TIMP-1 activated carcinoma-associated fibroblasts inhibit tumor apoptosis by activating SDF1/CXCR4 signaling in hepatocellular carcinoma

Oncotarget. 2015 May 20;6(14):12061-79. doi: 10.18632/oncotarget.3616.


Tissue inhibitor of metalloproteinase 1 (TIMP-1) is an endogenous inhibitor for MMPs that regulates the remodeling and turnover of the ECM during normal development and pathological conditions. Intriguingly, recent studies have shown that TIMP-1 plays a dual role in cancer progression. In this study, we found that TIMP-1 expression in HCC tissues is associated with advanced TNM stage, intrahepatic metastasis, portal vein invasion, and vasculature invasion. Notably, TIMP-1 expression in HCC tissue is significantly related to worse overall survival for patients with HCC after liver resection. Ectopic TIMP1 expression promoted the growth of HCC xenografts in nude mice. Both co-culture with Huh7 cells with a high level of TIMP-1 and TIMP1 treatment resulted in up-regulation of hallmarks of carcinoma-associated fibroblasts (CAFs) and accelerated cell proliferation, migration and invasion in immortalized liver fibroblasts (LFs) isolated from human normal liver tissue. By co-culture with CAFs, SDF-1/CXCR4/PI3K/AKT signaling was activated and apoptosis was markedly repressed with an increased Bcl-2/BAX ratio in Huh7 cells. Taken together, our observations suggest that TIMP-1 induces the trans-differentiation of LFs into CAFs, suppresses apoptosis via SDF-1/CXCR4/PI3K/AKT signaling and then promotes HCC progression. This protein may be a potential prognostic biomarker and therapeutic target for HCC.

Keywords: CAFs; HCC; TIMP-1; apoptosis; tumor microenvironment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Carcinoma, Hepatocellular / genetics*
  • Cell Proliferation
  • Female
  • Fibroblasts / metabolism*
  • Humans
  • Liver Neoplasms / genetics*
  • Male
  • Mice
  • Mice, Nude
  • Receptors, CXCR4 / metabolism*
  • Signal Transduction
  • Tissue Inhibitor of Metalloproteinase-1 / genetics*
  • Tissue Inhibitor of Metalloproteinase-1 / metabolism*
  • Transfection


  • Receptors, CXCR4
  • TIMP1 protein, human
  • Tissue Inhibitor of Metalloproteinase-1