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

• Published in: International journal of molecular sciences 2020-08, Vol.21 (16), p.5838
• Main Authors: Huang, Bor-Ren, Liu, Yu-Shu, Lai, Sheng-Wei, Lin, Hui-Jung, Shen, Ching-Kai, Yang, Liang-Yo, Lu, Dah-Yuu
• Format: Article
• Language: English
• Subjects: Acidosis; Acids; Adhesion; Brain cancer; Brain Neoplasms - enzymology; Brain Neoplasms - pathology; Breast cancer; CAIX (carbonic anhydrase IX); Cancer therapies; Carbon dioxide; Carbonic Anhydrase IX - metabolism; Cell Adhesion; Cell growth; Cell Line, Tumor; Cell Movement; Cell Polarity; Chemotherapy; Cytotoxicity; Datasets; Epidermal growth factor; Epidermal growth factor receptors; ErbB Receptors - metabolism; GBM (glioblastoma multiforme); Gene expression; Glioblastoma; Glioblastoma - enzymology; Glioblastoma - pathology; Growth factors; Humans; Hydrogen-Ion Concentration; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Hypoxia-inducible factor 1a; Hypoxia-inducible factors; hypoxic condition; Kinases; M2 polarization; Macrophages; Medical prognosis; Metabolism; Metabolites; Monocytes; Monocytes - pathology; Motility; Pancreatic cancer; Physiology; Polarization; Protein expression; Proteins; Regulatory proteins; Stat3 protein; STAT3 Transcription Factor - metabolism; Transcription; Tumor Hypoxia; Tumor Microenvironment; Tumor-Associated Macrophages - enzymology; Tumor-Associated Macrophages - pathology; Tumors; Vascular endothelial growth factor
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21165838

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.