KCNE3 Facilitates M1 Macrophage Polarization by Suppressing the Wnt/β-Catenin Pathway, Inhibiting Glioma Proliferation, Migration, and Invasion.

in Molecular carcinogenesis by Shangyu Liu, Qiao Li, Liang Niu, Peng Feng, Wenshan Li, Ying Dang, Juan Jia, Guoqiang Yuan, Yawen Pan

TLDR

  • This study reveals that suppressing KCNE3 can enhance antitumor responses in glioma by reprogramming TAMs to an M1 phenotype, offering a novel therapeutic strategy for glioma treatment.

Abstract

The glioma microenvironment is critical for tumor growth, where reprogramming M2-polarized tumor-associated macrophages/microglia (TAMs) to an antitumor M1 phenotype represents a promising therapeutic strategy. While the potassium channel regulatory subunit KCNE3 has been implicated in tumorigenesis across malignancies, its functional role in shaping the glioma microenvironment remains undefined. Here, we leveraged transcriptome data from the Gene Expression Omnibus (GEO) to identify KCNE3 as a TAM-enriched gene in gliomas. To interrogate its mechanistic contributions, we generated KCNE3-knockdown and overexpressing macrophages and evaluated their impact on glioma cells in coculture systems. Silencing KCNE3 in macrophages significantly attenuated glioma cell proliferation, migration, and invasion in vitro, accompanied by enhanced M1 polarization. Mechanistically, KCNE3 depletion suppressed Wnt/β-catenin signaling, driving increased secretion of pro-inflammatory cytokines TNF-α, IL-6, and IL-12. Conversely, KCNE3 overexpression reversed these effects, promoting M2-like characteristics and tumor-supportive behaviors. These findings establish KCNE3 as a key modulator of TAM phenotype and glioma progression, suggesting that targeted KCNE3 inhibition may disarm pro-tumorigenic immune responses to improve therapeutic outcomes. This study uncovers a novel actionable method in glioma immunotherapy.

Overview

  • The study investigates the role of potassium channel regulatory subunit KCNE3 in shaping the glioma microenvironment and its potential impact on glioma growth and progression.
  • The researchers used transcriptome data from the Gene Expression Omnibus (GEO) to identify KCNE3 as a TAM-enriched gene in gliomas and generated KCNE3-knockdown and overexpressing macrophages.
  • The primary objective is to understand the mechanistic contributions of KCNE3 in TAM phenotype and glioma progression, and its potential as a therapeutic target in glioma immunotherapy.

Comparative Analysis & Findings

  • Silencing KCNE3 in macrophages significantly attenuated glioma cell proliferation, migration, and invasion in vitro, accompanied by enhanced M1 polarization.
  • KCNE3 depletion suppressed Wnt/β-catenin signaling, driving increased secretion of pro-inflammatory cytokines TNF-α, IL-6, and IL-12.
  • Conversely, KCNE3 overexpression reversed these effects, promoting M2-like characteristics and tumor-supportive behaviors.

Implications and Future Directions

  • The study establishes KCNE3 as a key modulator of TAM phenotype and glioma progression, suggesting that targeted KCNE3 inhibition may disarm pro-tumorigenic immune responses to improve therapeutic outcomes.
  • Future research directions may include exploring the efficacy of KCNE3-targeted therapies in combination with other immunotherapies for glioma treatment.
  • Understanding the optimal timing and duration of KCNE3-targeted therapies in glioma treatment regimens will be crucial for optimal patient outcomes.
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