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Research Paper|Volume 15, Issue 20|pp 11033—11051

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

Shiue-Wei Lai1, Yi-Chiao Cheng2, Wen-Chien Huang3,4, Vijesh Kumar Yadav5,6, Iat-Hang Fong5,6, Chi-Tai Yeh5,6,7, Ching-Kuo Yang8, Wei-Hwa Lee9, Ming-Yao Chen5,6,10
  • 1Division of Hematology/Oncology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei City 114, Taiwan
  • 2Division of Colon and Rectal Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei City 114, Taiwan
  • 3Division of Thoracic Surgery, Department of Surgery, MacKay Memorial Hospital, Taipei 104, Taiwan
  • 4Department of Medicine, MacKay Medical College, New Taipei City 252, Taiwan
  • 5Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei City 110, Taiwan
  • 6Division of Gastroenterology and Hepatology, Department of Internal Medicine, Shuang Ho Hospital, New Taipei City 235, Taiwan
  • 7Continuing Education Program of Food Biotechnology Applications, College of Science and Engineering, National Taitung University, Taitung 95092, Taiwan
  • 8Division of Colorectal Surgery, Department of Surgery, Mackay Memorial Hospital, Taipei City 110, Taiwan
  • 9Department of Pathology, Taipei Medical University-Shuang Ho Hospital, New Taipei City 235, Taiwan
  • 10TMU Research Center for Digestive Medicine, Taipei Medical University, Taipei 110, Taiwan
Received: March 21, 2023Accepted: August 21, 2023Published: October 13, 2023
https://doi.org/10.18632/aging.205064

Copyright: © 2023 Lai et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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.