LINC00665 promotes the progression and immune evasion of lung cancer by facilitating the translation of TCF7 protein through dependence on IRES.

IF 5.3 2区医学 Q1 ONCOLOGY Cancer Cell International Pub Date : 2024-06-29 DOI:10.1186/s12935-024-03411-4

Chaonan Han, Jinchen Su, Yue Pei, Xiangyu Su, Di Zheng

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Abstract

Objective: To investigate the influence of LINC00665 on the development and immune evasion of lung cancer.

Methods: Tumor tissues and corresponding adjacent tissues were collected from 84 lung cancer patients, categorized into non-metastatic (n = 58) and metastatic (n = 26) groups. LINC00665 expression in lung cancer and metastatic lung cancer tissues was assessed via qRT-PCR. Pearson correlation analysis was conducted to examine the correlation between LINC00665 and immune-modulating cytokines (TGF-β, IL-10, IL-1β, IFN-γ, IL-2, TNF-α). A549 and H1299 cells, with relatively high LINC00665 expression, were used for in vitro studies. Cells were transfected with LINC00665-targeting shRNA, and changes in proliferation, apoptosis, migration, invasion, and NK cell cytotoxicity were assessed. Downstream molecular mechanisms of LINC00665 were investigated using GEO database analysis, highlighting the association with HHLA2. LINC00665's role in promoting HHLA2 expression via binding with TCF7 was explored. In low LINC00665-expressing A549/H1299 cells, overexpression of HHLA2 was performed to evaluate effects on malignant behavior and NK cell sensitivity. A xenograft model was established for in vivo validation through tumor volume and weight measurements, Ki-67 immunoreactivity analysis, and flow cytometry analysis of CD107a + NK cells.

Results: LINC00665, TCF7 mRNA, and HHLA2 mRNA expression levels were significantly higher in lung cancer tissues than adjacent tissues, with non-metastatic lung cancer showing higher expression than metastatic lung cancer. In metastatic lung cancer, LINC00665 positively correlated with immune-suppressive cytokines (TGF-β, IL-10, IL-1β) and negatively correlated with anti-tumor cytokines (IFN-γ, IL-2, TNF-α). LINC00665 knockdown significantly inhibited lung cancer cell growth and metastasis, promoting sensitivity to NK cells. Further analysis revealed that LINC00665 recruits transcription factor TCF7 to upregulate HHLA2 expression in lung cancer cells, thereby facilitating lung cancer development and immune escape.

Conclusion: LINC00665, through recruitment of TCF7 and upregulation of HHLA2, inhibits NK cell cytotoxicity, promoting the development and immune evasion of lung cancer.

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LINC00665 通过依赖 IRES 促进 TCF7 蛋白的翻译，从而促进肺癌的进展和免疫逃避。

目的：研究LINC00665对肺癌发生和免疫逃避的影响：研究 LINC00665 对肺癌发病和免疫逃避的影响：收集84例肺癌患者的肿瘤组织和相应的邻近组织，分为非转移组（58例）和转移组（26例）。通过 qRT-PCR 评估 LINC00665 在肺癌和转移性肺癌组织中的表达。对 LINC00665 和免疫调节细胞因子（TGF-β、IL-10、IL-1β、IFN-γ、IL-2、TNF-α）之间的相关性进行了皮尔逊相关分析。体外研究使用了 LINC00665 表达相对较高的 A549 和 H1299 细胞。用 LINC00665 靶向 shRNA 转染细胞，评估细胞增殖、凋亡、迁移、侵袭和 NK 细胞毒性的变化。利用 GEO 数据库分析研究了 LINC00665 的下游分子机制，突出了它与 HHLA2 的关联。研究还探讨了 LINC00665 通过与 TCF7 结合促进 HHLA2 表达的作用。在低LINC00665表达的A549/H1299细胞中过表达HHLA2，以评估其对恶性行为和NK细胞敏感性的影响。通过肿瘤体积和重量测量、Ki-67 免疫反应分析以及 CD107a + NK 细胞的流式细胞术分析，建立了异种移植模型进行体内验证：结果：LINC00665、TCF7 mRNA和HHLA2 mRNA在肺癌组织中的表达水平明显高于邻近组织，其中非转移性肺癌的表达水平高于转移性肺癌。在转移性肺癌中，LINC00665 与免疫抑制细胞因子（TGF-β、IL-10、IL-1β）呈正相关，而与抗肿瘤细胞因子（IFN-γ、IL-2、TNF-α）呈负相关。LINC00665 基因敲除能显著抑制肺癌细胞的生长和转移，提高对 NK 细胞的敏感性。进一步的分析表明，LINC00665能招募转录因子TCF7上调肺癌细胞中HHLA2的表达，从而促进肺癌的发展和免疫逃逸：结论：LINC00665通过招募TCF7和上调HHLA2抑制NK细胞的细胞毒性，促进肺癌的发展和免疫逃逸。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer Cell International ONCOLOGY-

CiteScore

10.90

自引率

1.70%

发文量

360

审稿时长

1 months

期刊介绍： Cancer Cell International publishes articles on all aspects of cancer cell biology, originating largely from, but not limited to, work using cell culture techniques. The journal focuses on novel cancer studies reporting data from biological experiments performed on cells grown in vitro, in two- or three-dimensional systems, and/or in vivo (animal experiments). These types of experiments have provided crucial data in many fields, from cell proliferation and transformation, to epithelial-mesenchymal interaction, to apoptosis, and host immune response to tumors. Cancer Cell International also considers articles that focus on novel technologies or novel pathways in molecular analysis and on epidemiological studies that may affect patient care, as well as articles reporting translational cancer research studies where in vitro discoveries are bridged to the clinic. As such, the journal is interested in laboratory and animal studies reporting on novel biomarkers of tumor progression and response to therapy and on their applicability to human cancers.