In addition to being an important mediator of migration and invasion of tumor cells, b3 integrin can also enhance TGF-beta 1 signaling. However, it is not known whether beta 3 might influence the induction of metastatic phenotype of tumor cells, especially non-metastatic tumor cells which express low level of beta 3. Here we report that H2O2 and HOCl, the reactive oxygen species produced by neutrophils, could cooperate with TGF-beta 1 to induce metastatic phenotype of non-metastatic hepatocellular carcinoma (HCC) cells. TGF-beta 1/H2O2/HOCl, but not TGF-beta 1 or H2O2/HOCl, induced beta 3 expression by triggering the enhanced activation of p38 MAPK. Intriguingly, beta 3 in turn promoted TGF-beta 1/H2O2/HOCl-mediated induction of metastatic phenotype of HCC cells by enhancing TGF-beta 1 signaling. beta 3 promoted TGF-beta 1/H2O2/HOCl-induced expression of itself via positive feed-back effect on p38 MAPK activation, and also promoted TGF-beta 1/H2O2/HOCl-induced expression of alpha 3 and SNAI2 by enhancing the activation of ERK pathway, thus resulting in higher invasive capacity of HCC cells. By enhancing MAPK activation, beta 3 enabled TGF-beta 1 to augment the promoting effect of H2O2/HOCl on anoikis-resistance of HCC cells. TGF-beta 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 beta 3 could suppress or abrogate the promoting effects of TGF-beta 1/H2O2/HOCl on invasive capacity, anoikis-resistance, and extravasation of HCC cells. These results suggest that beta 3 could function as a modulator to promote TGF-beta 1/H2O2/HOCl-mediated induction of metastatic phenotype of non-metastatic tumor cells, and that targeting beta 3 might be a potential approach in preventing the induction of metastatic phenotype of non-metastatic tumor cells.