Journal
ONCOTARGET
Volume 6, Issue 14, Pages 12061-12079Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.3616
Keywords
TIMP-1; CAFs; HCC; apoptosis; tumor microenvironment
Categories
Funding
- National Natural Scientific Foundation of China [81301743]
- Research Fund for the doctoral Program of High Education of China from Ministry of Education [20120201120090]
- Key Science and Technology Program of Shaanxi Province [2014K11-01-01-21]
- Fundamental Research Funds for the Basic Research Operating expenses Program of Central College - Xi'an Jiaotong University
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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.
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