Clock gene Per2 as a controller of liver carcinogenesis

Area of Science:

• Molecular biology
• Chronobiology
• Cancer research

Background:

• Environmental disruption of molecular clocks is linked to liver cancer.
• The specific role of the Period 2 (Per2) clock gene in liver carcinogenesis is not fully understood.

Purpose of the Study:

• To investigate the role of the Per2 gene in liver carcinogenesis.
• To examine the impact of Per2 mutation on cell proliferation, genomic instability, and inflammation during liver cancer development.

Main Methods:

• Assessed liver histopathology in mice with constitutive Per2 mutation (Per2m/m) and wild-type (WT) controls.
• Determined molecular and physiological circadian patterns in mice exposed to chronic diethylnitrosamine (DEN).
• Analyzed gene and protein expression related to proliferation, genomic instability, and inflammation.

Main Results:

• Per2m/m livers showed altered proliferation gene expression (e.g., c-Myc, Wee1, Ccnb1, K-ras) and deregulated inflammation (e.g., IL-6) even without DEN exposure.
• Per2m/m mice developed liver cancers nearly fourfold more frequently than WT mice after DEN exposure.
• Per2 mutation disrupted the liver molecular clock, increased c-Myc and Ccnb1, abolished P53 response, and promoted inflammation (IL-6, TNF-α).

Conclusions:

• Per2 mutation severely deregulates liver gene/protein expression linked to uncontrolled proliferation, genomic instability, and inflammation.
• Per2 mutation accelerates liver carcinogenesis significantly.
• The clock gene Per2 functions as a liver tumor suppressor from initiation through progression.