LINC00330/CCL2 轴介导的 ESCC TAM 重编程影响肿瘤进展。
LINC00330/CCL2 axis-mediated ESCC TAM reprogramming affects tumor progression.
机构信息
Henan Key Laboratory of Immunology and Targeted Drugs, Xinxiang Key Laboratory of Tumor Microenvironment and Immunotherapy, School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan, China.
State Key Laboratory of Liver Research, Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
出版信息
Cell Mol Biol Lett. 2024 May 20;29(1):77. doi: 10.1186/s11658-024-00592-8.
BACKGROUND
Tumor-associated macrophages (TAMs) significantly influence the progression, metastasis, and recurrence of esophageal squamous cell carcinoma (ESCC). The aberrant expression of long noncoding RNAs (lncRNAs) in ESCC has been established, yet the role of lncRNAs in TAM reprogramming during ESCC progression remains largely unexplored.
METHODS
ESCC TAM-related lncRNAs were identified by intersecting differentially expressed lncRNAs with immune-related lncRNAs and performing immune cell infiltration analysis. The expression profile and clinical relevance of LINC00330 were examined using the TCGA database and clinical samples. The LINC00330 overexpression and interference sequences were constructed to evaluate the effect of LINC00330 on ESCC progression. Single-cell sequencing data, CIBERSORTx, and GEPIA were utilized to analyze immune cell infiltration within the ESCC tumor microenvironment and to assess the correlation between LINC00330 and TAM infiltration. ESCC-macrophage coculture experiments were conducted to investigate the influence of LINC00330 on TAM reprogramming and its subsequent effect on ESCC progression. The interaction between LINC00330 and C-C motif ligand 2 (CCL2) was confirmed through transcriptomic sequencing, subcellular localization analysis, RNA pulldown, silver staining, RNA immunoprecipitation, and other experiments.
RESULTS
LINC00330 is significantly downregulated in ESCC tissues and strongly associated with poor patient outcomes. Overexpression of LINC00330 inhibits ESCC progression, including proliferation, invasion, epithelial-mesenchymal transition, and tumorigenicity in vivo. LINC00330 promotes TAM reprogramming, and LINC00330-mediated TAM reprogramming inhibits ESCC progression. LINC00330 binds to the CCL2 protein and inhibits the expression of CCL2 and downstream signaling pathways. CCL2 is critical for LINC00330-mediated TAM reprogramming and ESCC progression.
CONCLUSIONS
LINC00330 inhibited ESCC progression by disrupting the CCL2/CCR2 axis and its downstream signaling pathways in an autocrine fashion; and by impeding CCL2-mediated TAM reprogramming in a paracrine manner. The new mechanism of TAM reprogramming mediated by the LINC00330/CCL2 axis may provide potential strategies for targeted and immunocombination therapies for patients with ESCC.
背景
肿瘤相关巨噬细胞（TAMs）显著影响食管鳞状细胞癌（ESCC）的进展、转移和复发。已经证实长链非编码 RNA（lncRNAs）在 ESCC 中的异常表达，但 lncRNAs 在 ESCC 进展过程中对 TAM 重编程的作用仍在很大程度上未被探索。
方法
通过将差异表达的 lncRNAs 与免疫相关的 lncRNAs 进行交集，并进行免疫细胞浸润分析，鉴定 ESCC TAM 相关 lncRNAs。使用 TCGA 数据库和临床样本检测 LINC00330 的表达谱和临床相关性。构建 LINC00330 过表达和干扰序列，以评估 LINC00330 对 ESCC 进展的影响。利用单细胞测序数据、CIBERSORTx 和 GEPIA 分析 ESCC 肿瘤微环境中的免疫细胞浸润，并评估 LINC00330 与 TAM 浸润的相关性。进行 ESCC-巨噬细胞共培养实验，以研究 LINC00330 对 TAM 重编程的影响及其对 ESCC 进展的后续影响。通过转录组测序、亚细胞定位分析、RNA 下拉、银染、RNA 免疫沉淀等实验证实 LINC00330 与 C-C 基序配体 2（CCL2）之间的相互作用。
结果
LINC00330 在 ESCC 组织中显著下调，与患者预后不良密切相关。过表达 LINC00330 抑制 ESCC 进展，包括体内增殖、侵袭、上皮-间充质转化和致瘤性。LINC00330 促进 TAM 重编程，LINC00330 介导的 TAM 重编程抑制 ESCC 进展。LINC00330 与 CCL2 蛋白结合，抑制 CCL2 及其下游信号通路的表达。CCL2 是 LINC00330 介导的 TAM 重编程和 ESCC 进展所必需的。
结论
LINC00330 通过自分泌方式破坏 CCL2/CCR2 轴及其下游信号通路，以及通过旁分泌方式阻碍 CCL2 介导的 TAM 重编程，从而抑制 ESCC 进展。LINC00330/CCL2 轴介导的 TAM 重编程的新机制可能为 ESCC 患者提供靶向和免疫联合治疗的潜在策略。
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