STEAP2 promotes osteosarcoma progression by inducing epithelial–mesenchymal transition via the PI3K/AKT/mTOR signaling pathway and is regulated by EFEMP2

Abstract

ABSTRACT This study was designed to explore the prognostic significance and functionality of STEAP2 (six-transmembrane epithelial antigen of prostate 2) in osteosarcomas and determine whether EFEMP2 (Epidermal growth factor-containing fibulin-like extracellular matrix protein 2) targets STEAP2 to facilitate osteosarcoma cell infiltration and migration. STEAP2 expression in peritumoral tissues, osteosarcoma, benign fibrous dysplasia, osteosarcoma cells, normal osteoblastic hFOB cells, and various invasive subclones was evaluated using IHC, ICC, and qRT-PCR. We also evaluated the association between STEAP2 expression and disease outcome using Kaplan–Meier analyses and then investigated STEAP2 regulation and its functional effects using both in vitro and in vivo assays. The results revealed that the upregulation of STEAP2 in osteosarcoma tissues positively correlated with both the malignant osteosarcoma phenotype and poor patient outcomes. In addition, STEAP2 expression induced epithelial–mesenchymal transition (EMT) via the PI3K/AKT/mTOR axis and facilitated osteosarcoma cell infiltration and migration. Changes in EFEMP2 expression resulted in correlating changes in STEAP2 expression, with EFEMP2-overexpressing osteosarcoma cells exhibiting a less invasive phenotype and reduced EMT following STEAP2 inhibition. It is also worth noting that although EFEMP2 overexpression activated the PI3K/AKT/mTOR pathway promoting EMT, it did not affect osteosarcoma cells in which STEAP2 or Akt was knocked down. Thus, we can conclude that STEAP2 acts as an oncogene in osteosarcoma progression, while EFEMP2 enables PI3K/AKT/mTOR axis initiation and EMT by partly targeting STEAP2, thereby facilitating osteosarcoma cell infiltration and migration.