Combined Functional Genome Survey of Therapeutic Targets for Clear Cell Carcinoma of the Kidney

• Published in: Japanese journal of clinical oncology Vol. 41; no. 7; pp. 847 - 853
• Main Authors: Ito, Hideaki, Honda, Kazufumi, Satow, Reiko, Arai, Eri, Shitashige, Miki, Ono, Masaya, Sakuma, Tomohiro, Sakano, Shigeru, Naito, Katsusuke, Matsuyama, Hideyasu, Yamada, Tesshi
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.07.2011
• Subjects: Adenocarcinoma, Clear Cell - drug therapy; Adenocarcinoma, Clear Cell - genetics; Adenocarcinoma, Clear Cell - pathology; Adult; Aged; Biomarkers, Tumor - genetics; Cell Line, Tumor; Cell Proliferation; Exons; Female; Gene Expression Regulation, Neoplastic; Genome, Human - genetics; Genome-Wide Association Study; Humans; Kidney Neoplasms - drug therapy; Kidney Neoplasms - genetics; Kidney Neoplasms - pathology; Male; Middle Aged; Molecular Targeted Therapy; Neoplasm Staging; Reproducibility of Results; Reverse Transcriptase Polymerase Chain Reaction; RNA, Small Interfering - analysis; Transcription, Genetic; Up-Regulation; molecular targeting therapy; renal cell carcinoma; small interfering RNA; exon array; functional screening
• ISSN: 0368-2811; 1465-3621
• DOI: 10.1093/jjco/hyr060

Objective Emerging molecular targeting therapeutics have been incorporated into the management of advanced renal cell carcinoma; however, their efficacy remains limited. The aim of this study was to catalog potential therapeutic target molecules for renal cell carcinoma. Methods We first selected genes up-regulated in clear cell renal cell carcinoma relative to surrounding normal kidney tissues in 10 patients (Study Cohort) using high-density exon arrays that detect all potential transcripts predicted in the human genome. The selected genes were subjected to independent validation in another set of 10 patients (Validation Cohort) using real-time reverse transcriptase polymerase chain reaction and functional screening using small interfering RNA in six clear cell renal cell carcinoma cell lines. Results We identified 164 genes whose expression was significantly elevated in clear cell renal cell carcinoma (P< 0.0001 [Student's t-test] and at least a 3-fold change in transcription signal). We finally extracted 33 genes required for maintaining cell proliferation in at least two clear cell renal cell carcinoma cell lines. The 33 genes included 13 genes known to be associated with the development/progression of renal cell carcinoma, including CAIX and FLT-1, confirming the robustness of the current strategy. Conclusions Through a combination of genome-wide expression and functional assays, we identified a set of genes with high potential as targets for drug development. This method is rapid and comprehensive and could be applied to the discovery of diagnostic biomarkers and therapeutic targets for cancers other than clear cell renal cell carcinoma.