Cell migration is the hallmark of
cancer regulating anchorage independent growth and invasiveness of
tumor cells.
Hyaluronan (HA), an ECM
polysaccharide is shown to regulate this process. In the present report, we demonstrated, supplementation of purified recombinant
hyaluronan binding protein 1(HABP1/p32/gC1qR) from human fibroblast
cDNA enhanced migration potential of highly invasive
melanoma (B16F10) cells. Exogenous HABP1 adhered to the cell surface transiently and was shown to interact and colocalize with α(v)β(3)
integrin, a regulatory molecule of cell migration. In HABP1 treated cells, the phosphorylation of nuclear factor inducing
kinase (NIK) and IκBα was observed, followed by nuclear translocation of p65 subunit of NFκB, along with its
DNA-binding and transactivation, resulting in upregulation of
MT1-MMP expression and finally MMP-2 activation. To substantiate our findings, prior to HABP1 treatment, the expression of NIK was reduced by
small interfering RNA mediated knockdown and confirmed the inhibition of nuclear translocation of p65 subunit of NFκB and upregulation of
MT1-MMP expression. In addition, the use of
curcumin, an anti-
cancer drug, or
GRGDSP, the blocking
peptide along with exogenous HABP1, inhibited such NFκB-dependent pathway, confirming that HABP1-induced cell migration is α(v)β(3)
integrin-mediated and downstream signaling by NFκB. Finally, we translated the in vitro data in mice model and observed enhanced
tumor growth with higher
MT1-MMP expression and MMP-2 activation in the
tumors upon injection of HABP1 treated
melanoma cells. The treatment of
curcumin, the anticancer
drug along with HABP1, inhibited the migration, expression of
MT1-MMP and activation of MMP-2 and finally
tumor growth supports the involvement of HABP1 in
tumor formation.