EMMPRIN acts as a Tumor Promoter in Oral SCC

The extracellular matrix metalloproteinase inducer (EMMPRIN), found on the surface of many tumor cells, stimulates the production of matrix metalloproteinases (MMPs) by fibroblasts.

Objective: To evaluate its possible role as a tumor promoter.

Methods: we used two approaches: 1) We overexpressed EMMPRIN in poorly invasive SCC9 cells to establish the SCC9EMMP cell line. 2) We knocked down EMMPRIN expression in highly invasive SCC9ƒ"6 cells by siRNA and established siRNA cells. The resulting cell lines were then evaluated for migration on Fibronectin. Migration of SCC9EMMP cells was significantly greater than the SCC9 cell line; whereas siRNA cell migration was reduced compared to the control cells. In addition, MMP expression was altered by EMMPRIN levels. Expression of MMP 2, 3, and 9 was elevated in SCC9EMMP. In contrast, MMP expression by siRNA was reduced compared to the control cells. We previously showed that TN-C was neo-expressed in oral SCC. To simulate the in vivo environment, we used a coculture system in which oral SCC cells were grown together with peritumor fibroblasts (PTF) and evaluated for TN-C. Cocultures of SCC9EMMP/PTF deposited several-fold greater levels of TN-C than did the control cultures (SCC9/PTF). Cocultures of siRNA/PTF cells deposited low levels of TN-C, compared to the control. In the presence of the broad spectrum MMP inhibitor, GM6001, TN-C deposition by SCC9EMMP cocultures was suppressed. Finally, SCC cells overexpressing SCC9EMMP cells were injected into the hindflank of athymic mice and followed for tumor growth. SCC9EMMP cells produced tumors that were on average 4 fold larger than those formed by control SCC9 cells.

Results:These results suggest that EMMPRIN regulates migration, MMP production, deposition of TN-C and in vivo growth.

Conclusion: EMMPRIN may represent a novel target for development of future anti-tumor strategies. R01 DE12856, R01 DE11930 and P01DE13904