Abstract
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.
Highlights
Hepatocellular carcinoma (HCC) is an aggressive cancer that frequently occurs in the setting of chronic hepatitis infection and liver cirrhosis
As assessed by the Mann-Whitney U test, it was demonstrated that Tissue inhibitor of metalloproteinase 1 (TIMP-1) expression is significantly higher in HCC tissues compared with adjacent liver tissues (P < 0.001, Figure 1B)
tissue inhibitor of matrix metalloproteinases (TIMPs)-1 expression in HCC tissues was remarkably related to Edmonson–Steiner classification (r = 8.16, P = 0.004), tumor node metastasis (TNM) stage (r = 8.39, P = 0.004), portal vein invasion (r = 11.94, P < 0.001) and intrahepatic metastases (r = 13.09, P < 0.001), whereas no significant correlation was found between TIMP-1 expression in HCC tissues and gender (r = 0.21, P = 0.647), age (r = 2.89, P = 0.089), HBV infection (r = 0.31, P = 0.578), liver cirrhosis (r < 0.01, P = 0.955), serumα-fetoprotein (AFP) level (r = 0.79, P = 0.374), tumor size (r = 2.42, P = 0.120), and vasculature invasion (r = 0.39, P = 0.533)
Summary
Hepatocellular carcinoma (HCC) is an aggressive cancer that frequently occurs in the setting of chronic hepatitis infection and liver cirrhosis. Overexpression of TIMP-1 was www.impactjournals.com/oncotarget found in pancreatic cancer [8], laryngeal squamous cell carcinoma [9] and lung adenocarcinoma [10], whereas its expression is lost in prostate adenocarcinoma [11]. It appears that TIMP-1 exerts different effects on tumor progression in various cancers. There are limited studies of the role of TIMP-1 in HCC progression
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