Scholarlink

Background <p>The tumor microenvironment of oral squamous cell carcinoma (OSCC) is shaped by complex metabolite-mediated cell-cell communication (mCCC), the functional role of which remains incompletely understood. This study aimed to identify key mCCC pathways in OSCC and elucidate the mechanisms by which tumor cells respond to these metabolic signals.</p> Methods <p>Single-cell RNA sequencing data from the Gene Expression Omnibus (GEO) database were analyzed using the Metabolite-mediated cell communication modeling by single-cell transcriptome algorithm to identify mCCC events. High-dimensional weighted gene co-expression network analysis (hdWGCNA), in combination with the Mime algorithm, was employed to construct prognostic models and screen for core genes. Enhancer regions were identified by analyzing histone H3 lysine 27 acetylation (H3K27ac) chromatin immunoprecipitation sequencing data from the GEO database. Chromatin immunoprecipitation-quantitative PCR was performed to validate H3K27ac and transcription factor enrichment at these enhancers. M2 macrophages were cultured under glutamine-deprived conditions to generate conditioned medium. OSCC cells treated with L-methionine-DL-sulfoximine were cultured in M2 macrophage-derived conditioned medium, and cell proliferation and invasion were assessed using Cell Counting Kit-8 and Transwell assays.</p> Results <p>Glutamine secretion from M2 macrophages to tumor cells, mediated by SLC38A5, was identified as the core mCCC pathway upregulated in metastatic OSCC lesions. Knockdown of SLC38A5 significantly inhibited the uptake of M2 macrophage-derived glutamine by OSCC cells, thereby suppressing their proliferation and invasion. CNIH4 was identified as a key effector mediating the response of OSCC cells to M2 macrophage-derived glutamine. Mechanistically, the transcriptional activation of <i>CNIH4</i> was driven by the direct binding of the transcription factor FOXM1 to its enhancer. Notably, M2 macrophage-derived glutamine upregulated the activity of the <i>CNIH4</i> enhancer and promoted FOXM1 recruitment in a coordinated manner. Overexpression of CNIH4 rescued the impaired proliferation and invasion induced by FOXM1 knockdown, an effect dependent on the uptake of M2 macrophage-derived glutamine.</p> Conclusions <p>In the OSCC microenvironment, glutamine derived from M2 macrophages is taken up by tumor cells through SLC38A5. This process enhances FOXM1 binding to the <i>CNIH4</i> enhancer, thereby activating <i>CNIH4</i> expression and promoting OSCC cell proliferation and invasion. Targeting the glutamine/SLC38A5/FOXM1/CNIH4 axis may offer a rational strategy for mCCC-based precision therapy.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Glutamine-mediated crosstalk between M2 macrophages and tumor cells via the SLC38A5/FOXM1/CNIH4 axis promotes oral squamous cell carcinoma progression

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月19日

查看全文
  • Yuanhang Liu,
  • Jie Guo,
  • Hui Xu,
  • Xiaoxue Xu,
  • Xinxin Jin,
  • Yahong Zhang,
  • Yongle Qiu

摘要

Background

The tumor microenvironment of oral squamous cell carcinoma (OSCC) is shaped by complex metabolite-mediated cell-cell communication (mCCC), the functional role of which remains incompletely understood. This study aimed to identify key mCCC pathways in OSCC and elucidate the mechanisms by which tumor cells respond to these metabolic signals.

Methods

Single-cell RNA sequencing data from the Gene Expression Omnibus (GEO) database were analyzed using the Metabolite-mediated cell communication modeling by single-cell transcriptome algorithm to identify mCCC events. High-dimensional weighted gene co-expression network analysis (hdWGCNA), in combination with the Mime algorithm, was employed to construct prognostic models and screen for core genes. Enhancer regions were identified by analyzing histone H3 lysine 27 acetylation (H3K27ac) chromatin immunoprecipitation sequencing data from the GEO database. Chromatin immunoprecipitation-quantitative PCR was performed to validate H3K27ac and transcription factor enrichment at these enhancers. M2 macrophages were cultured under glutamine-deprived conditions to generate conditioned medium. OSCC cells treated with L-methionine-DL-sulfoximine were cultured in M2 macrophage-derived conditioned medium, and cell proliferation and invasion were assessed using Cell Counting Kit-8 and Transwell assays.

Results

Glutamine secretion from M2 macrophages to tumor cells, mediated by SLC38A5, was identified as the core mCCC pathway upregulated in metastatic OSCC lesions. Knockdown of SLC38A5 significantly inhibited the uptake of M2 macrophage-derived glutamine by OSCC cells, thereby suppressing their proliferation and invasion. CNIH4 was identified as a key effector mediating the response of OSCC cells to M2 macrophage-derived glutamine. Mechanistically, the transcriptional activation of CNIH4 was driven by the direct binding of the transcription factor FOXM1 to its enhancer. Notably, M2 macrophage-derived glutamine upregulated the activity of the CNIH4 enhancer and promoted FOXM1 recruitment in a coordinated manner. Overexpression of CNIH4 rescued the impaired proliferation and invasion induced by FOXM1 knockdown, an effect dependent on the uptake of M2 macrophage-derived glutamine.

Conclusions

In the OSCC microenvironment, glutamine derived from M2 macrophages is taken up by tumor cells through SLC38A5. This process enhances FOXM1 binding to the CNIH4 enhancer, thereby activating CNIH4 expression and promoting OSCC cell proliferation and invasion. Targeting the glutamine/SLC38A5/FOXM1/CNIH4 axis may offer a rational strategy for mCCC-based precision therapy.