TIMP-3 Expression Associates with Malignant Behaviors and Predicts Favorable Survival in HCC

Abstract

The tissue inhibitors of metalloproteinases (TIMPs) are proteins that specifically inhibit the proteolytic activity of the matrix metalloproteinases (MMPs). TIMP-3, the only member of the TIMPs that can tightly bind to the extracellular matrix, has been identified as a unique tumor suppressor that demonstrates the ability to inhibit tumor angiogenesis, invasion, and metastasis. This study aimed to detect the expression of TIMP-3 in hepatocellular carcinoma (HCC) and investigate the association between TIMP-3 expression and its clinicopathological significance in HCC patients. In the current study, reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting of HCC cell lines and one-step quantitative reverse transcription PCR (qPCR) and immunohistochemistry (IHC) analyses in HCC tissues were performed, to characterize the TIMP-3 expression. Kaplan-Meier survival and Cox regression analyses were utilized to evaluate the prognosis of 101 HCC patients. The results showed that the expression of TIMP-3 in HCC was significantly decreased relative to that of non-cancerous cells and tissues. Furthermore, the TIMP-3 expression was statistically associated with malignant behaviors of HCC, including portal vein invasion (p = 0.036) and lymph node metastasis (p = 0.030). Cox regression analysis revealed that TIMP-3 expression was an independent prognostic factor for disease-free survival (p = 0.039) and overall survival (p = 0.049). These data indicate that TIMP-3 expression is a valuable prognostic biomarker for HCC and that TIMP-3 expression suggests a favorable prognosis for HCC patients.

Hepatocyte specific TIMP3 expression prevents diet dependent fatty liver disease and hepatocellular carcinoma

“…Recent studies have identified TIMP3 as a tumor suppressor as its expression is silenced in malignant tumors including hepatocellular carcinoma (HCC) 18 , 19 . To evaluate the role of hepatic Timp3 overexpression in HCC, we have used a model of diethylnitrosamine (DEN) administration combined with dietary induced obesity.…”

Functional roles of circular RNAs during epithelial-to-mesenchymal transition

“…Yu J et al linked the circRNA cSMARCA5/miR-17-3p/miR-181b-5p/TIMP3 regulatory pathway to EMT in HCC [125]. TIMP3 has been reported to be a tumor cell suppressor in several studies and inactivates the EMT program [126,127]. It has been found that the decrease in circRNA cSMARCA5 facilitates HCC cell migration and metastasis and downregulates TIMP3 transcription by absorbing miR-17-3p and miR-181b-5p [125].…”

Folic‐Acid‐Mediated Functionalized Gold Nanocages for Targeted Delivery of Anti‐miR‐181b in Combination of Gene Therapy and Photothermal Therapy against Hepatocellular Carcinoma

“…Immunohistochemical (IHC) analysis was performed as described previously. [ 47,48 ] In brief, formalin-fi xed, paraffi n-embedded tissues from the mice were prepared and paraffi n sections were incubated with a primary TIMP3 Rabbit mAb (Cell Signaling Technology, USA) in PBS, washed and then incubated with a horseradish peroxidase-conjugated antibody (Santa Cruz Biotechnology, CA, USA). Negative controls were included by replacement of the primary antibody with PBS.…”