Human METCAM/MUC18 as a Novel Biomarker to Drive and its Specific SiRNAs to Block the Malignant Progression of Prostate Cancer

Abstract

METCAM/MUC18, an integral membrane cell adhesion molecule (CAM) in the Ig-like gene superfamily, is capable of performing typical functions of CAMs, such as cell-cell and cell-extracellular interactions, crosstalk with intracellular signaling pathways, and modulating social behaviors. METCAM/MUC18 is not expressed in >90% of the epithelial cells of normal prostate, or in 100% of benign prostatic hyperplasia (BPH), but is expressed in >80% of prostatic intracellular neoplasia (PIN), high grade prostate cancers, and metastatic lesions. Its expression is also correlated with the malignant progression of mouse prostate adenocarcinoma in a transgenic model, TRAMP. Overexpression of human METCAM/MUC18 increases epithelial-to-mesenchymal transition (in vitro motility and in vitro invasiveness) of prostate cancer cells and in vivo tumorigenesis and metastasis to multiple organs after orthotopic injection of human prostatic cancer LNCaP cells in male nude mice. From our preliminary studies, it appears to regulate these processes via increasing proliferation, up-regulating the AKT-signaling pathway, increasing aerobic glycolysis, and augmenting angiogenesis of prostate cancer cells, but has no effect on apoptosis. Furthermore, soluble METCAM/MUC18 could block angiogenesis of LNCaP tumors and specific shRNAs in a lentivirus vector block tumorigenesis of DU145 cells in an athymic nude mouse model. Taken together, METCAM/MUC18 may be a useful novel biomarker for early diagnosis of the malignant potential of prostate cancer, but also a metastatic progression gene to drive the malignant progression of prostate cancer in a pre-clinic mouse model. METCAM/ MUC18-specific siRNAs and its derived oligo-peptides may be useful as therapeutic agents to block the malignant progression of the cancer.