Abstract
Environmental disruption of molecular clocks promoted liver carcinogenesis and accelerated cancer progression in rodents. We investigated the specific role of clock gene Period 2 (Per2) for liver carcinogenesis and clock-controlled cellular proliferation, genomic instability and inflammation. We assessed liver histopathology, and determined molecular and physiology circadian patterns in mice on chronic diethylnitrosamine (DEN) exposure according to constitutive Per2 mutation. First, we found that Per2m/m liver displayed profound alterations in proliferation gene expression, including c-Myc derepression, phase-advanced Wee1, and arrhythmic Ccnb1 and K-ras mRNA expressions, as well as deregulated inflammation, through arrhythmic liver IL-6 protein concentration, in the absence of any DEN exposure. These changes could then make Per2m/m mice more prone to subsequently develop liver cancers on DEN. Indeed, primary liver cancers were nearly fourfold as frequent in Per2m/m mice as compared to wild-type (WT), 4 months after DEN exposure. The liver molecular clock was severely disrupted throughout the whole carcinogenesis process, including the initiation stage, i.e. within the initial 17 days on DEN. Per2m/m further exhibited increased c-Myc and Ccnb1 mean 24h expressions, lack of P53 response, and arrhythmic ATM, Wee1 and Ccnb1 expressions. DEN-induced tumor related inflammation was further promoted through increased protein concentrations of liver IL-6 and TNF-α as compared to WT during carcinogenesis initiation. Per2 mutation severely deregulated liver gene or protein expressions related to three cancer hallmarks, including uncontrolled proliferation, genomic instability, and tumor promoting inflammation, and accelerated liver carcinogenesis several-fold. Clock gene Per2 acted here as a liver tumor suppressor from initiation to progression.
Highlights
Hepatocellular carcinoma (HCC) is the sixth most frequent cancer and the third most common cause of cancer mortality worldwide [1]
The regulatory role of clock gene Period 2 (Per2) was first investigated for circadian clock, proliferation, genomic instability, and inflammation, through comparing selected gene or protein circadian expressions in the liver of WildType (WT) and Per2 mutant mice (Per2m/m) mice
Circadian transcription of Bmal1, Rev-erbα, Cry1, and Cry2 were phase-advanced by 2- to 5-h, and circadian amplitudes of Bmal1, Reverbα, and Cry1 were dampened by 19% to 59% in Per2m/m as compared to WT mice (Hotelling t-tests for phase and amplitude comparisons, p< 0.001 for each gene) (Supplementary Figure S1A; Table 1)
Summary
Hepatocellular carcinoma (HCC) is the sixth most frequent cancer and the third most common cause of cancer mortality worldwide [1]. We aimed at determining the role of Per in liver carcinogenesis To address this question, chronic exposure to diethylnitrosamine (DEN) was used as a model for inducing rodent HCC, whose histology and genetic signature have been considered to be similar to poor prognosis human HCC [4]. Circadian rhythms with an about 24-h period characterize the expression patterns of 10-40% of mouse liver transcripts [5, 6]. These molecular rhythms are controlled by a genetic molecular clock in each cell [7]. Mammalian CTS coordination and adjustment to environmental cycles is insured by the suprachiasmatic nuclei (SCN), a neuronal pacemaker located in the anterior hypothalamus [8]
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