title: Disruption of clock gene expression in human colorectal liver metastases.
abstract: The circadian timing system controls about 40 % of the transcriptome and is important in the regulation of a wide variety of biological processes including metabolic and proliferative functions. Disruption of the circadian clock could have significant effect on human health and has an important role in the development of cancer. Here, we compared the expression levels of core clock genes in primary colorectal cancer (CRC), colorectal liver metastases (CRLM), and liver tissue within the same patient. Surgical specimens of 15 untreated patients with primary CRC and metachronous CRLM were studied. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to measure the expression of 10 clock genes: CLOCK, BMAL1, PER1, PER2, PER3, CRY1, CRY2, CSNK1E, TIM, TIPIN, and 2 clock-controlled genes: Cyclin-D1, and WEE1. Expression levels of 7 core clock genes were downregulated in CRLM: CLOCK (p = 0.006), BMAL1 (p = 0.003), PER1 (p = 0.003), PER2 (p = 0.002), PER3 (p < 0.001), CRY1 (p = 0.002), and CRY2 (p < 0.001). In CRC, 5 genes were downregulated: BMAL1 (p = 0.02), PER1 (p = 0.004), PER2 (p = 0.008), PER3 (p < 0.001), and CRY2 (p < 0.001). CSNK1E was upregulated in CRC (p = 0.02). Cyclin-D1 and WEE1 were both downregulated in CRLM and CRC. Related to clinicopathological factors, a significant correlation was found between low expression of CRY1 and female gender, and low PER3 expression and the number of CRLM. Our data demonstrate that the core clock is disrupted in CRLM and CRC tissue from the same patient. This disruption may be linked to altered cell-cycle dynamics and carcinogenesis.
authors: Department of Surgery, Erasmus University Medical Center, Wytemaweg 80, 3015 CN, Rotterdam, Netherlands.
authors: Sander A
authors: SA
authors: Huisman
authors: Department of Surgery, Erasmus University Medical Center, Wytemaweg 80, 3015 CN, Rotterdam, Netherlands.
authors: Ali R
authors: AR
authors: Ahmadi
authors: Department of Surgery, Erasmus University Medical Center, Wytemaweg 80, 3015 CN, Rotterdam, Netherlands.
authors: Jan N M
authors: JN
authors: IJzermans
authors: Department of Surgery, Erasmus University Medical Center, Wytemaweg 80, 3015 CN, Rotterdam, Netherlands.
authors: Cees
authors: C
authors: Verhoef
authors: Department of Molecular Genetics, Erasmus University Medical Center, Wytemaweg 80, 3015 CN, Rotterdam, Netherlands.
authors: Gijsbertus T J
authors: GT
authors: van der Horst
authors: Department of Surgery, Erasmus University Medical Center, Wytemaweg 80, 3015 CN, Rotterdam, Netherlands. r.w.f.debruin@erasmusmc.nl.
authors: Ron W F
authors: RW
authors: de Bruin
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism*; D057906:Circadian Clocks; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000556:secondary; D008297:Male; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D056926:CLOCK Proteins
keywords: Circadian clock; Colorectal cancer; Colorectal liver metastases; Rhythms