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Molecular Oncology, Markers, Clinical Correlates |
Drug Discovery Program [J. A., S. M. S.], Head and Neck Sarcoma Programs [C. M-C.], and Molecular Oncology Program [L. M., T. M-A.], H. Lee Moffitt Cancer Center and Research Institute, Departments of Oncology and Biochemistry & Molecular Biology, Department of Interdisciplinary Oncology [C. M-C.] University of South Florida, Tampa, Florida 33612
Purpose: In contrast to Ras small GTPases, which contribute to human malignancy when overexpressed or constitutively activated, convincing evidence for the involvement of Ras homologous (Rho) GTPases in human cancer is still missing. In cell culture and animal models, RhoB antagonizes malignant transformation, but no data are available regarding the expression of RhoB in human tumors. In this study, we have analyzed the status of the RhoB protein and the closely related family member RhoA in human head and neck squamous cell carcinomas.
Experimental Design: Protein immunoexpression was quantitated by image analysis in the context of tumor invasion and differentiation. To account for possible individual variations, expression levels of RhoB and RhoA were evaluated in the tumor and its adjacent nonneoplastic tissue. Potential gene deletions or mutations were assessed by PCR and RT-PCR.
Results: RhoB expression is readily detected in normal epithelium, carcinomas in situ, and well-differentiated tumors, but it becomes weak to undetectable as tumors become deeply invasive and poorly differentiated. In contrast, Ki67 (proliferation marker) and RhoA protein levels increase with tumor progression. Furthermore, whereas in nonneoplastic keratinocytes RhoB is localized mainly in the nucleus, in carcinomas RhoB is predominantly located in the cytoplasm. RhoB gene deletions or mutations were not found.
Conclusions: These results give additional support to the notion that RhoB may play a tumor suppressive role in squamous cell carcinomas of the head and neck. The lack of RhoB expression in deeply invasive carcinoma argues against inhibition of RhoB farnesylation as a mediator of farnesyltransferase inhibitors’ antitumor activity.
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