Transcriptional signatures of Ral GTPase are associated with aggressive clinicopathologic characteristics in human cancer.

Abstract

RalA and RalB are small GTPases that support malignant development and progression in experimental models of bladder, prostate, and squamous cancer. However, demonstration of their clinical relevance in human tumors remains lacking. Here, we developed tools to evaluate Ral protein expression, activation, and transcriptional output and evaluated their association with clinicopathologic parameters in common human tumor types. To evaluate the relevance of Ral activation and transcriptional output, we correlated RalA and RalB activation with the mutational status of key human bladder cancer genes. We also identified and evaluated a transcriptional signature of genes that correlates with depletion of RalA and RalB in vivo. The Ral transcriptional signature score, but not protein expression as evaluated by immunohistochemistry, predicted disease stage, progression to muscle invasion, and survival in human bladder cancers and metastatic and stem cell phenotypes in bladder cancer models. In prostate cancer, the Ral transcriptional signature score was associated with seminal vesicle invasion, androgen-independent progression, and reduced survival. In squamous cell carcinoma, this score was decreased in cancer tissues compared with normal mucosa, validating the experimental findings that Ral acts as a tumor suppressor in this tumor type. Together, our findings show the clinical relevance of Ral in human cancer and provide a rationale for the development of Ral-directed therapies.

• Authors: Steven C Smith, Alexander S Baras, Charles R Owens, Garrett Dancik, Dan Theodorescu
• Journal: Cancer research (Cancer Res) Vol. 72 Issue 14 Pg. 3480-91 (Jul 15 2012) ISSN: 1538-7445 [Electronic] United States
• PMID: 22586063 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• RNA, Small Interfering
• Ralb protein, human
• RALA protein, human
• ral GTP-Binding Proteins

Topics

• Carcinoma, Squamous Cell (genetics)
• Cell Line, Tumor
• Enzyme Activation
• Gene Expression Profiling
• Humans
• Immunohistochemistry
• Mutation
• Neoplasm Invasiveness (genetics)
• Neoplasm Metastasis (genetics)
• Neoplasms (genetics)
• Neoplastic Stem Cells (metabolism)
• Prognosis
• RNA, Small Interfering (pharmacology)
• Urinary Bladder Neoplasms (genetics, metabolism, pathology)
• ral GTP-Binding Proteins (genetics, metabolism)