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Identification of Hypoxia-Regulated Proteins in Head and Neck Cancer by Proteomic and Tissue Array Profiling

¹ Department of Radiation Oncology, Center for Clinical Sciences Research, ² Department of Surgery, Palo Alto VA Health Care System, Palo Alto, CA; ³ Department of Pathology, and ⁴ Department of Otolaryngology, Stanford University Medical Center, Stanford, California

Hypoxia within solid tumors decreases therapeutic efficacy, and identification of hypoxia markers may influence the choice of therapeutic modality. Here, we used a proteomic approach to identify hypoxia-regulated proteins and validated their use as endogenous indicators of tumor hypoxia. Using two-dimensional gel electrophoresis and PowerBlot (antibody-based array), we identified a group of 20 proteins that are increased 1.5-fold during hypoxia. The majority of these proteins such as IB kinase ß (IKKß), MKK3b, highly expressed in cancer (HEC), density-regulated protein 1, P150^glued, nuclear transport factor 2, binder of ARL 2, Paxillin, and transcription termination factor I have not been previously reported to be hypoxia inducible. The increase in these proteins under hypoxia was mediated through posttranscriptional mechanisms. We additionally characterized the role of IKKß, a regulator of the nuclear factor-B transcription factor, during hypoxia. We demonstrated that IKKß mediates cell survival during hypoxia and is induced in a variety of squamous cell carcinoma cell lines. Furthermore, we showed that IKKß expression from tumor specimens correlated with tumor oxygenation in patients with head and neck squamous cell carcinomas. These data suggest that IKKß is a novel endogenous marker of tumor hypoxia and may represent a new target for anticancer therapy.

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