Xiao Yu1, Maode Wang2, Jie Zuo3, Alafate Wahafu1, Ping Mao1, Ruichun Li1, Wei Wu1, Wanfu Xie1, Jia Wang4. 1. Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, PR China. 2. Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, PR China; Center of Brain Science, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, PR China. 3. The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710004, PR China. 4. Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, PR China; Center of Brain Science, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, PR China. Electronic address: jiawang_xjtu@163.com.
Abstract
AIMS: To investigate the underlying mechanism by which glioblastoma (GBM) cells gain temozolomide (TMZ) resistance and to clarify novel therapeutic targets and new prognostic biomarkers for GBM. MAIN METHODS: A genome-wide hierarchical bi-clustering based on previously published microarray databases identified Nuclear Factor I A (NFIA) as one of the most significantly upregulated genes correlated to TMZ resistance in GBM. Then, the potential biological functions of NFIA in oncogenesis and chemoresistance were clarified by qRT-PCR, Western blotting and in vivo xenograft models with artificially induced TMZ-resistant U87 cells. Additionally, immunohistochemistry (IHC) assays were performed to explore the clinical significance of NFIA in glioma patients. Last, luciferase reporter assay was performed to study the transcriptional regulation of NFIA on the nuclear factor κb (NF-kB) pathway. KEY FINDINGS: NFIA was correlated with TMZ resistance in GBM. Clinically, elevated NFIA expression was significantly correlated with adverse outcomes of glioma patients, especially in GBM patients. Moreover, NFIA contributed to the acquired TMZ resistance of GBM cells, while suppression of NFIA via lentivirus reduced cell proliferation, tumorigenesis and resistance to TMZ of GBM. Additionally, NFIA promoted transcription activity that regulated the expression of NF-kB. Last, NFIA induced phosphorylation of NF-kB p65 at serine 536, thus inducing TMZ resistance in GBM cells. Altogether, our study suggests that NFIA-dependent transcriptional regulation of NF-kB contributes to acquired TMZ resistance in GBM. SIGNIFICANCE: Abnormally activated NFIA-NF-kB signaling was strongly correlated with acquired TMZ resistance and poor prognosis in GBM, and it could be a new therapeutic target for TMZ-resistant GBM.
AIMS: To investigate the underlying mechanism by which glioblastoma (GBM) cells gain temozolomide (TMZ) resistance and to clarify novel therapeutic targets and new prognostic biomarkers for GBM. MAIN METHODS: A genome-wide hierarchical bi-clustering based on previously published microarray databases identified Nuclear Factor I A (NFIA) as one of the most significantly upregulated genes correlated to TMZ resistance in GBM. Then, the potential biological functions of NFIA in oncogenesis and chemoresistance were clarified by qRT-PCR, Western blotting and in vivo xenograft models with artificially induced TMZ-resistant U87 cells. Additionally, immunohistochemistry (IHC) assays were performed to explore the clinical significance of NFIA in gliomapatients. Last, luciferase reporter assay was performed to study the transcriptional regulation of NFIA on the nuclear factor κb (NF-kB) pathway. KEY FINDINGS:NFIA was correlated with TMZ resistance in GBM. Clinically, elevated NFIA expression was significantly correlated with adverse outcomes of gliomapatients, especially in GBMpatients. Moreover, NFIA contributed to the acquired TMZ resistance of GBM cells, while suppression of NFIA via lentivirus reduced cell proliferation, tumorigenesis and resistance to TMZ of GBM. Additionally, NFIA promoted transcription activity that regulated the expression of NF-kB. Last, NFIA induced phosphorylation of NF-kB p65 at serine 536, thus inducing TMZ resistance in GBM cells. Altogether, our study suggests that NFIA-dependent transcriptional regulation of NF-kB contributes to acquired TMZ resistance in GBM. SIGNIFICANCE: Abnormally activated NFIA-NF-kB signaling was strongly correlated with acquired TMZ resistance and poor prognosis in GBM, and it could be a new therapeutic target for TMZ-resistant GBM.