Hypoxia plays an important role in the tumor microenvironment by allowing the development and maintenance of cancer cells, but the regulatory mechanisms by which tumor cells adapt to hypoxic conditions are not yet well understood. MicroRNAs are recognized as a new class of master regulators that control gene expression and are responsible for many normal and pathological cellular processes. Studies have shown that hypoxia inducible factor 1 (HIF1) regulates a panel of microRNAs, whereas some of microRNAs target HIF1. The interaction between microRNAs and HIF1 can account for many vital events relevant to tumorigenesis, such as angiogenesis, metabolism, apoptosis, cell cycle regulation, proliferation, metastasis, and resistance to anticancer therapy. This review will summarize recent findings on the roles of hypoxia and microRNAs in human cancer and illustrate the machinery by which microRNAs interact with hypoxia in tumor cells. It is expected to update our knowledge about the regulatory roles of microRNAs in regulating tumor microenvironments and thus benefit the development of new anticancer drugs.

Metabolism under hypoxia is significantly different from that under normoxia. It has been well elucidated that HIF-1 (hypoxia-inducible factor-1) plays a central role in regulating glucose metabolism under hypoxia; however, the role of HIF-1 in lipid metabolism has not yet been well addressed. In the present study we demonstrate that HIF-1 promotes LDL (low-density lipoprotein) and VLDL (very-LDL) uptake through regulation of VLDLR (VLDL receptor) gene expression under hypoxia. Increased VLDLR mRNA and protein levels were observed under hypoxic or DFO (deferoxamine mesylate salt) treatment in MCF7, HepG2 and HeLa cells. Using dual-luciferase reporter and ChIP (chromatin immunoprecipitation) assays we confirmed a functional HRE (hypoxia-response element) which is localized at +405 in exon 1 of the VLDLR gene. Knockdown of HIF1A (the α subunit of HIF-1) and VLDLR, but not HIF2A (the α subunit of HIF-2), attenuated hypoxia-induced lipid accumulation through affecting LDL and VLDL uptake. Additionally we also observed a correlation between HIF-1 activity and VLDLR expression in hepatocellular carcinoma specimens. The results of the present study suggest that HIF-1-mediated VLDLR induction influences intracellular lipid accumulation through regulating LDL and VLDL uptake under hypoxia.

Anticoagulants take over: In its fully reduced form, vitamin K helps to catalyze an oxidation reaction essential for blood coagulations, but it must be regenerated in each reaction through reduction. Liu et al. determined the structures of the enzyme responsible, vitamin K epoxide reductase, bound to an oxidized vitamin K substrate or with anticoagulants, including the widely prescribed drug warfarin. Understanding how these molecules bind and inhibit explains some variations in the therapeutic response as well as resistance for anticoagulants used in pest control. Science , this issue p. 43

Coagulation factor IX (FIX) is a vitamin K dependent protein and its deficiency causes hemophilia B, an X-linked recessive bleeding disorder. More than 1000 mutations in the F9 gene have been identified in hemophilia B patients. Here, we systematically summarize the structural and functional characteristics of FIX and the pathogenic mechanisms of the mutations that have been identified to date. The mechanisms of FIX deficiency are diverse in these mutations. Deletions, insertions, duplications, and indels generally lead to severe hemophilia B. Those in the exon regions generate either frame shift or inframe mutations, and those in the introns usually cause aberrant splicing. Regarding point mutations, the bleeding phenotypes vary from severe to mild in hemophilia B patients. Generally speaking, point mutations in the F9 promoter region result in hemophilia B Leyden, and those in the introns cause aberrant splicing. Point mutations in the coding sequence can be missense, nonsense, or silent mutations. Nonsense mutations generate truncated FIX that usually loses function, causing severe hemophilia B. Silent mutations may lead to aberrant splicing or affect FIX translation. The mechanisms of missense mutation, however, have not been fully understood. They lead to FIX deficiency, often by affecting FIX’s translation, protein folding, protein stability, posttranslational modifications, activation to FIXa, or the ability to form functional Xase complex. Understanding the molecular mechanisms of FIX deficiency will provide significant insight for patient diagnosis and treatment.