Advanced solid tumors are exposed to hypoxic conditions over longer periods of time as they grow. Tumor hypoxia is a major factor that induces malignant progression, but most previous studies on tumor hypoxia were performed under short‐term hypoxia for up to 72 hours and few studies have focused on tumor response to chronic hypoxic conditions. Here we show a molecular mechanism by which chronic hypoxia promotes invasive behavior in prostate cancer cells. We found that an epithelial‐mesenchymal transition (EMT)‐driving transcription factor, slug, is specifically upregulated under chronic hypoxia and promotes tumor cell migration and invasion. Unexpectedly, processes associated with EMT, such as loss of E‐cadherin, are not observed under chronic hypoxia. Instead, expression of ephrin‐B1, a ligand of Eph‐related receptor tyrosine kinases, is markedly induced by slug through E‐box motifs and promotes cell migration and invasion. Furthermore, slug and ephrin‐B1 are highly coexpressed in chronic hypoxic cells of human prostate adenocarcinoma tissues after androgen deprivation, which is known to cause tumor hypoxia. Taken together, these results indicate that chronic hypoxia‐induced slug promotes invasive behavior of prostate cancer cells by activating the expression of ephrin‐B1. In addition, ephrin‐B1 may be a novel therapeutic target in combination with androgen deprivation therapy for aggressive prostate cancer.

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Helicobacter pylori infection is the strongest known risk factor of stomach cancer. Strains harboring the virulence factor CagA (cytotoxin-associated gene A) significantly stimulate host inflammatory response, which increases the risk of ulceration and cancer. However, the mechanisms by which CagA triggers prolonged inflammation with mucosal damage remain elusive. Based on a large-scale genetic screen using Drosophila, we identified a novel CagA target Synaptotagmin-like protein 2-a, Slp2-a, an effector of small GTPase Rab27. Using gastric organoid-derived monolayers of polarized mucous cells, we demonstrated that CagA inhibited Slp2-a-mediated docking of mucous granules to the plasma membrane by direct binding to Slp2-a. We further observed aberrant cytoplasmic retention of mucus in human gastric mucosa infected with CagA-expressing strains. These results suggest that CagA could be disrupting the protective mucous barrier by inhibiting Slp2-a-mediated mucous granule exocytosis, which may lead to mucosal damage from luminal acid and pepsin to promote inflammation leading to cancer.

Drug disposition after topical application to the skin has not been fully elucidated, especially after repeated application. We conducted a clinical trial to evaluate the pharmacokinetics in the stratum corneum of healthy adults after repeated application of lanoconazole cream as a model drug. We applied 25 mg of 1% lanoconazole cream onto the pre-specified areas on the participants' back once daily for 5 days. The stratum corneum was sampled twice on each study day using a standardized tape-stripping method, and the amount of lanoconazole contained in the samples was quantified using the tandem mass spectrometry method. The obtained data were used to evaluate lanoconazole pharmacokinetics in the stratum corneum. The amount of lanoconazole in the stratum corneum after once daily repeated administration reached a steady state on day 3, and it was eliminated from the stratum corneum with a half-life of approximately 11 h after discontinuing application.