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?3 integrin promotes TGF-?1/H2O2/HOCl-mediated induction of metastatic phenotype of hepatocellular carcinoma cells by enhancing TGF-?1 signaling.

ABSTRACT: In addition to being an important mediator of migration and invasion of tumor cells, ?3 integrin can also enhance TGF-?1 signaling. However, it is not known whether ?3 might influence the induction of metastatic phenotype of tumor cells, especially non-metastatic tumor cells which express low level of ?3. Here we report that H2O2 and HOCl, the reactive oxygen species produced by neutrophils, could cooperate with TGF-?1 to induce metastatic phenotype of non-metastatic hepatocellular carcinoma (HCC) cells. TGF-?1/H2O2/HOCl, but not TGF-?1 or H2O2/HOCl, induced ?3 expression by triggering the enhanced activation of p38 MAPK. Intriguingly, ?3 in turn promoted TGF-?1/H2O2/HOCl-mediated induction of metastatic phenotype of HCC cells by enhancing TGF-?1 signaling. ?3 promoted TGF-?1/H2O2/HOCl-induced expression of itself via positive feed-back effect on p38 MAPK activation, and also promoted TGF-?1/H2O2/HOCl-induced expression of ?3 and SNAI2 by enhancing the activation of ERK pathway, thus resulting in higher invasive capacity of HCC cells. By enhancing MAPK activation, ?3 enabled TGF-?1 to augment the promoting effect of H2O2/HOCl on anoikis-resistance of HCC cells. TGF-?1/H2O2/HOCl-induced metastatic phenotype was sufficient for HCC cells to extravasate from circulation and form metastatic foci in an experimental metastasis model in nude mice. Inhibiting the function of ?3 could suppress or abrogate the promoting effects of TGF-?1/H2O2/HOCl on invasive capacity, anoikis-resistance, and extravasation of HCC cells. These results suggest that ?3 could function as a modulator to promote TGF-?1/H2O2/HOCl-mediated induction of metastatic phenotype of non-metastatic tumor cells, and that targeting ?3 might be a potential approach in preventing the induction of metastatic phenotype of non-metastatic tumor cells.

SUBMITTER: Feng XX

PROVIDER: S-EPMC3832483 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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β3 integrin promotes TGF-β1/H2O2/HOCl-mediated induction of metastatic phenotype of hepatocellular carcinoma cells by enhancing TGF-β1 signaling.

Feng Xin-Xia XX Liu Mei M Yan Wei W Zhou Zhen-Zhen ZZ Xia Yu-Jia YJ Tu Wei W Li Pei-Yuan PY Tian De-An DA

PloS one 20131118 11

In addition to being an important mediator of migration and invasion of tumor cells, β3 integrin can also enhance TGF-β1 signaling. However, it is not known whether β3 might influence the induction of metastatic phenotype of tumor cells, especially non-metastatic tumor cells which express low level of β3. Here we report that H2O2 and HOCl, the reactive oxygen species produced by neutrophils, could cooperate with TGF-β1 to induce metastatic phenotype of non-metastatic hepatocellular carcinoma (HC ...[more]

PMID: 24260309

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Project description:Transforming growth factor β (TGF-β) plays a critical role in wound healing and the pathogenesis of fibrosis (scarring). Three isoforms of TGF-β have been identified in mammals. Previous studies have shown that the addition of TGF-β1 (T1) or -β2 (T2) to human corneal fibroblasts (HCF) cultured in a 3-dimensional construct resulted in a fibrotic matrix, while the addition of TGF-β3 (T3) resulted in the production of enhanced non-fibrotic matrix as compared to control (Vitamin C [VitC] only). In the current investigation, we undertook the molecular comparison of fibrosis-related gene expression in T1 or T3-treated HCF to gain further insights into the regulation and roles of these two isoforms on the fibrotic response. HCF were cultured in 100 mm dishes in basic medium (Eagles minimum essential medium [EMEM] with 10% fetal bovine serum [FBS]). At 70-80% confluency, cells were exposed to basic medium with 0.5 mM 2-O-α-d-glucopyranosyl-l-ascorbic acid (VitC) ± 2 ng/ml of T1 or T3. After 4 h or 3 days, cells were harvested, and mRNA or protein was isolated. Fibrosis related mRNA levels were assayed using a commercial qRT-PCR Array. Selected proteins were examined using Western blotting (WB). Experiments were performed 6 times for the qRT-PCR and 4 times for WB for each condition. qRT-PCR results showed that most of the fibrosis-related genes were up or downregulated in HCF exposed to T1 or T3 as compared with VitC control. At 4 h, only Smad7 expression was significantly altered in T3-treated HCF, compared to T1, and at 3 days, five genes were altered. WB confirmed that T1 significantly decreased Smad7 expression compared to T3 and control, and that the expression of thrombospondin-1 in T3-stimulated HCF was enhanced compared to T1-treated cells. Finally, both T1 and T3 decreased Smad3 expression dramatically at both time points. At early time points, T1 and T3 have similar effects on expression of fibrosis related genes; however, with a longer exposure, an increasing number of genes were differentially expressed. Interestingly, most of the differentially expressed gene products are secreted by the cells and may be related to the modulation of extracellular matrix.

Dataset Information

?3 integrin promotes TGF-?1/H2O2/HOCl-mediated induction of metastatic phenotype of hepatocellular carcinoma cells by enhancing TGF-?1 signaling.

Publications

β3 integrin promotes TGF-β1/H2O2/HOCl-mediated induction of metastatic phenotype of hepatocellular carcinoma cells by enhancing TGF-β1 signaling.

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