STC1-Based Activation of NF-κB Signaling Pathway Induces Epthithelial–Mesenchymal Transition Thus Promotes Progression and Temozolomide Resistance of Glioblastoma

Acquired resistance to chemotherapy, especially to temozolomide (TMZ), is a major challenge correlated with the treatment failure of glioblastoma (GBM). Stanniocalcin-1 (STC1) is a glycoprotein hormone involved in multiple biological processes in cancer cells. However, the function and underlying mechanism of STC1 in GBM still remain unclear. To this end, exploring the potential functional role and mechanism of STC1 inducing TMZ resistance becomes an urgent need for individual individualized strategies for GBM. The GSE151680 dataset was obtained from the GEO database; thus, bioinformatic analysis was performed by using R software (version 4.2.0) to screen the differentially expressed genes correlated to TMZ resistance in GBM. Cox regression and nonnegative matrix factorization (NMF) analysis were conducted to establish a prognostic model. Additionally, immunohistochemistry (IHC) staining, qRT-PCR, and western blot were used to investigate the expression of STC1 in GBM tissues and non-tumor controls. Mechanically, loss-of-function and gain-of-function assays were performed to validate the biological functions of STC1 on the malignant biological characters and TMZ resistance of GBM cells. Besides, the enrichment analysis was performed to investigate the downstream pathway of STC1. In this study, STC1 was selected as the gene candidate correlated to TMZ resistance according to the results of Cox regression and NMF analysis. Additionally, increased expression of STC1 could be observed in GBM and was significantly correlated to poor prognosis in GBM. Besides, multiple malignant characters including proliferation, migration, invasion, tumorigenesis, and TMZ resistance of GBM could be markedly reduced by exogenous downregulation of STC1; contrarily, overexpression of STC1 promoted the malignant behaviors and drug resistance of GBM cells. Moreover, GO, KEGG, and GSEA analysis revealed that STC1 induced epithelial-mesenchymal transition (EMT) via activation of NF-κB signaling. Furthermore, the treatment of TNF-α (an activator of the NF-κB pathway) partially reversed the inhibitory effect of sh-STC1 on the proliferation and metastasis in GBM cells. In conclusion, STC1 induced EMT thus enhances the malignancies and drug resistance of GBM cells by activating the NF-κB pathway, providing new evidence for clinical drug development in GBM.