N-acetyl-L-aspartyl-L-glutamate peptidase-like 2 is overexpressed in cancer and promotes a pro-migratory and pro-metastatic phenotype.
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.
1] Uro-Oncology Research Group, Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK [2] Cancer Research UK Biomarker Initiative, Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
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Whitaker
Uro-Oncology Research Group, Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
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Shiong
Uro-Oncology Research Group, Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
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Kay
Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
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Grönberg
1] Department of Histopathology and ISH Core Facility, Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK [2] Department of Histopathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
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Warren
Department of Pathology, Karolinska Institute, Stockholm, Sweden.
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Seipel
Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
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Wiklund
Uro-Oncology Research Group, Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
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Thomas
Department of Pathology, Karolinska Institute, Stockholm, Sweden.
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Wiklund
1] Department of Histopathology and ISH Core Facility, Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK [2] Department of Histopathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
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Miller
Bioinformatics Core Facility, Cancer Research UK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge, UK.
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Menon
Uro-Oncology Research Group, Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
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Ramos-Montoya
Bioinformatics Core Facility, Cancer Research UK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge, UK.
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Vowler
Uro-Oncology Research Group, Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
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Massie
Department of Pathology, Karolinska Institute, Stockholm, Sweden.
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Egevad
Uro-Oncology Research Group, Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
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Neal
D000954:Antigens, Surface / Q000235:genetics* / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics*; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D043425:Glutamate Carboxypeptidase II / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D018613:Microscopy, Confocal; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D011468:Prostatectomy / Q000379:methods; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000601:surgery; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000954:Antigens, Surface; D014408:Biomarkers, Tumor; C000597036:NAALADL2 protein, human; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II