METCAM/MUC18 plays a tumor promoter role in the development of nasopharyngeal carcinoma type III

Abstract

Our previous studies by testing the effects of huMETCAM/MUC18 over-expression on the tumorigenesis of the NPC-TW01 cell line supports the notion that huMETCAM/MUC18 plays a tumor suppressor role in the development of nasopharyngeal carcinoma (NPC) type I. However, it is not clear if this notion also holds true for another NPC cell line, NPC-TW04, which was established from NPC type III. For this purpose, we further investigated the effects of huMETCAM/MUC18 over-expression in the NPC-TW04 cell line on their in vitro cellular behaviors and in vivo tumorigenesis in athymic nude mice. First, the G418-resistant clones were obtained after transfection of the huMETCAM/MUC18 cDNA into the NPC-TW04 cell line. Then, one NPC-TW04 clone, which expressed a high level of huMETCAM/MUC18, and one empty vector (control) clone were used for testing effects of huMETCAM/MUC18 over-expression on their in vitro behaviors (intrinsic growth rate, motility, and invasiveness, and growth on three-dimensional basement membrane) and in vivo tumorigenesis (via subcutaneous injection) in the athymic nude mice. Time course of tumor proliferation and final tumor volumes/weights were determined. Tumor sections were used for histology and immunohistochemistry (IHC) analyses. Tumor lysates were used to determine levels of huMETCAM/MUC18 and various downstream key effectors. We found that over-expression of huMETCAM/MUC18 increased in vitro motility and invasiveness, induced the invasive growth in the 3D basement membrane culture assay, and increased in vivo tumorigenicity of NPC-TW04 cell line. The expression levels of downstream effectors, such as an anti-apoptosis index, proliferation index, an index of metabolic switch to aerobic glycolysis, angiogenesis indexes and survival pathway index, were increased, whereas the pro-apoptosis index decreased in the tumors. Thus, contrary to the role of huMETCAM/MUC18 in the NPC-TW01 cells, huMETCAM/MUC18 over-expression in the NPC-TW04 cells increased epithelial-to-mesenchymal transition and also in vitro invasive growth and in vivo tumorigenesis, suggesting that it plays a tumor promoter role in the development of NPC type III by reducing apoptosis and increasing anti-apoptosis, angiogenesis, proliferation and metabolic switch to aerobic glycolysis.