CD147 functions as the signaling receptor for extracellular divalent copper in hepatocellular carcinoma cells

Elevated copper levels in tumor microenvironment are directly correlated to cancer progression in a variety of malignancies. Copper is required in angiogenesis, and promotes the proliferation and metastasis of cancer cells. However, the molecular mechanism of copper in promoting cancer progression remains elusive. Here we report that CD147 serves as a signaling receptor for extracellular Cu(2+) in hepatocellular carcinoma (HCC) cells. Cu(2+) binds to the extracellular membrane-proximal domain of CD147 and mediates its self-association. Cu(2+)-mediated self-association of CD147 activates PI3K/Akt signaling pathway leading to the up-regulation of matrix metalloproteinase MMP-2 and MMP-14 in HCC cells. Cu(2+)-induced CD147 self-association also enhances the ability of HCC cells to stimulate MMP-2 expression from neighboring fibroblasts, as well as increases the invasiveness of HCC cells which is abolished by the copper chelator tetrathiomolybdate. We have mapped the interfaces and identified the key residues of CD147 involved in the Cu(2+) induced self-association. The Cu(2+) binding deficient CD147 mutant abolishes the stimulating effects of Cu(2+) on HCC cells. Our study reveals a novel extracellular signaling role of copper in promoting cancer cell metastasis, which implies that targeting the Cu(2+)-induced self-association of CD147 is a new strategy for cancer treatment.