2. Academic Validation
  3. ROCK1 drives colorectal cancer liver metastasis via PRKCH-mediated bioenergetic reprogramming

ROCK1 drives colorectal cancer liver metastasis via PRKCH-mediated bioenergetic reprogramming

  • Cell Signal. 2025 Oct 18:112174. doi: 10.1016/j.cellsig.2025.112174.
Yue Luo 1,  Yishan Xu 2,  Xi Chen 2,  Shitong Wang 2,  Xinheng Liu 2,  Guihua Jin 2,  RenPin Chen 3,  Huajun Yu 4,  Liyi Li 5
Affiliations

Affiliations

  • 1 Department of Gastrointestinal Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325035, PR China; Wenzhou Key Laboratory of Integrated Traditional Chinese and Western Medicine Treatment for Gastrointestinal Diseases, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325035, PR China.
  • 2 Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, PR China.
  • 3 Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, PR China. Electronic address: lightfish.8@163.com.
  • 4 Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, PR China. Electronic address: yuhuajun@wmu.edu.cn.
  • 5 Department of Gastrointestinal Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325035, PR China; Wenzhou Key Laboratory of Integrated Traditional Chinese and Western Medicine Treatment for Gastrointestinal Diseases, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325035, PR China. Electronic address: liliyi@wmu.edu.cn.
PMID: 41115563 DOI: 10.1016/j.cellsig.2025.112174
Abstract

Colorectal Cancer (CRC) metastasis, particularly to the liver, is a primary contributor to cancer-related deaths, yet the underlying molecular drivers remain insufficiently defined. This study identifies Rho-associated coiled-coil kinase 1 (ROCK1) as a central regulator of CRC metastatic progression. Analysis of patient samples revealed significantly elevated ROCK1 expression in liver metastases relative to primary tumors. Functional assays demonstrated that ROCK1 depletion impaired CRC cell migration and inhibited hepatic colonization in vivo, while ROCK1 overexpression promoted a metastatic phenotype. Mechanistically, ROCK1 loss led to downregulation of EMT markers, including N-Cadherin and β-catenin. Transcriptomic profiling uncovered protein kinase C eta (PRKCH) as a downstream effector of ROCK1, with PRKCH expression markedly reduced following ROCK1 knockdown. Functional silencing of PRKCH suppressed CRC cell motility and disrupted metabolic homeostasis by reducing glycolytic flux and mitochondrial respiration. Conversely, PRKCH overexpression partially restored migration and bioenergetic function in ROCK1-deficient cells. Further investigation identified the ERK2-CREB1 signaling axis as critical for ROCK1-driven PRKCH transcription, with pharmacological or genetic inhibition of ERK2 or CREB1 reducing PRKCH expression. CREB1 binding to the PRKCH promoter was validated using luciferase reporter assays. Collectively, these findings reveal a novel ROCK1-ERK2-CREB1-PRKCH signaling pathway that coordinates EMT and metabolic reprogramming to drive CRC liver metastasis, highlighting PRKCH as a promising therapeutic target in advanced CRC.

Keywords

Cancer metastasis; ERK2-CREB1 axis; Glycolysis; Protein kinase C eta; Rho-associated coiled-coil kinase 1.

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