Stanniocalcin-2 promotes epithelial–mesenchymal transition and invasiveness in hypoxic human ovarian cancer cells

Abstract

The human glycoprotein, stanniocalcin-2 (STC2) is a HIF-1 target gene that is found to be associated with tumor development. The relationship of the prognostic outcome to the level of its expression in cancer tissues is controversial; however experimental evidence suggests that STC2 is a positive regulator of cancer progression. In the present study, we investigated if the expression of STC2 in hypoxic cells is associated with cancer invasion and metastasis. We studied the epithelial–mesenchymal transition (EMT) markers in STC2-silenced and over-expressed SKOV3 cells maintained in hypoxic condition. Western blot and immunocytochemical analysis revealed that the stable expression of exogenous STC2 promoted EMT, as revealed by the increase of N-cadherin/vimentin but a decrease of E-cadherin levels. This observation was further confirmed by colony formation assay where the STC2 stably transfected cells showed high degree of motility with fibroblast morphology under hypoxic condition. In conducting invasion assay in hypoxia, the STC2 stably transfected cells showed high degree of invasiveness. This observation was correlated with the significant increase of MMP2 and MMP9 expression in the STC2 stably transfected cells. In HUVEC/SKOV3 co-culture invasion study, endothelial invasion was found to be enhanced by the seeding of STC2 stably transfected cells in the lower compartment. These observations were possibly mediated by an increase of ROS and activated ERK1/2 levels in the cells. Collectively, the finding provides the first evidence that STC2 is a positive regulator in tumor progression at hypoxia.