Purpose: The expression of suppressors of cytokine signaling 1 (SOCS1) and SOCS3 genes is dysregulated in several solid tumors, causing aberrant activation of cell growth and survival signaling pathways. In this study, we analyzed SOCS1 and SOCS3 gene expression in glioblastoma multiforme (GBM) and studied the role of each protein in GBM cell signaling and radiation resistance. Experimental Design: SOCS1and SOCS3 gene expression was analyzed in 10 GBM cell lines by reverse transcription-PCR and Western blotting. SOCS3 expression was also studied in 12 primary GBM tissues by immunohistochemistry.The methylation status of the SOCS1and SOCS3 loci was determined by methylation-specific PCR. Extracellular signal-regulated kinase (ERK)-mitogen-activated protein kinase (MAPK) activation in GBM cell lines overexpressing SOCS1 or lacking SOCS3 was determined by phosphorylated-specific Western blotting. Radiation responses in SOCS1-positive and SOCS3-deficient GBM cell lines and fibroblasts from wild-type and SOCS1or SOCS3 knockout mice were studied in a clonogenic survival assay.Results: All GBM cell lines tested lacked SOCS1expression, whereas GBM cell lines and primary GBM tumor samples constitutively expressed SOCS3. SOCS1 gene repression was linked to hypermethylation of the SOCS1genetic locus in GBM cells. Reintroduction of SOCS1or blocking SOCS3 expression sensitized cells to radiation and decreased the levels of activated ERK MAPKs in GBM cells. Conclusions: SOCS1and SOCS3 are aberrantly expressed in GBM cell lines and primary tissues. Altered SOCS gene expression leads to increased cell signaling through the ERK-MAPK pathway and may play a role in disease pathogenesis by enhancing GBM radioresistance.

Purpose: Epithelial cell adhesion molecule (EpCAM) is a widely expressed adhesion molecule in epithelial cancers. The purpose of this study is to determine the protein expression patterns of EpCAM in renal cell carcinoma (RCC) using tissue arrays linked to a clinicopathological database to evaluate both its predictive power in patient stratification and its suitability as a potential target for immunotherapeutic treatment strategies.Experimental Design: The University of California, Los Angeles kidney cancer tissue microarray contains specimens from 417 patients treated with nephrectomy. EpCAM protein expression in tumors and matched morphologically normal renal tissues was evaluated using anti-EpCAM immunohistochemistry. The resultant expression reactivity was correlated with clinicopathological variables.Results: EpCAM is consistently expressed in the distal nephron on normal renal epithelium. Clear cell RCCs show minimal and infrequent EpCAM expression, whereas chromophobe and collecting duct RCCs both demonstrate intense and frequent expression. Of 318 clear cell carcinomas used in the analysis, 10% were EpCAM positive in >50% of cells, and 8% of patients would be considered candidates for EpCAM-based therapy, based on high expression [>mod-erate intensity and frequent (>50%) expression] and the need for systemic treatment. EpCAM expression was an independent prognostic factor for improved disease-specific survival, with a multivariate hazard ratio of 0.63 (P ‫؍‬ 0.017; 95% confidence interval, 0.43-0.92).Conclusions: EpCAM is a novel prognostic molecular marker in RCC patients, and its positive expression is an independent predictor associated with improved survival. However, high expression in morphologically normal renal tissues and minimal or absent expression in clear cell carcinomas will likely limit the utility of this epithelial marker in targeted treatments of this most common RCC type.

array. FEN-1 nuclear expression was scored based on the percentage of target cells staining positively, and correlated with Gleason score, preoperative prostate-specific antigen (PSA) level and pathological stage. The time to PSA recurrence was also analysed. RESULTSThe mean expression of FEN-1 was significantly higher in cancer (36.7%) than in normal (13.2%), BPH (4.5%) and PIN (15.4%) specimens ( P < 0.001). FEN-1 expression was significantly correlated with Gleason score (ó = 0.23, P = 0.002). A higher preoperative serum PSA level ( P = 0.015), Gleason score ≥ 7 ( P < 0.001), seminal vesicle invasion ( P < 0.001) and capsular involvement ( P = 0.004) were associated with PSA recurrence, whereas FEN-1 expression was not. In a multivariate analysis, only Gleason score ≥ 7 ( P < 0.001), seminal vesicle invasion ( P = 0.005) and capsular involvement ( P = 0.009) were retained as independent predictors for PSA recurrence. CONCLUSIONSFEN-1 is overexpressed in prostate cancer compared with matched normal prostate, and its expression increases with tumour dedifferentiation, as shown by increasing Gleason score. These results suggest that FEN-1 might be a potential marker for selecting patients at high risk, and a potential target for prostate cancer diagnosis and therapy.

BACKGROUND Alterations of expression of the cytoskeletal proteins Gelsolin and E‐cadherin have been implicated in urothelial carcinoma tumorigenesis. However, it is not clear how these altered expressions associate with tumor progression, nor is it clear how these protein markers provide prognostic value for urothelial carcinomas. METHODS Primary urothelial carcinoma tissue microarrays were constructed for 146 patients with urothelial carcinoma. Where available, four replicate tissue samples of invasive tumor, adjacent dysplastic and in situ lesions, and benign tumors were arrayed for each case, resulting in a total of 1208 tissue spots. Immunohistochemical staining for Gelsolin, E‐cadherin, p53, and Ki67 (MIB‐1) was performed on the arrays. For each marker, the maximum staining intensity (Max), the percentage of positive staining (Pos), and the product of both Max and Pos (MaxPos) were analyzed. RESULTS Compared with the benign fields, the expression of both cytoskeletal proteins decreased in premalignant and malignant lesions. For Gelsolin, decreased MaxPos was seen in premalignant and preinvasive lesions. However, with an increase in tumor grade and stage, there was a gradual increase in Gelsolin (P < 0.05 for both). E‐cadherin expression decreases mainly in high‐grade lesions (carcinoma in situ and Grade 3 tumors). Univariate and multivariate analyses showed that Gelsolin Max was a strong independent predictor for the probability of tumor recurrence and for early tumor recurrence in high‐grade or high‐stage tumors, as well as a strong indicator for tumor progression. CONCLUSIONS Gelsolin and E‐cadherin have distinctive expression patterns. Gelsolin, but not E‐cadherin, provides independent prognostic information for high‐grade urothelial carcinomas. Cancer 2002;95:1247–57. © 2002 American Cancer Society. DOI 10.1002/cncr.10823

These results suggest that Na,K-adenosine triphosphatase alpha1-subunit expression patterns may be a useful clinical prognosticator for renal clear cell carcinoma. The Na,K-adenosine triphosphatase beta1-subunit was not found to be a useful prognosticator in this setting.