# 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.

## Key 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.