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a Departments of Medicine and Cellular & Structural Biology, San Antonio Cancer Institute, University of Texas Health Science Center, San Antonio, Texas, USA
Key Words: hypoxia • hypoxia-inducible factor (HIF) • hypoxia-inducible factor subunit • microarray • multiple endocrine neoplasia Type 2 (MEN 2) • mutation • neurofibromatosis Type 1 (NF1) • oxidoreductase • oxidative stress • paraganglioma • pathway intersection • pheochromocytoma • prolyl hydroxylase • RET • intracellular signaling • succinate dehydrogenase (SDH) • succinate dehydrogenase subunit B (SDHB) • succinate dehydrogenase subunit C (SDHC) • succinate dehydrogenase subunit D (SDHD) • transcription profiling • von Hippel–Lindau (VHL)
Address for correspondence: Patricia Dahia, Departments of Medicine and Cellular & Structural Biology, University of Texas Health Science Center, 7703 Floyd Curl Drive, Room No. 5053-R3, MC 7880, San Antonio-TX 8229-3900, USA. Voice: 210-567-4866; fax: 210-567-1956. e-mail: dahia{at}uthscsa.edu
Pheochromocytomas and paragangliomas are neural-crest–derived tumors that arise from mutations in RET, VHL, NF1, and in the genes-encoding succinate dehydrogenase (SDH) subunits B (SDHB), C (SDHC), and D (SDHD). Despite their genetic diversity, these tumors cannot be clearly distinguished on the basis of their primary mutation. We recently identified two major transcriptional programs embedded within familial and sporadic pheochromocytomas and paragangliomas using global expression profiling. This review will summarize the major results of these studies and discuss their implications. The transcription data revealed that: (a) tumors with mutations in VHL, SDHB, and SDHD genes share a transcription signature of hypoxia, angiogenesis, and oxidoreductase imbalance; (b) SDHB protein is suppressed in tumors with mutations in SDHB and SDHD, and also in a subset of tumors with VHL mutations; and (c) HIF1
 is involved in the SDHB downregulation observed in these tumors. These results are consistent with the existence of a close interconnection between the VHL and SDH pathways mediated predominantly by hypoxia and oxidoreductase signals. It further suggests that low SDHB levels indicative of impaired mitochondrial complex II function may be a shared element of these pheochromocytomas. SDHB may thus constitute a marker for tumors with abnormal hypoxic profile.
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