TIMP-1 mediates the inhibitory effect of interleukin-6 on the proliferation of a hepatocarcinoma cell line in a STAT3-dependent manner

Abstract

The tissue inhibitor of metalloproteinases (TIMP)-1 is a multifunctional protein which is not only an inhibitor of matrix metalloproteinases (MMPs) but also to have a possible "cytokine-like" action. Here, we first compared mRNA expression of TIMP-1 and MMP-9 in BEL-7402 (a hepatocellular carcinoma cell line), L-02 (a normal liver cell line) and QSG-7701 (a cell line derived from peripheral tissue of liver carcinoma) using real-time quantitative RT-PCR. By evaluating the variation of the MMP-9/TIMP-1 ratio as an index of reciprocal changes of the expression of the two genes, we observed that the MMP-9/TIMP-1 ratio was about 13-and 5-fold higher in BEL-7402 than in L-02 and QSG-7701, respectively. Significantly, overexpression of TIMP-1 decreased the MMP-9/TIMP-1 ratio in BEL-7402 and then inhibited the cell growth to 60% and reduced the migration to about 30%. Meanwhile, our data showed that interleukin-6 (IL-6) (100 ng/mL) could also inhibited the cell growth of BEL-7402. Further studies indicated that TIMP-1 mediated the inhibitory effect of IL-6 on BEL-7402 cell proliferation in a STAT3-dependent manner, which could further accelerate the expression of the cyclindependent kinase inhibitor p21. A dominant negative STAT3 mutant totally abolished IL-6-induced TIMP-1 expression and its biological functions. The present results demonstrate that TIMP-1 may be one of the mediators that regulate the inhibitory effect of IL-6 on BEL-7402 proliferation in which STAT3 signal transduction and p21 up-regulation also play important roles.

Silicon‐based quantum dots induce inflammation in human lung cells and disrupt extracellular matrix homeostasis

“…These changes in MMPs expression and activity were similar to the molecular events involved in the pathogenesis of chronic rhino-sinusitis without nasal polyps, which involves high levels of IL-6 and IL-8 that trigger fibrosis by up-regulating TIMP-1 in fibroblasts [55]. In addition, the stimulation of TIMP-1 protein expression by IL-6, which was suggested in the present study, has also been reported in rat hepatocytes [56] and was indicated as a mechanism of cell growth inhibition [57], although a protective role of IL-6 associated with the induction of TIMP-1 was noted in hyperoxic acute lung injury [58].…”

In vitro effect of N-acetylcysteine on hepatocyte injury caused by dichlorodiphenyltrichloroethane and its metabolites

“…This may also explain why ROS generation was not seen in HepG2 cells in the present study but was reported in L-02 hepatocytes. 40 Although both these cell lines are of human origin, the former is cancerous (HepG2), while the latter is not (L-02), 43 thereby possessing different genotypic and phenotypic features. Furthermore, it is well established that HepG2 cells do not possess the metabolic capacity of their innate in vivo counterparts, 44 which may also explain the results of the present study.…”

Bystin-like protein is upregulated in hepatocellular carcinoma and required for nucleologenesis in cancer cell proliferation

“…This latter line was derived from liver carcinoma peripheral tissue taken from a 35-year-old woman [50] and has been used in recent years for HCC studies [28,51,52]. Cells were grown in Dulbecco's modified Eagle medium (DMEM, Invitrogen) supplemented with 10% (v/v) heat-inactivated fetal bovine serum, 2 mM glutamine, 100 U/ml penicillin and 0.1 µg/ml streptomycin at 37 °C in an atmosphere of 5% CO 2 .…”