ABSTRACT
Increasing evidence links deregulation of the ubiquitin-specific proteases 22 (USP22) deubitiquitylase to cancer development and progression in a select group of tumor types, but its specificity and underlying mechanisms of action are not well defined. Here we show that USP22 is a critical promoter of lethal tumor phenotypes that acts by modulating nuclear receptor and oncogenic signaling. In multiple xenograft models of human cancer, modeling of tumor-associated USP22 deregulation demonstrated that USP22 controls androgen receptor accumulation and signaling, and that it enhances expression of critical target genes coregulated by androgen receptor and MYC. USP22 not only reprogrammed androgen receptor function, but was sufficient to induce the transition to therapeutic resistance. Notably, in vivo depletion experiments revealed that USP22 is critical to maintain phenotypes associated with end-stage disease. This was a significant finding given clinical evidence that USP22 is highly deregulated in tumors, which have achieved therapeutic resistance. Taken together, our findings define USP22 as a critical effector of tumor progression, which drives lethal phenotypes, rationalizing this enzyme as an appealing therapeutic target to treat advanced disease.
Subject(s)
Biomarkers, Tumor/metabolism , Prostatic Neoplasms, Castration-Resistant/enzymology , Thiolester Hydrolases/metabolism , Adenocarcinoma/enzymology , Adenocarcinoma/genetics , Adenocarcinoma/metabolism , Androgen Receptor Antagonists/pharmacology , Animals , Cell Culture Techniques , Cell Line, Tumor , Disease Models, Animal , Disease Progression , Gene Expression , Gene Expression Regulation, Neoplastic , Heterografts , Humans , Male , Mice , Mice, SCID , Prostatic Neoplasms, Castration-Resistant/genetics , Prostatic Neoplasms, Castration-Resistant/metabolism , Proteasome Endopeptidase Complex/genetics , Proteasome Endopeptidase Complex/metabolism , Receptors, Androgen/metabolism , Thiolester Hydrolases/deficiency , Thiolester Hydrolases/genetics , Ubiquitin ThiolesteraseABSTRACT
BACKGROUND: Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is central to discerning the diagnosis of solid pancreatic tumors through tissue acquisition. Test performance is affected by a number of factors including location of mass within the pancreas, presence of onsite cytology technologist, and number of passes with the needle. The influence of tumor size has not been well studied. AIM: The objective of the current study was to determine whether the size of mass affects the diagnostic accuracy for solid pancreatic lesions aspirated under EUS guidance. METHODS: Data were collected retrospectively on all patients with solid pancreatic masses undergoing EUS-FNA from June 2003 to August 2010. The cytology samples were reported as positive, suspicious for malignancy, atypical, negative, or nondiagnostic. The gold standard for a cytological diagnosis was histological confirmation or clinical follow-up of more than 6 months with repeat imaging. Patients were divided into five groups based upon lesion size as follows: (a) less than 1 cm, (b) 1-2 cm, (c) 2-3 cm, (d) 3-4 cm, and (e) greater than 4 cm. Performance characteristics of EUS-FNA including sensitivity, specificity, and accuracy were compared for each group. Accuracy was defined as the ratio of the sum of true-positive and true-negative values divided by the number of lesions. RESULTS: We identified 583 patients with solid pancreatic lesions in which EUS-FNA was performed and adequate cellularity was obtained (47% men, mean age 65 ± 1.4 (SE) years). Overall, 486 (83%) of lesions were pancreatic adenocarcinoma, 18 (3%) were neuroendocrine tumors, 12 (2%) were lymphomas, and 67 (12%) were benign lesions. The median size of the mass was 3 cm (range, 0.5-7 cm). A mean of 4.9 passes (range, 1-9 passes) was needed to obtain adequate samples from lesions. The overall yield of obtaining adequate samples for diagnosis was 85%. When stratified by size, the EUS-FNA sensitivity for lesions with size <1, 1-2, 2-3, 3-4, and >4 cm was 40, 75.9, 86.9, 93.2, and 91.6%, respectively; EUS-FNA sensitivity strongly correlate with tumor size (p < 0.001). Similarly, the accuracy of EUS-FNA increased as lesion size increased, ranging from 47% for tumors less than 1 cm to 88% for tumors greater than 4 cm (p < 0.05). Location of tumor and number of needle passes did not significantly influence EUS-FNA performance characteristics. CONCLUSIONS: The sensitivity and diagnostic accuracy of EUS-FNA for solid pancreatic lesions is strongly correlated with tumor size. Sensitivity and accuracy decrease significantly for tumors that are smaller than 1 cm.
