Colorectal liver metastases with a disrupted circadian rhythm phase shift the peripheral clock in liver and kidney

Abstract

Circadian clock genes regulate 10-15% of the transcriptome, and might function as tumor suppressor genes. Relatively little is known about the circadian clock in tumors and its effect on surrounding healthy tissues. Therefore, we compared the 24-hr expression levels of key circadian clock genes in liver and kidney of healthy control mice with those of mice bearing C26 colorectal tumor metastases in the liver. Metastases were induced by injection of C26 colorectal carcinoma cells into the spleen. Subsequently, tumor, liver and kidney tissue was collected around the clock to compare circadian rhythmicity. Expression levels of five clock genes (Rev-Erba, Per1, Per2, Bmal1 and Cry1) and three clock-controlled genes (CCGs; Dbp, p21 and Wee1) were determined by qRT-PCR. Liver and kidney tissue of healthy control mice showed normal 24-hr oscillations of all clock genes and CCGs, consistent with normal circadian rhythmicity. In colorectal liver metastases, however, 24-hr oscillations were completely absent for all clock genes and CCGs except Cry1. Liver and kidney tissue of tumor-bearing mice showed a shift in clock periodicity relative to control mice. In the liver we observed a phase advance, whereas in the kidney the phase was delayed. These data show that hepatic metastases of C26 colon carcinoma with a disrupted circadian rhythm phase shift liver and kidney tissue clocks, which strongly suggests a systemic effect on peripheral clocks. The possibility that tumors may modify peripheral clocks to escape from ordinary circadian rhythms and in this way contribute to fatigue and sleep disorders in cancer patients is discussed.The circadian timing system plays an essential role in the development of cancer. Cancer cells carry a similar machinery of increased proliferation rate, reduced apoptotic sensitivity and escaping cell-cycle control. These parameters are controlled by the circadian clock. [1][2][3][4] Circadian rhythms are generated by a molecular oscillator composed of a set of clock genes that act in a cellautonomous way and are present in all cell types. These clocks are coordinated by a master clock in the neurons of the suprachiasmatic nuclei (SCN), which is located in the anterior hypothalamus. 5 Peripheral clocks are regulated by the SCN through both the autonomic nervous system and neuroendocrine systems. Clocks in the SCN neurons and peripheral cells make use of the same set of clock genes. 6 The positive branch of the mammalian clock machinery consists of CLOCK (Circadian Locomotor Output Cycles Kaput) and BMAL1 (Brain-Muscle Arnt-Like protein 1). CLOCK and BMAL1 are transcription factors that heterodimerize and activate transcription of the Cryptochrome (Cry1 and Cry2) and Period (Per1 and Per2) genes by binding to E-box elements in their promoters. After being synthesized in the cytoplasm, CRY and PER proteins heterodimerize and enter the nucleus where they inhibit CLOCK-BMAL1-mediated transcription and accordingly close the negative feedback loop. 7 The core mechanism is more complex than a single autor...

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