CD147 functions as the signaling receptor for extracellular divalent copper in hepatocellular carcinoma cells
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Pengfei Ding1,*, Xin Zhang2,*, Shujuan Jin1, Bo Duan1, Pengxiang Chu1, Yufei Zhang1, Zhi-Nan Chen2, Bin Xia1 and Fei Song2
1Beijing Nuclear Magnetic Resonance Center, School of Life Sciences, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China
2Department of Cell Biology, State Key Laboratory of Cancer Biology, Cell Engineering Research Center, The Fourth Military Medical University, Xi’an 710032, China
*These authors contributed equally to this work
Bin Xia, email: [email protected]
Fei Song, email: [email protected]
Keywords: CD147, extracellular divalent copper, matrix metalloproteinase, invasion, hepatocellular carcinoma
Received: January 13, 2017 Accepted: April 24, 2017 Published: May 09, 2017
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 Cu2+ in hepatocellular carcinoma (HCC) cells. Cu2+ binds to the extracellular membrane-proximal domain of CD147 and mediates its self-association. Cu2+-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. Cu2+-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 Cu2+ induced self-association. The Cu2+ binding deficient CD147 mutant abolishes the stimulating effects of Cu2+ on HCC cells. Our study reveals a novel extracellular signaling role of copper in promoting cancer cell metastasis, which implies that targeting the Cu2+-induced self-association of CD147 is a new strategy for cancer treatment.
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