Analysis of circadian rhythmicity in a mouse hepatocarcinoma model
Circadian rhythms are controlled at the cellular level by a molecular clock consisting of several genes/proteins engaged in a transcription-translation-degradation feedback loop. These core clock proteins regulate thousands of tissue-specific genes, and signals from the suprachiasmatic nucleus, located in the hypothalamus, maintain synchronicity among tissue clocks. Regarding circadian control in neoplastic tissues, reports to date have demonstrated anomalous circadian function in tumor models and cultured tumor cells. We have extended these studies by analyzing circadian rhythmicity genome-wide in a mouse model of liver cancer, in which mice treated with diethylnitrosamine at 15 days develop liver tumors by 6 months. We injected tumor-bearing and control tumor-free mice with the DNA damaging anticancer drug cisplatin every 2 hours over a 24 hour cycle; 2 hours after each injection mice were sacrificed and gene expression was measured as transcription-coupled DNA repair by the excision repair sequencing assay. Rhythmic expression of several core clock genes was observed in both healthy liver and tumor, with clock genes in tumor exhibiting typically robust amplitudes, and a modest phase advance. Among the hundreds of clock-controlled genes, many of those rhythmic in liver were not rhythmic in tumors. Surprisingly, many genes rhythmic in tumors were not rhythmic in healthy liver. These rhythmic in tumor only genes exhibited peak expression times mainly in daytime hours, in contrast to the more common pre-dawn and pre-dusk expression times seen in healthy liver. Differential expression of genes in tumor and healthy liver across time may present an opportunity for more efficient anticancer drug treatment as a function of treatment time.