The von Hippel-Lindau tumor suppressor protein (pVHL) is a substrate receptor for the mammalian SCF-2 E3 ubiquitin ligase complex that targets several substrates for ubiquitination and proteasomal degradation. Among these targets are the α-regulatory subunits of the hypoxia-inducible factor (HIF). VHL−/− cells constitutively overexpress hypoxia-inducible genes through both transcriptional and posttranscriptional mechanisms and form tumors when injected into nude mice. Reintroduction of pVHL into VHL−/− cell lines restores normal oxygen-dependent regulation of these genes and suppresses tumor formation in the mouse xenograft assay. We report here that short hairpin RNA-mediated inactivation of HIF phenocopies the effects of pVHL reintroduction with respect to decreased expression of hypoxia-inducible genes, decreased ability to promote vascular endothelial cell proliferation in vitro, and tumor growth suppression in vivo. In addition, HIF inactivation abrogated the cellular response to hypoxia, indicating that HIF is the only pVHL target required for this response. These data suggest that deregulation of hypoxia-inducible genes in VHL−/− cells can be attributed mainly to deregulation of HIF and validate HIF as a therapeutic anticancer drug target.

Disseminated cancer presenting in pregnancy is extremely rare and its presentation can easily be obscured by pregnancy and physiological changes that occur with it. This case describes a patient who was diagnosed incidentally following investigations for preeclampsia. Despite initially being thought to be of low risk, the final diagnosis was that of metastasis from a primary cancer of an unknown origin, most likely a gastric adenocarcinoma. Although patients are under thorough observation throughout their pregnancy, this case highlights the potential need for additional investigations or adjustment of current practices. It also draws attention to the lack of sufficient reporting of cancer in pregnancy, which, considering its rarity, greatly influences how patients are managed.