Abstract
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 (HCC) cells. TGF-β1/H2O2/HOCl, but not TGF-β1 or H2O2/HOCl, induced β3 expression by triggering the enhanced activation of p38 MAPK. Intriguingly, β3 in turn promoted TGF-β1/H2O2/HOCl-mediated induction of metastatic phenotype of HCC cells by enhancing TGF-β1 signaling. β3 promoted TGF-β1/H2O2/HOCl-induced expression of itself via positive feed-back effect on p38 MAPK activation, and also promoted TGF-β1/H2O2/HOCl-induced expression of α3 and SNAI2 by enhancing the activation of ERK pathway, thus resulting in higher invasive capacity of HCC cells. By enhancing MAPK activation, β3 enabled TGF-β1 to augment the promoting effect of H2O2/HOCl on anoikis-resistance of HCC cells. TGF-β1/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 β3 could suppress or abrogate the promoting effects of TGF-β1/H2O2/HOCl on invasive capacity, anoikis-resistance, and extravasation of HCC cells. These results suggest that β3 could function as a modulator to promote TGF-β1/H2O2/HOCl-mediated induction of metastatic phenotype of non-metastatic tumor cells, and that targeting β3 might be a potential approach in preventing the induction of metastatic phenotype of non-metastatic tumor cells.
Highlights
Integrin expression is crucial for the migratory and invasive capability of tumor cells
We investigated whether H2O2 and HOCl could cooperate with transforming growth factor b1 (TGF-b1) to induce the metastatic phenotype of non-metastatic Hepatocellular carcinoma (HCC) cells, and whether b3 expression is required for the induction
To investigate whether H2O2 and HOCl could cooperate with TGF-b1 to induce the metastatic phenotype of non-metastatic HCC cells, we first analyzed the effect of TGF-b1, H2O2 and HOCl on invasive capacity of HepG2 and Huh7 cells
Summary
Integrin expression is crucial for the migratory and invasive capability of tumor cells. Hepatocellular carcinoma (HCC) cells express several integrins which have been identified as the mediators of their migration and invasion, including a1b1, a2b1, a3b1, a6b1, avb, avb, and avb5 [1,2,3,4,5,6]. B3 has been found to modulate transforming growth factor b1 (TGF-b1) signaling in some types of cells [10,11] It is not known whether b3 might be involved in the induction of metastatic phenotype of tumor cells by functioning as modulatory factor. A3 expression is required but not sufficient for the invasiveness of HCC cells, since TGF-b1-treated non-metastatic
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