Dysregulated expression of slingshot protein phosphatase 1 (SSH1) disrupts circadian rhythm and WNT signaling associated to hepatocellular carcinoma pathogenesis.

Abstract

Growing evidence underscores the circadian rhythm's essential function in liver stability and disease. Its disruption is progressively linked with metabolic issues, oncogene triggers, and heightened cancer susceptibility. Research points to slingshot protein phosphatase 1 (SSH1), a modulator of cofilin-1 (CFL-1), as instrumental in the reformation of the actin cytoskeleton, thereby impacting the invasiveness of various cancer types. Yet, the dynamics of SSH1's influence on liver cell stemness and circadian activity remain unclear. Through in-silico, tissue analysis, and functional assays, the study reveals a significant SSH1 expression in HCC samples, compared to non-cancerous counterparts, across six HCC platforms (AUC between 0.62 and 0.77, p < 0.01). The aberrant expression of SSH1 was correlated with poor patients' survival (HR = 1.70, p = 0.0063) and progression-free (HR = 1.477, p = 0.0187) survival rates. Targeting SSH1, either via Sennoside A or CRISPR SSH1 in Huh7 cells (Huh7-SSH1-/-) significantly suppressed cell viability, migration, invasion, colony and tumorsphere formation of the Huh7-SSH1-/- cells. Mechanistically, we showed that downregulated SSH1 expression suppressed CLOCK, BMAL1, WNT3, β-catenin, LRP5/6, BCL2, VIM and Snail, with concomitant upregulated CFL-1/2, and CRY1 expression, indicating dysregulated circadian rhythm and WNT/β-catenin oncogenic pathway deactivation. Treatments in reflected notable tumor size reductions in the mice treated with SenAlight (1.76-fold, p < 0.01) and SenAdark (3.79-fold, p < 0.01). The expression of SSH1, CLOCK, BMAL1 and β-catenin proteins were significantly downregulated in the SenAlight and SenAdark mice; this was more so in the SenAdark mice. This reveals a potential treatment approach for HCC patients.

• Authors: Shiue-Wei Lai, Yi-Chiao Cheng, Wen-Chien Huang, Vijesh Kumar Yadav, Iat-Hang Fong, Chi-Tai Yeh, Ching-Kuo Yang, Wei-Hwa Lee, Ming-Yao Chen
• Journal: Aging (Aging (Albany NY)) Vol. 15 Issue 20 Pg. 11033-11051 (10 13 2023) ISSN: 1945-4589 [Electronic] United States
• PMID: 37837551 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Protein Phosphatase 1
• beta Catenin
• ARNTL Transcription Factors
• SSH1 protein, human
• Phosphoprotein Phosphatases
• SSH1 protein, mouse

Topics

• Humans
• Animals
• Mice
• Carcinoma, Hepatocellular (genetics)
• Protein Phosphatase 1
• beta Catenin
• Wnt Signaling Pathway
• ARNTL Transcription Factors
• Liver Neoplasms (genetics)
• Cell Line, Tumor
• Gene Expression Regulation, Neoplastic
• Cell Proliferation
• Phosphoprotein Phosphatases