clockworks. Collaborative interactions may take place within the coding-noncoding RNA regulatory networks. We aimed to evaluate the cross-talk among miRNAs and clock genes in colorectal cancer (CRC). We performed an integrative analysis of miRNA-miRNA and miRNA-mRNA interactions on high-throughput molecular profiling of matched human CRC tissue and non-tumor mucosa, pinpointing core clock genes and their targeting miRNAs. Data obtained in silico were validated in CRC patients and human colon cancer cell lines. In silico we found severe alterations of clock gene–related coding-noncoding RNA regulatory networks in tumor tissues, which were later corroborated by the analysis of human CRC specimens and experiments performed in vitro. In conclusion, specific miRNAs target and regulate the transcription/translation of clock genes and clock gene-related miRNA-miRNA as well as mRNA-miRNA interactions are altered in colorectal cancer. Exploration of the interplay between specific miRNAs and genes, which are critically involved in the functioning of the biological clock, provides a better understanding of the importance of the miRNA-clock genes axis and its derangement in colorectal cancer.

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Section: Methodsmentioning

confidence: 99%

Analysis of clock gene-miRNA correlation networks reveals candidate drivers in colorectal cancer

et al. 2016

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“…This trend was generally preserved in sub-groups of patients, but the difference reached level of significance only in left-sided colorectum in men. There is a substantial data supporting the assumption that expression of cry2 in colorectal tumor tissue differs in comparison to adjacent healthy mucosa [17,18]. Expression of cry2 was down-regulated in colorectal tissue, similar to other genes involved in the circadian feedback loop (i.e., per1 and per2) [17,18].…”

Section: Figure 2 Five-year Survival Curves For Women Patients With mentioning

confidence: 67%

“…Recent knowledge of CRC induced changes in cry1 expression is inconclusive [17][18][19]. It is possible that changes in cry1 expression may be linked to certain clinical and pathological features because reduced levels of cry1 expression were observed in females, older patients (62-74 years) and in tumors located in the transverse colon [18]. Another study reports the highest expression of cry1 in tumors located in the distal colon compared to other colon parts [17].…”

Section: Discussionmentioning

confidence: 99%

“…There is a substantial data supporting the assumption that expression of cry2 in colorectal tumor tissue differs in comparison to adjacent healthy mucosa [17,18]. Expression of cry2 was down-regulated in colorectal tissue, similar to other genes involved in the circadian feedback loop (i.e., per1 and per2) [17,18]. This agrees with our results, and also with the significant positive correlation between cry2 expression in tumor tissue and tumor location observed in male patients with grade 2, as in our original observation.…”

Section: Figure 2 Five-year Survival Curves For Women Patients With mentioning

confidence: 97%

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The expression of clock genes cry1 and cry2 in human colorectal cancer and tumor adjacent tissues correlates differently dependent on tumor location

Hasakova

Vician

Reis

et al. 2018

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Colorectal cancer (CRC) exhibits differences in its features depending on the location of the tumor. The role of the circadian system in carcinogenesis is accepted, and many studies report different clock gene expression in tumors compared to healthy tissue. However, little attention is given to the changes in clock genes in tumors arising from various locations across the colon and rectum. The aim of our study was to investigate the expression of the clock genes cry1 and cry2 in human CRC tissue and tissue adjacent to colorectal tumors in a cohort of 64 patients by real time PCR. Expression of cry1 in the entire patient cohort was higher in tumors compared to adjacent tissues in the right-sided colon but not in the left-sided colorectum. Difference in cry1 expression between tumor and adjacent tissue in the right-sided colon was preserved in women and a trend was observed in men. Higher expression of cry1 in the right-sided colon tumor tissue was associated with worse survival in women and the expression of cry1 in the left-sided colorectum was significantly higher in the adjacent tissue compared to tumor in men but not in women. Expression of cry2 was lower in the tumor than in adjacent tissue in both the right and left-sided colorectum. This trend was generally preserved, but the difference reached significance level only in the male left-sided colon, and cry2 expression in the tumor tissue significantly correlated with location of the tumor in men with grade 2 cancer. Finally, we detected significant correlation between tumor location and cry1 expression in the adjacent tissue and the combined results establish that tumor influence on adjacent tissue is dependent on tumor location. Changed clock gene expression should therefore be considered in specific CRC patient sub-groups.

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“…Decreased mRNA or protein expressions of Cry1 and/or Cry2 were reported for human HCC, as well as for human cancers of the breast, endometrium, ovary, prostate, colon, pancreas, head-and-neck, brain, skin and blood cells. [39][40][41][42] Yet, the relevance of Cry1/Cry2 deficiency for carcinogenesis was debated. A prior report showed that Cry1/Cry2 deficiency promoted g-radiation-induced lymphomas in mice.…”

Section: Discussionmentioning

confidence: 99%

Critical cholangiocarcinogenesis control by cryptochrome clock genes

et al. 2017

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A coordinated network of molecular circadian clocks in individual cells generates 24-hr rhythms in liver metabolism and proliferation. Circadian disruption through chronic jet lag or Per2 clock gene mutation was shown to accelerate hepatocarcinoma development in mice. As divergent effects were reported for clock genes Per and Cry regarding xenobiotic toxicity, we questioned the role of Cry1 and Cry2 in liver carcinogenesis. Male WT and Cry1 Cry2 mice (C57Bl/6 background) were chronically exposed to diethylnitrosamine (DEN) at ZT11. Rest-activity and body temperature rhythms were monitored using an implanted radiotransmitter. Serum aspartate and alanine aminotransferases (AST and ALT) were determined on four occasions during the progression stage. After 7 months, serum alkaline phosphatases (ALP) were determined, and livers were sampled for microscopic tumor nodule counting and histopathology. Five months after initiation of DEN treatment, we found that Cry1 Cry2 mice developed severe liver dysplasia, as evident from the increased AST, ALT and ALP levels, as compared to WT mice. DEN exposure induced primary liver cancers in nearly fivefold as many Cry1 Cry2 mice as compared to WT mice (p = 0.01). Microscopic study revealed no difference in the average number of hepatocarcinomas and a nearly eightfold increase in the average number of cholangiocarcinomas in Cry1 Cry2 mice, as compared to WT mice. This study validated the hypothesis that molecular circadian clock disruption dramatically increased chemically induced liver carcinogenesis. In addition, the pronounced shift toward cholangiocarcinoma in DEN exposed Cry1 Cry2 mice revealed a critical role of the Cry clock genes in bile duct carcinogenesis.

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Deregulated expression of cryptochrome genes in human colorectal cancer

Cited by 38 publications

References 49 publications

Analysis of clock gene-miRNA correlation networks reveals candidate drivers in colorectal cancer

Analysis of clock gene-miRNA correlation networks reveals candidate drivers in colorectal cancer

The expression of clock genes cry1 and cry2 in human colorectal cancer and tumor adjacent tissues correlates differently dependent on tumor location

Critical cholangiocarcinogenesis control by cryptochrome clock genes

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