Circadian gene Cry1 inhibits the tumorigenicity of hepatocellular carcinoma by the BAX/BCL2-mediated apoptosis pathway

TL;DR

The circadian gene Cry1 helps prevent liver cancer by promoting cell death through the BAX/BCL2 pathway, and its low levels are linked to worse outcomes.

Contribution

This study identifies Cry1 as a tumor suppressor in hepatocellular carcinoma via the BAX/BCL2-mediated apoptosis pathway.

Findings

Low Cry1 expression in HCC correlates with poor prognosis and reduced survival.

Cry1 overexpression inhibits cancer cell proliferation and migration, while its depletion increases these processes.

Cry1 modulates apoptosis by regulating BAX and BCL2 expression levels.

Abstract

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, and emerging evidence implicates circadian rhythm disruption in its pathogenesis. Here, we identified the core circadian gene Cryptochrome1 (Cry1) as a potential tumor suppressor in HCC. Clinical analysis revealed that low Cry1 expression correlated with poor prognosis, showing a median survival of 36 vs 47 months, and Cry1 expression was significantly reduced in HCC cell lines (0.6-fold in SMMC-7721 vs LO2). Functional studies demonstrated that Cry1 overexpression reduced proliferation by 30% with more cells in the G1 phase, as well as inhibited migration/invasion, while Cry1 knockdown increased proliferation by 50% with less cells in the G1 phase and increased migration/invasion. Finally, we found Cry1 depletion downregulated pro-apoptotic BAX and upregulated anti-apoptotic BCL2, while Cry1 overexpression produced the opposite effects, suggesting its role in apoptosis via the BCL2/BAX-mediated apoptosis pathway. These findings indicate that Cry1 acts as a tumor suppressor in HCC, providing insights into the circadian dysfunction-cancer pathogenesis connection and its potential as a diagnostic biomarker and therapeutic target requires further verification through preclinical and clinical investigations in the future.

Figures