1. N-acetyl-L-aspartyl-L-glutamate peptidase-like 2 is overexpressed in cancer and promotes a pro-migratory and pro-metastatic phenotype
- Author
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Benjamin Thomas, Suraj Menon, Henrik Grönberg, Fredrik Wiklund, Amanda H. Seipel, Anne Y. Warren, Charles E. Massie, L L Shiong, David E. Neal, Hayley C. Whitaker, Joseph Kay, Sarah L. Vowler, Peter Wiklund, Antonio Ramos-Montoya, L. Egevad, and Jodi Miller
- Subjects
Glutamate Carboxypeptidase II ,Male ,Cancer Research ,Blotting, Western ,AGR2 ,Kaplan-Meier Estimate ,Biology ,Prostate cancer ,Cell Movement ,Cell Line, Tumor ,Neoplasms ,Genetics ,medicine ,Glutamate carboxypeptidase II ,Biomarkers, Tumor ,Humans ,Neoplasm Metastasis ,Molecular Biology ,Neoplasm Staging ,Regulation of gene expression ,Prostatectomy ,Gene knockdown ,Microscopy, Confocal ,Reverse Transcriptase Polymerase Chain Reaction ,Gene Expression Profiling ,Cancer ,Prostatic Neoplasms ,Cell cycle ,medicine.disease ,Prognosis ,Molecular biology ,Immunohistochemistry ,Gene Expression Regulation, Neoplastic ,Membrane protein ,Antigens, Surface ,RNA Interference ,Neoplasm Grading ,Follow-Up Studies - Abstract
N-acetyl-L-aspartyl-L-glutamate peptidase-like 2 (NAALADL2) is a member of the glutamate carboxypeptidase II family, best characterized by prostate-specific membrane antigen (PSMA/NAALAD1). Using immunohistochemistry (IHC), we have shown overexpression of NAALADL2 in colon and prostate tumours when compared with benign tissue. In prostate cancer, NAALADL2 expression was associated with stage and Grade, as well as circulating mRNA levels of the NAALADL2 gene. Overexpression of NAALADL2 was shown to predict poor survival following radical prostatectomy. In contrast to PSMA/NAALAD1, NAALADL2 was localized at the basal cell surface where it promotes adhesion to extracellular matrix proteins. Using stable knockdown and overexpression cell lines, we have demonstrated NAALADL2-dependent changes in cell migration, invasion and colony-forming potential. Expression arrays of the knockdown and overexpression cell lines have identified nine genes that co-expressed with NAALADL2, which included membrane proteins and genes known to be androgen regulated, including the prostate cancer biomarkers AGR2 and SPON2. Androgen regulation was confirmed in a number of these genes, although NAALADL2 itself was not found to be androgen regulated. NAALADL2 was also found to regulate levels of Ser133 phosphorylated C-AMP-binding protein (CREB), a master regulator of a number of cellular processes involved in cancer development and progression. In combination, these data suggest that changes in expression of NAALADL2 can impact upon a number of pro-oncogenic pathways and processes, making it a useful biomarker for both diagnosis and prognosis.
- Published
- 2013