MEOX2-mediated regulation of Cathepsin S promotes cell proliferation and motility in glioma

Abstract

Nuclear transcription factor Mesenchyme Homeobox 2 (MEOX2) is a homeobox gene that is originally discovered to suppress the growth of vascular smooth muscle and endothelial cells. However, whether or not it is connected to cancer is yet unknown. Here, we report that MEOX2 functions as a tumor-initiating element in glioma. Bioinformatic analyses of public databases and investigation of MEOX2 expression in patients with glioma demonstrated that MEOX2 was abundant at both mRNA and protein levels in glioma. MEOX2 expression was shown to be inversely linked with the prognosis of glioma patients. MEOX2 inhibition changed the morphology of glioma cells, inhibited cell proliferation and motility, whereas had no effect on cell apoptosis. Besides, silencing MEOX2 also hampered the epithelial-mesenchymal transition (EMT), focal adhesion formation, and F-actin assembly. Overexpression of MEOX2 exhibited opposite effects. Importantly, RNA-sequencing, ChIP-qPCR assay, and luciferase reporter assay revealed Cathepsin S (CTSS) as a novel transcriptional target of MEOX2 in glioma cells. Consistently, MEOX2 causes glioma tumor development in mice and greatly lowers the survival period of tumor-bearing mice. Our findings indicate that MEOX2 promotes tumorigenesis and progression of glioma partially through the regulation of CTSS. Targeting MEOX2-CTSS axis might be a promising alternative for the treatment of glioma.

Integrated Analysis Identifies MEOX2 as a Malignant Driver and Prognostic Biomarker in Brain Glioma

“…Furthermore, we showed that MEOX2 positively regulates AKT/mTORC1 pathways, and exerted its function on downstream c-MYC/CDK1 axis to regulate cell proliferation and Bax to regulate cell apoptosis. It's noted that recent studies demonstrated that MEOX2 controlled ERK1/2 activity; however, we found that neither MEOX2 KD nor OE affected ERK1/2 signaling (Wang et al 2022). Nevertheless, more experimental work was needed to clarify the molecular mechanisms by which MEOX2 regulates glioma malignancy.…”

“…As for glioma, previous studies showed that MEOX2 expression was signi cantly correlated with OS, and may serve as a prognostic predictor (Tachon et al 2019). Recently, two independent groups demonstrated that MEOX2 regulates glioma proliferation, motility, and glioma stem cell survival (Tachon et al 2021;Wang et al 2022). However, the repertoire of MEOX2 on glioma was still largely unknown.…”

“…MEOX2, a homeobox transcriptional factor, is located at the 7p21.2 locus and reported to have a dual role in several types of peripheral cancers (Ávila-Moreno et al 2014; Tian et al 2018). Recently, two independent groups demonstrated the effects of MEOX2 on glioma growth (Wang et al 2022) and glioma stem cell survival (Tachon et al 2021). However, the expression pattern and biological functions of MEOX2 in GBM remain not fully understood.…”

Interferon‐γ inducible protein 30 promotes the epithelial–mesenchymal transition‐like phenotype and chemoresistance by activating EGFR/AKT/GSK3β/β‐catenin pathway in glioma

“…20 Given these observations, the terms "proneural-to-mesenchymal transition" or the "EMT-like" process have been proposed. 21,22 A better understanding of the molecular regulation of the EMT-like process during tumor spreading will help to provide potential therapeutic interventions to target this program when treating glioma.…”

“…Although the central nervous system (CNS) lacks this critical tissue component, 19 a range of changes in EMT‐associated activators, including decreased expression of various epithelial markers (occludins, E‐cadherin, ZO‐1) and increased expression of mesenchymal markers (N‐cadherin, vimentin, and fibronectin), were observed during glioma progression 20 . Given these observations, the terms “proneural‐to‐mesenchymal transition” or the “EMT‐like” process have been proposed 21,22 . A better understanding of the molecular regulation of the EMT‐like process during tumor spreading will help to provide potential therapeutic interventions to target this program when treating glioma.…”