PER1 enhances vascular normalization in hepatocellular carcinoma facilitating HIF-1α nuclear translocation

Abstract Background: Blood vessels play a significant role in the pathogenesis of hepatocellular carcinoma (HCC). Emerging evidence suggests that dysregulation of the circadian clock gene, period 1 (PER1), is closely associated with HCC tumorigenesis. However, it remains unknown whether PER1 regulate the angiogenesis in HCC. Methods: The Cancer Genome Atlas data was utilized for bioinformatics analysis to evaluate the potential clinical significance of PER1. Western Blot (WB) was employed to detect expression of PER1 in tumors and adjacent tissues. Subcutaneous xenograft models were used to investigate the biological function of PER1. Hematoxylin and eosin staining, immunohistochemical analysis, WB, RT-qPCR, and co-immunoprecipitation techniques were employed to elucidate the underlying mechanism of PER1. Results: The expression of PER1 was significantly downregulated and exhibited a positive correlation with favorable clinicopathological characteristics in HCC patients. Overexpression of PER1 led to decreased cell proliferation and contributed to the maintenance of vascular normalization in nude mice. Conversely, silencing of PER1 resulted in the opposite effect. Mechanistically, PER1 orchestrated the balance between proangiogenic and antiangiogenic factors by binding to HIF-1α, thereby promoting malignant tumor progression. Conclusion: Our findings demonstrated that the PER1/HIF-1α signaling axis plays a critical role in promoting vascular normalization in HCC by effectively balancing proangiogenic and antiangiogenic factors.