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Increased Expression of SIM2-s Protein Is a Novel Marker of Aggressive Prostate Cancer

Authors' Affiliations: Sections for ¹ Pathology and ² Microbiology and Immunology, The Gade Institute and ³ Department of Surgery, Haukeland University Hospital; Sections for ⁴ Microbiology and Immunology and ⁵ Pathology, The Gade Institute; Departments of ⁶ Informatics and ⁷ Surgical Sciences; and ⁸ Computational Biology Unit, Bergen Center for Computational Science, University of Bergen, Bergen, Norway; and ⁹ Institute for Systems Biology, Seattle, Washington

Requests for reprints: Lars A. Akslen, Department of Pathology, The Gade Institute, Haukeland University Hospital, N-5021 Bergen, Norway. Phone: 47-55-97-31-82/47-55-97-31-73 (secr.); Fax: 47-55-97-31-58; E-mail: Lars.Akslen{at}gades.uib.no.

Purpose: The human SIM2 gene is located within the Down's syndrome critical region of chromosome 21 and encodes transcription factors involved in brain development and neuronal differentiation. SIM2 has been assigned a possible role in the pathogenesis of solid tumors, and the SIM2-short isoform (SIM2-s) was recently proposed as a molecular target for cancer therapy. We previously reported SIM2 among the highly up-regulated genes in 29 prostate cancers, and the purpose of our present study was to examine the expression status of SIM2 at the transcriptional and protein level as related to outcome in prostate cancer.

Experimental Design: By quantitative PCR, mRNA in situ hybridization, and immunohistochemistry, we evaluated the expression and significance of SIM2 isoforms in 39 patients with clinically localized prostate cancer and validated the expression of SIM2-s protein in an independent cohort of 103 radical prostatectomies from patients with long and complete follow-up.

Results: The SIM2 isoforms (SIM2-s and SIM2-l) were significantly coexpressed and increased in prostate cancer. Tumor cell expression of SIM2-s protein was associated with adverse clinicopathologic factors like increased preoperative serum prostate-specific antigen, high histologic grade, invasive tumor growth with extra-prostatic extension, and increased tumor cell proliferation by Ki-67 expression. SIM2-s protein expression was significantly associated with reduced cancer-specific survival in multivariate analyses.

Conclusions: These novel findings indicate for the first time that SIM2 expression might be important for clinical progress of human cancer and support the recent proposal of SIM2-s as a candidate for targeted therapy in prostate cancer.

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