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Ubiquitin COOH-Terminal Hydrolase 1: A Biomarker of Renal Cell Carcinoma Associated with Enhanced Tumor Cell Proliferation and Migration[?Q1: Running head: UCHL1, a Biomarker of RCC. Short title OK?Q1]

Authors' Affiliations: ¹ Institute of Medical Immunology, Martin-Luther-University Halle-Wittenberg, Halle, Germany; ² IIIrd Department of Internal Medicine, Johannes-Gutenberg University; ³ Clinic for Urology, University Clinic Mainz, Mainz, Germany; ⁴ Bayer HealthCare AG, Wuppertal, Germany; and ⁵ Fred Hutchinson Cancer Research Center, Seattle, Washington

Requests for reprints: Barbara Seliger, Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, Magdeburger Strasse 2, 06112 Halle, Germany. Phone: 49-345-557-4054; Fax: 49-345-557-4055; E-mail: Barbara.Seliger{at}medizin.uni-halle.de.

Purpose: Renal cell carcinoma (RCC) accounts for 2% to 3% of all malignancies. It represents one of the most radiation- and chemotherapy-resistant tumors and surgical resections are only effective in organ-defined disease. However, RCC is an immunogenic tumor with response rates to immunotherapies between 10% and 20% of the treated patients. Due to the currently inefficient therapies and the low 5-year survival rates of RCC patients, novel diagnostic, prognostic, and therapeutic markers are urgently needed for this disease.

Experimental Design: Proteome-based approaches were used to identify (a) differentially expressed proteins in RCC compared with normal kidney epithelium and (b) proteins that are able to induce an antibody response in RCC patients. Based on these experiments, a promising candidate was subsequently validated by reverse transcription-PCR, Western blot analyses, and immunohistochemistry. In addition, functional assays were done in generated transfectants.

Results: The ubiquitin COOH-terminal hydrolase L1 (UCHL1) was found to be differentially expressed in both RCC lesions and RCC cell lines and immunoreactive using patients' sera. UCHL1 expression was often down-regulated in primary RCC when compared with normal kidney epithelium but dependent on the RCC subtype, the von Hippel-Lindau phenotype, and the tumor grading. Moreover, the frequency and the level of UCHL1 expression were higher in metastases when compared with primary RCC lesions. Gain-of-function transfectants exhibited a significant higher proliferation and migration rate than UCHL1-negative RCC cells.

Conclusions: UCHL1 expression seems to be associated with the metastatic phenotype of RCC and therefore might serve as potential biomarker for the diagnosis and prognosis of RCC patients.