GNA13 promotes brain metastasis of non-small cell lung cancer and EMT through the WNT/β catenin signaling pathway.

IF 4.6 2区 生物学 Q2 CELL BIOLOGY
Frontiers in Cell and Developmental Biology Pub Date : 2025-09-26 eCollection Date: 2025-01-01 DOI:10.3389/fcell.2025.1652200
Jia-Qi Wu, Han-Peng Zou, Ruo-Yue Fan, Jing Cai, Ping Wei, Ming-Fang He, Jin Xiang
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引用次数: 0

Abstract

Background: Brain metastasis (BM) remains a major challenge in non-small cell lung cancer (NSCLC) treatment, with poorly understood mechanisms.

Methods: A zebrafish xenograft model was established using the H1299 cell line to study NSCLC BM. RNA-Seq identified differentially expressed genes (DEGs) in metastasized to brain vs. non-metastasized cells. Clinical relevance of DEGs was validated using The Cancer Genome Atlas (TCGA) and Kaplan-Meier survival analysis. The anti-proliferation, migration, and invasion effects of GNA13 were also detected using CCK8 assay, scratch wound healing assay, and transwell assay in vitro. The in vivo effects of GNA13 in proliferation and migration were further examined in zebrafish embryos. Additionally, real-time quantitative PCR (RT-qPCR) and Western Blot were performed to validate and explore the underlying molecular mechanisms.

Results: Through comprehensive RNA-Seq analysis of zebrafish xenograft model, we identified 177 DEGs significantly associated with NSCLC BM. KEGG and GO enrichment identified GNA13 as a key mediator in NSCLC BM. Clinical correlation analysis confirmed that GNA13 expression was associated with NSCLC BM and poor prognosis in lung cancer patients. Functional validation revealed that GNA13 knockdown reduced H1299 cell viability, migration, and invasion, whereas overexpression in A549 cells increased viability migration, and invasion in vitro. These in vitro findings were further validated in vivo, where GNA13 overexpression promoted tumor proliferation and metastatic potential. GNA13 was shown to activate the Wnt/β-catenin signaling pathway and induce epithelial-mesenchymal transition (EMT), thereby enhancing the metastatic potential of lung cancer cells.

Conclusion: This study identifies GNA13 as a key gene of lung cancer BM. GNA13 promotes EMT and enhances the proliferation and metastatic capacity of lung cancer cells by activating the Wnt/β-catenin signaling pathway. These findings suggest that GNA13 may serve as a potential therapeutic target for preventing or treating BM in NSCLC.

GNA13通过WNT/β catenin信号通路促进非小细胞肺癌脑转移和EMT。
背景:脑转移(BM)仍然是非小细胞肺癌(NSCLC)治疗的主要挑战,其机制尚不清楚。方法:采用H1299细胞系建立斑马鱼移植瘤模型,研究非小细胞肺癌骨髓转移。RNA-Seq鉴定了脑转移细胞与非转移细胞的差异表达基因(DEGs)。使用癌症基因组图谱(TCGA)和Kaplan-Meier生存分析验证deg的临床相关性。通过CCK8法、抓伤愈合法和transwell法检测GNA13的抗增殖、迁移和侵袭作用。在斑马鱼胚胎中进一步研究了GNA13对增殖和迁移的体内影响。此外,通过实时定量PCR (RT-qPCR)和Western Blot验证和探索潜在的分子机制。结果:通过对斑马鱼异种移植模型的全面RNA-Seq分析,我们鉴定出177个与NSCLC BM显著相关的deg。KEGG和GO富集鉴定了GNA13是NSCLC脑转移的关键介质。临床相关分析证实GNA13表达与肺癌患者NSCLC BM及预后不良相关。功能验证表明,GNA13敲低可降低H1299细胞的活力、迁移和侵袭,而A549细胞的过表达可提高H1299细胞的活力、迁移和侵袭。这些体外研究结果在体内得到进一步验证,其中GNA13过表达促进肿瘤增殖和转移潜力。GNA13可激活Wnt/β-catenin信号通路,诱导上皮-间质转化(epithelial-mesenchymal transition, EMT),从而增强肺癌细胞的转移潜能。结论:本研究确定GNA13是肺癌BM的关键基因。GNA13通过激活Wnt/β-catenin信号通路促进EMT,增强肺癌细胞的增殖和转移能力。这些发现提示GNA13可能作为预防或治疗非小细胞肺癌脑转移的潜在治疗靶点。
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来源期刊
Frontiers in Cell and Developmental Biology
Frontiers in Cell and Developmental Biology Biochemistry, Genetics and Molecular Biology-Cell Biology
CiteScore
9.70
自引率
3.60%
发文量
2531
审稿时长
12 weeks
期刊介绍: Frontiers in Cell and Developmental Biology is a broad-scope, interdisciplinary open-access journal, focusing on the fundamental processes of life, led by Prof Amanda Fisher and supported by a geographically diverse, high-quality editorial board. The journal welcomes submissions on a wide spectrum of cell and developmental biology, covering intracellular and extracellular dynamics, with sections focusing on signaling, adhesion, migration, cell death and survival and membrane trafficking. Additionally, the journal offers sections dedicated to the cutting edge of fundamental and translational research in molecular medicine and stem cell biology. With a collaborative, rigorous and transparent peer-review, the journal produces the highest scientific quality in both fundamental and applied research, and advanced article level metrics measure the real-time impact and influence of each publication.
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