Abstract:
Circadian rhythm regulates cellular differentiation and physiology and shapes the immune
response. Altered expression of clock genes might lead to the onset of common malignant cancers,
including Renal Cell Carcinoma (RCC). Data from Cancer Genome Atlas (TCGA) indicate that clock
genes PER1-3, CRY2, CLOCK, NR1D2 and RORa are overexpressed in RCC tissues and correlate
with patients’ prognosis. The expression of clock genes could finely tune transcription factor activity
in RCC and is associated with the extent of immune cell infiltration. The clock system interacts
with hypoxia-induced factor-1 (HIF-1 ) and regulates the circadian oscillation of mammalian
target of rapamycin (mTOR) activity thereby conditioning the antitumor effect of mTOR inhibitors.
The stimulation of natural killer (NK) cell activity exerted by the administration of interferon- ,
a cornerstone of the first era of immunotherapy for RCC, relevantly varies according to circadian
dosing time. Recent evidence demonstrated that time-of-day infusion directly affects the efficacy
of immune checkpoint inhibitors in cancer patients. Compounds targeting the circadian clock have
been identified and their role in the era of immunotherapy deserves to be further investigated. In this
review, we aimed at addressing the impact of clock genes on the natural history of kidney cancer and
their potential therapeutic implications.
