Hypoxia-induced HIF-1α/VASN promotes bladder cancer progression.

Hypoxia-inducible factor-1 α (HIF-1α) is important in regulating the hypoxia adaptive response of bladder cancer. Vasorin (VASN) is closely related to tumor development. However, the role of VASN in hypoxia-induced bladder cancer remains to be clarified. To establish the hypoxia model, low-grade bladder cancer cell line RT4 was cultured under hypoxic conditions. RT4 cells were transfected with small interfering RNA to inhibit HIF-1α and VASN expression, and transfected with VASN overexpression plasmid to increase VASN expression. Wound healing and transwell assays were used to assess cell migration. Western blot was performed to detect epithelial-mesenchymal transformation (EMT)-related proteins, and YAP/TAZ and PTEN/AKT pathways expression. We found that VASN was increased in bladder cancer tissues and cell lines (RT4 and T24). Hypoxia promoted low-grade bladder cancer cell migration and EMT progression. Furthermore, the level of VASN was up-regulated under hypoxia in RT4 cells. Functional experiments revealed that hypoxia-induced bladder cancer cell migration through up-regulating VASN. Besides, VASN regulated the YAP/TAZ and PTEN/AKT pathways. Notably, VASN expression was positively correlated with HIF-1α expression. HIF-1α activated VASN expression in hypoxia-induced RT4 cells. Therefore, our findings support the first direct evidence that VASN participates in the adaptive response to hypoxia in bladder cancer, which highlights VASN as a potential target for bladder cancer.