scholarly journals CAIX Regulates GBM Motility and TAM Adhesion and Polarization through EGFR/STAT3 under Hypoxic Conditions

2020 ◽  
Vol 21 (16) ◽  
pp. 5838
Author(s):  
Bor-Ren Huang ◽  
Yu-Shu Liu ◽  
Sheng-Wei Lai ◽  
Hui-Jung Lin ◽  
Ching-Kai Shen ◽  
...  
Keyword(s):  
Hypoxia Inducible Factor ◽  
Growth Factor Receptor ◽  
Carbonic Anhydrases ◽  
Monocyte Adhesion ◽  
Hypoxic Conditions ◽  
Receptor Signal ◽  
Caix Expression ◽  
Epidermal Growth ◽  
The Stability ◽  
Transcription 3

Carbonic anhydrases (CAs) are acid–base regulatory proteins that modulate a variety of physiological functions. Recent findings have shown that CAIX is particularly upregulated in glioblastoma multiforme (GBM) and is associated with a poor patient outcome and survival rate. An analysis of the GSE4290 dataset of patients with gliomas showed that CAIX was highly expressed in GBM and was negatively associated with prognosis. The expression of CAIX under hypoxic conditions in GBM significantly increased in protein, mRNA, and transcriptional activity. Importantly, CAIX upregulation also regulated GBM motility, monocyte adhesion to GBM, and the polarization of tumor-associated monocytes/macrophages (TAM). Furthermore, the overexpression of CAIX was observed in intracranial GBM cells. Additionally, epidermal growth factor receptor/signal transducer and activator of transcription 3 regulated CAIX expression under hypoxic conditions by affecting the stability of hypoxia-inducible factor 1α. In contrast, the knockdown of CAIX dramatically abrogated the change in GBM motility and monocyte adhesion to GBM under hypoxic conditions. Our results provide a comprehensive understanding of the mechanisms of CAIX in the GBM microenvironment. Hence, novel therapeutic targets of GBM progression are possibly developed.

scholarly journals Monocarboxylate Transporter 4 Regulates Glioblastoma Motility and Monocyte Binding Ability

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 380 ◽  
Author(s):  
Sheng-Wei Lai ◽  
Hui-Jung Lin ◽  
Yu-Shu Liu ◽  
Liang-Yo Yang ◽  
Dah-Yuu Lu
Keyword(s):  
Cell Motility ◽  
Hypoxia Inducible Factor ◽  
Growth Factor Receptor ◽  
Specific Protein ◽  
Monocarboxylate Transporter ◽  
Monocyte Adhesion ◽  
Ph Homeostasis ◽  
Hypoxic Conditions ◽  
Patient Database ◽  
Novel Therapeutic Strategies

Glioblastoma (GBM) is characterized by severe hypoxic and acidic stress in an abnormal microenvironment. Monocarboxylate transporter (MCT)4, a pH-regulating protein, plays an important role in pH homeostasis of the glycolytic metabolic pathways in cancer cells. The present study showed that GBM exposure to hypoxic conditions increased MCT4 expression. We further analyzed the glioma patient database and found that MCT4 was significantly overexpressed in patients with GBM, and the MCT4 levels positively correlated with the clinico-pathological grades of gliomas. We further found that MCT4 knockdown abolished the hypoxia-enhanced of GBM cell motility and monocyte adhesion. However, the overexpression of MCT4 promoted GBM cell migration and monocyte adhesion activity. Our results also revealed that MCT4-regulated GBM cell motility and monocyte adhesion are mediated by activation of the serine/threonine-specific protein kinase (AKT), focal adhesion kinase (FAK), and epidermal growth factor receptor (EGFR) signaling pathways. Moreover, hypoxia mediated the acetylated signal transducer and activator of transcription (STAT)3 expression and regulated the transcriptional activity of hypoxia inducible factor (HIF)-1α in GBM cell lines. In a GBM mouse model, MCT4 was significantly increased in the tumor necrotic tissues. These findings raise the possibility for the development of novel therapeutic strategies targeting MCT4.

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