Melatonin modulates dysregulated circadian clocks in mice with diethylnitrosamine‐induced hepatocellular carcinoma

Abstract

Disruption of circadian rhythms, which are regulated by the circadian clock machinery, plays an important role in different long-term diseases including hepatocellular carcinoma (HCC). Melatonin has been reported to alleviate promotion and progression of HCC, but the potential contribution of circadian clock modulation is unknown. We investigated the effects of melatonin in mice which received diethylnitrosamine (DEN) (35 mg/kg body weight ip) once a week for 8 weeks. Melatonin was given at 5 or 10 mg kg d ip beginning 4 weeks after the onset of DEN administration and ending at the sacrifice time (10, 20, 30, or 40 weeks). Liver expression of Bmal1, Clock, Npas2, Rorα, and Sirt1 increased, whereas Cry1, Per1, Per2, Per3, CK1ε, Rev-erbα, and Rev-erbβ decreased following DEN administration. Melatonin treatment prevented changes in the expression of clock genes, and this effect was accompanied by an upregulation of the MT1 receptor and reduced levels of the hypoxia-inducible factors Hif-1α and Hif-2α. An increased expression of p21, p53, and PARP1/2, a higher Bax/Bcl-2 ratio, and a lower expression of Cyclin D1, CDK6, HSP70, HSP90, and GRP78 proteins were also observed in melatonin-treated mice. Melatonin significantly potentiated the suppression of proliferation and cell cycle arrest induced by the synthetic REV-ERB agonist SR9009 in human Hep3B cells, and BMAL1 knocking down attenuated the pro-apoptotic and antiproliferative effect of melatonin. Results support a contribution of changes in the circadian clock components to the beneficial effects of melatonin in HCC and highlight the usefulness of strategies modulating the circadian machinery in hepatocarcinogenesis.

Melatonin and circadian rhythms in liver diseases: Functional roles and potential therapies

“…85 DEN elevated gene expression of CLOCK and BMAL1, and decreased expression of PER1, PER2, and CRY1, but melatonin injection inhibited these gene expression changes. 85 Another study analyzed the efficacy of the combination of stem cell therapy and melatonin administration in DEN rat models. 86 Although both transplantation of bone marrow-derived MSCs isolated from young rats as well as melatonin administration (20 mg/kg, twice a week for 5 weeks, i.p.…”

“…A previous study administered melatonin (5 or 10 mg/kg per day for 10, 20, 30, or 40 weeks via i.p. injection) to DEN mice and demonstrated that melatonin inhibited HCC development and improved liver conditions during DEN‐induced liver injury . DEN elevated gene expression of CLOCK and BMAL1 , and decreased expression of PER1 , PER2 , and CRY1 , but melatonin injection inhibited these gene expression changes .…”

“…injection) to DEN mice and demonstrated that melatonin inhibited HCC development and improved liver conditions during DEN‐induced liver injury . DEN elevated gene expression of CLOCK and BMAL1 , and decreased expression of PER1 , PER2 , and CRY1 , but melatonin injection inhibited these gene expression changes . Another study analyzed the efficacy of the combination of stem cell therapy and melatonin administration in DEN rat models .…”

Period 2-Induced Activation of Autophagy Improves Cardiac Remodeling After Myocardial Infarction

“…Mice that received diethylnitrosamine showed a lower expression of per2 and a higher Bax/Bcl-2 ratio in the liver. 37 However, in young per2 knockout mice, the ratio of Bcl-2/Bax is increased. 38 The interaction between Bcl-2 and Beclin 1 is necessary both in autophagy and apoptosis.…”

Consequences of Artificial Light at Night: The Linkage between Chasing Darkness Away and Epigenetic Modifications

“…Physiological blood concentration of melatonin blocked human leiomyosarcoma (soft tissue sarcoma) proliferation by inhibiting tumor metabolic and genetic pathways presumable by suppression of cellular cAMP levels via melatonin receptor [80]. In hepatocellular carcinoma-induced mice, melatonin treatment suppressed tumor cell proliferation through arresting the cell cycle [81]. The metastatic activity of oral squamous cell carcinoma was notably reduced by melatonin-mediated inhibition of tumor-associated neutrophils [82], inflammatory cells involved in promoting several solid tumors [83].…”