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

Song T, Dou C, Jia Y, Tu K, Zheng X - Oncotarget (2015)

Bottom Line: Notably, TIMP-1 expression in HCC tissue is significantly related to worse overall survival for patients with HCC after liver resection.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.This protein may be a potential prognostic biomarker and therapeutic target for HCC.

View Article: PubMed Central - PubMed

Affiliation: Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.

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.

No MeSH data available.


Related in: MedlinePlus

TIMP-1 expression is up-regulated in HCC tissuesA. TIMP-1 protein is mainly expressed in the cytoplasm of tumor cells, and TIMP-1 expression in HCC tissues was remarkably higher (a) compared with adjacent liver tissues (b). B. As shown in the vertical scatter plot, the IHC scores in the TIMP-1 high group (mean value: 5.57) was notably higher than that in the TIMP-1 low/non group with a mean value 3.28 (P < 0.001) after analysis by the Mann-Whitney U test.
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Figure 1: TIMP-1 expression is up-regulated in HCC tissuesA. TIMP-1 protein is mainly expressed in the cytoplasm of tumor cells, and TIMP-1 expression in HCC tissues was remarkably higher (a) compared with adjacent liver tissues (b). B. As shown in the vertical scatter plot, the IHC scores in the TIMP-1 high group (mean value: 5.57) was notably higher than that in the TIMP-1 low/non group with a mean value 3.28 (P < 0.001) after analysis by the Mann-Whitney U test.

Mentions: The results of IHC revealed the cytoplasmic staining of the TIMP-1 protein (Figure 1A). Positive TIMP-1 protein expression was observed in 94/100 (94%) HCC cases. TIMP-1 expression was increased in tumor cells compared with benign tissues in 76.6% of the HCC tumors examined. As assessed by the Mann-Whitney U test, it was demonstrated that TIMP-1 expression is significantly higher in HCC tissues compared with adjacent liver tissues (P < 0.001, Figure 1B). The relationship between TIMP-1 and the clinicopathological parameters of 100 HCCs was statistically examined, and the results are listed in Table 1. TIMP-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).


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

Song T, Dou C, Jia Y, Tu K, Zheng X - Oncotarget (2015)

TIMP-1 expression is up-regulated in HCC tissuesA. TIMP-1 protein is mainly expressed in the cytoplasm of tumor cells, and TIMP-1 expression in HCC tissues was remarkably higher (a) compared with adjacent liver tissues (b). B. As shown in the vertical scatter plot, the IHC scores in the TIMP-1 high group (mean value: 5.57) was notably higher than that in the TIMP-1 low/non group with a mean value 3.28 (P < 0.001) after analysis by the Mann-Whitney U test.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4494923&req=5

Figure 1: TIMP-1 expression is up-regulated in HCC tissuesA. TIMP-1 protein is mainly expressed in the cytoplasm of tumor cells, and TIMP-1 expression in HCC tissues was remarkably higher (a) compared with adjacent liver tissues (b). B. As shown in the vertical scatter plot, the IHC scores in the TIMP-1 high group (mean value: 5.57) was notably higher than that in the TIMP-1 low/non group with a mean value 3.28 (P < 0.001) after analysis by the Mann-Whitney U test.
Mentions: The results of IHC revealed the cytoplasmic staining of the TIMP-1 protein (Figure 1A). Positive TIMP-1 protein expression was observed in 94/100 (94%) HCC cases. TIMP-1 expression was increased in tumor cells compared with benign tissues in 76.6% of the HCC tumors examined. As assessed by the Mann-Whitney U test, it was demonstrated that TIMP-1 expression is significantly higher in HCC tissues compared with adjacent liver tissues (P < 0.001, Figure 1B). The relationship between TIMP-1 and the clinicopathological parameters of 100 HCCs was statistically examined, and the results are listed in Table 1. TIMP-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).

Bottom Line: Notably, TIMP-1 expression in HCC tissue is significantly related to worse overall survival for patients with HCC after liver resection.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.This protein may be a potential prognostic biomarker and therapeutic target for HCC.

View Article: PubMed Central - PubMed

Affiliation: Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.

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.

No MeSH data available.


Related in: MedlinePlus