The MIR181A2HG/miR-5680/VCAN-CD44 Axis Regulates Gastric Cancer Lymph Node Metastasis by Promoting M2 Macrophage Polarization

IF 2.9 2区医学 Q2 ONCOLOGY

Cancer Medicine Pub Date : 2025-01-16 DOI:10.1002/cam4.70600

Weijie Zang, Yongpu Yang, Junjie Chen, Qinsheng Mao, Wanjiang Xue, Yilin Hu

{"title":"The MIR181A2HG/miR-5680/VCAN-CD44 Axis Regulates Gastric Cancer Lymph Node Metastasis by Promoting M2 Macrophage Polarization","authors":"Weijie Zang, Yongpu Yang, Junjie Chen, Qinsheng Mao, Wanjiang Xue, Yilin Hu","doi":"10.1002/cam4.70600","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Background</h3>\n \n <p>Lymphatic metastasis in gastric cancer (GC) profoundly influences its prognosis, but the precise mechanism remains elusive. In this study, we identified the long noncoding RNA MIR181A2HG as being upregulated in GC and associated with LNs metastasis and prognosis.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>The expression of MIR181A2HG in GC was identified through bioinformatics screening analysis and qRT-PCR validation. Both in vitro and in vivo functional studies revealed that MIR181A2HG facilitates lymphangiogenesis and lymphatic metastasis. Techniques such as immunofluorescence, immunohistochemistry, qRT-PCR, ELISA, CHIP, RNA-pulldown, luciferase reporter assay, and Co-IP were employed to investigate the mechanism of MIR181A2HG in LNs metastasis of GC.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>MIR181A2HG overexpressed in GC signifies an unfavorable prognosis and drives M2 polarization of TAMs enhancing lymphangiogenesis. Mechanistically, MIR181A2HG/miR-5680 axis as a novel ceRNA regulatory axis to upregulate versican (VCAN). On one hand, VCAN interacts with CD44 receptors on the surface of TAMs through paracrine secretion, promoting M2 macrophage polarization and subsequently enhancing the secretion of VEGF-C, ultimately facilitating lymphangiogenesis. On the other hand, VCAN binds to CD44 receptors on the surface of GC cells through autocrine secretion, activating the Hippo pathway and upregulating SP1, thereby promoting the transcription of MIR181A2HG and establishing a feedback loop driving lymphatic metastasis.</p>\n </section>\n \n <section>\n \n <h3> Conclusion</h3>\n \n <p>This study highlights the pivotal role of MIR181A2HG in GC progression and LNs metastasis. MIR181A2HG-based targeted therapy would represent a novel strategy for GC.</p>\n </section>\n </div>","PeriodicalId":139,"journal":{"name":"Cancer Medicine","volume":"14 2","pages":""},"PeriodicalIF":2.9000,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11739459/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer Medicine","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/cam4.70600","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"ONCOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Background

Lymphatic metastasis in gastric cancer (GC) profoundly influences its prognosis, but the precise mechanism remains elusive. In this study, we identified the long noncoding RNA MIR181A2HG as being upregulated in GC and associated with LNs metastasis and prognosis.

Methods

The expression of MIR181A2HG in GC was identified through bioinformatics screening analysis and qRT-PCR validation. Both in vitro and in vivo functional studies revealed that MIR181A2HG facilitates lymphangiogenesis and lymphatic metastasis. Techniques such as immunofluorescence, immunohistochemistry, qRT-PCR, ELISA, CHIP, RNA-pulldown, luciferase reporter assay, and Co-IP were employed to investigate the mechanism of MIR181A2HG in LNs metastasis of GC.

Results

MIR181A2HG overexpressed in GC signifies an unfavorable prognosis and drives M2 polarization of TAMs enhancing lymphangiogenesis. Mechanistically, MIR181A2HG/miR-5680 axis as a novel ceRNA regulatory axis to upregulate versican (VCAN). On one hand, VCAN interacts with CD44 receptors on the surface of TAMs through paracrine secretion, promoting M2 macrophage polarization and subsequently enhancing the secretion of VEGF-C, ultimately facilitating lymphangiogenesis. On the other hand, VCAN binds to CD44 receptors on the surface of GC cells through autocrine secretion, activating the Hippo pathway and upregulating SP1, thereby promoting the transcription of MIR181A2HG and establishing a feedback loop driving lymphatic metastasis.

Conclusion

This study highlights the pivotal role of MIR181A2HG in GC progression and LNs metastasis. MIR181A2HG-based targeted therapy would represent a novel strategy for GC.

查看原文本刊更多论文

MIR181A2HG/miR-5680/VCAN-CD44轴通过促进M2巨噬细胞极化调控胃癌淋巴结转移。

背景：胃癌的淋巴转移严重影响其预后，但其确切机制尚不清楚。在本研究中，我们发现长链非编码RNA MIR181A2HG在胃癌中表达上调，并与LNs转移和预后相关。方法：通过生物信息学筛选分析和qRT-PCR验证，鉴定MIR181A2HG在GC中的表达。体外和体内功能研究表明，MIR181A2HG促进淋巴管生成和淋巴转移。采用免疫荧光、免疫组织化学、qRT-PCR、ELISA、CHIP、rna -pull - down、荧光素酶报告基因法、Co-IP等技术探讨MIR181A2HG在胃癌LNs转移中的作用机制。结果：MIR181A2HG在GC中过表达预示预后不良，并驱动tam的M2极化，增强淋巴管生成。在机制上，MIR181A2HG/miR-5680轴作为一个新的ceRNA调控轴上调versican （VCAN）。一方面，VCAN通过旁分泌与tam表面的CD44受体相互作用，促进M2巨噬细胞极化，进而增强VEGF-C的分泌，最终促进淋巴管生成。另一方面，VCAN通过自分泌与GC细胞表面的CD44受体结合，激活Hippo通路，上调SP1，从而促进MIR181A2HG的转录，建立驱动淋巴转移的反馈回路。结论：本研究突出了MIR181A2HG在胃癌进展和LNs转移中的关键作用。基于mir181a2hg的靶向治疗将代表一种新的GC治疗策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Cancer Medicine ONCOLOGY-

CiteScore

5.50

自引率

2.50%

发文量

907

审稿时长

19 weeks

期刊介绍： Cancer Medicine is a peer-reviewed, open access, interdisciplinary journal providing rapid publication of research from global biomedical researchers across the cancer sciences. The journal will consider submissions from all oncologic specialties, including, but not limited to, the following areas: Clinical Cancer Research Translational research ∙ clinical trials ∙ chemotherapy ∙ radiation therapy ∙ surgical therapy ∙ clinical observations ∙ clinical guidelines ∙ genetic consultation ∙ ethical considerations Cancer Biology: Molecular biology ∙ cellular biology ∙ molecular genetics ∙ genomics ∙ immunology ∙ epigenetics ∙ metabolic studies ∙ proteomics ∙ cytopathology ∙ carcinogenesis ∙ drug discovery and delivery. Cancer Prevention: Behavioral science ∙ psychosocial studies ∙ screening ∙ nutrition ∙ epidemiology and prevention ∙ community outreach. Bioinformatics: Gene expressions profiles ∙ gene regulation networks ∙ genome bioinformatics ∙ pathwayanalysis ∙ prognostic biomarkers. Cancer Medicine publishes original research articles, systematic reviews, meta-analyses, and research methods papers, along with invited editorials and commentaries. Original research papers must report well-conducted research with conclusions supported by the data presented in the paper.