肝素结合型 EGF 样生长因子通过 miR-126 控制小鼠结直肠癌和结肠炎相关癌症模型中肿瘤的形成/生长和蛋白水解龛。

IF 8.1 1区 生物学 Q1 CELL BIOLOGY
Yousef Salama, Shinya Munakata, Taro Osada, Satoshi Takahashi, Koichi Hattori, Beate Heissig
{"title":"肝素结合型 EGF 样生长因子通过 miR-126 控制小鼠结直肠癌和结肠炎相关癌症模型中肿瘤的形成/生长和蛋白水解龛。","authors":"Yousef Salama, Shinya Munakata, Taro Osada, Satoshi Takahashi, Koichi Hattori, Beate Heissig","doi":"10.1038/s41419-024-07126-2","DOIUrl":null,"url":null,"abstract":"<p><p>MicroRNAs, including the tumor-suppressor miR-126 and the oncogene miR-221, regulate tumor formation and growth in colitis-associated cancer (CAC) and colorectal cancer (CRC). This study explores the impact of the epithelial cytokine heparin-binding epidermal growth factor (HB-EGF) and its receptor epidermal growth factor receptor (EGFR) on the pathogenesis of CAC and CRC, particularly in the regulation of microRNA-driven tumor growth and protease expression. In murine models of CRC and CAC, lack of miR-126 and elevated miR-221 expression in colonic tissues enhanced tumor formation and growth. MiR-126 downregulation in colon cells established a pro-tumorigenic proteolytic niche by targeting HB-EGF-active metalloproteinase-7, -9 (MMP7/MMP9), disintegrin, and metalloproteinase domain-containing protein 9, and modulating chemokine-mediated recruitment of HB-EGF-loaded inflammatory cells. Mechanistically, downregulation of HB-EGF and EGFR in the colon suppressed miR-221 and enhanced miR-126 expression via activating enhancer-binding protein 2 alpha. Reintroducing miR-126 reduced tumor development and HB-EGF expression. Combining miR-126 reintroduction, which targets specific HB-EGF-active proteases but not ADAM17, with MMP inhibitors like Batimastat or Marimastat effectively suppressed tumor growth. This combination normalized protease expression and balanced miR-126 and miR-221 levels in developing and growing tumors. These findings demonstrate that suppressing HB-EGF and EGFR1 shifts the balance from oncogenic miR-221 to tumor-suppressive miR-126 action. Consequently, normalizing miR-126 expression could open new avenues for treating patients with CAC and CRC, and this normalization is intertwined with the anticancer efficacy of MMP inhibitors.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":null,"pages":null},"PeriodicalIF":8.1000,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11487245/pdf/","citationCount":"0","resultStr":"{\"title\":\"Heparin-binding EGF-like growth factor via miR-126 controls tumor formation/growth and the proteolytic niche in murine models of colorectal and colitis-associated cancers.\",\"authors\":\"Yousef Salama, Shinya Munakata, Taro Osada, Satoshi Takahashi, Koichi Hattori, Beate Heissig\",\"doi\":\"10.1038/s41419-024-07126-2\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>MicroRNAs, including the tumor-suppressor miR-126 and the oncogene miR-221, regulate tumor formation and growth in colitis-associated cancer (CAC) and colorectal cancer (CRC). This study explores the impact of the epithelial cytokine heparin-binding epidermal growth factor (HB-EGF) and its receptor epidermal growth factor receptor (EGFR) on the pathogenesis of CAC and CRC, particularly in the regulation of microRNA-driven tumor growth and protease expression. In murine models of CRC and CAC, lack of miR-126 and elevated miR-221 expression in colonic tissues enhanced tumor formation and growth. MiR-126 downregulation in colon cells established a pro-tumorigenic proteolytic niche by targeting HB-EGF-active metalloproteinase-7, -9 (MMP7/MMP9), disintegrin, and metalloproteinase domain-containing protein 9, and modulating chemokine-mediated recruitment of HB-EGF-loaded inflammatory cells. Mechanistically, downregulation of HB-EGF and EGFR in the colon suppressed miR-221 and enhanced miR-126 expression via activating enhancer-binding protein 2 alpha. Reintroducing miR-126 reduced tumor development and HB-EGF expression. Combining miR-126 reintroduction, which targets specific HB-EGF-active proteases but not ADAM17, with MMP inhibitors like Batimastat or Marimastat effectively suppressed tumor growth. This combination normalized protease expression and balanced miR-126 and miR-221 levels in developing and growing tumors. These findings demonstrate that suppressing HB-EGF and EGFR1 shifts the balance from oncogenic miR-221 to tumor-suppressive miR-126 action. Consequently, normalizing miR-126 expression could open new avenues for treating patients with CAC and CRC, and this normalization is intertwined with the anticancer efficacy of MMP inhibitors.</p>\",\"PeriodicalId\":9734,\"journal\":{\"name\":\"Cell Death & Disease\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":8.1000,\"publicationDate\":\"2024-10-17\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11487245/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cell Death & Disease\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1038/s41419-024-07126-2\",\"RegionNum\":1,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell Death & Disease","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1038/s41419-024-07126-2","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0

摘要

包括肿瘤抑制因子miR-126和致癌基因miR-221在内的微RNA调控结肠炎相关癌(CAC)和结直肠癌(CRC)中肿瘤的形成和生长。本研究探讨了上皮细胞因子肝素结合表皮生长因子(HB-EGF)及其受体表皮生长因子受体(EGFR)对 CAC 和 CRC 发病机制的影响,尤其是对微 RNA 驱动的肿瘤生长和蛋白酶表达的调控。在小鼠 CRC 和 CAC 模型中,结肠组织中 miR-126 的缺乏和 miR-221 表达的升高会促进肿瘤的形成和生长。通过靶向 HB-EGF-活性金属蛋白酶-7、-9(MMP7/MMP9)、崩解素和含金属蛋白酶结构域的蛋白 9,以及调节趋化因子介导的 HB-EGF-loaded 炎症细胞的招募,下调结肠细胞中的 miR-126 建立了一个有利于肿瘤的蛋白水解生态位。从机理上讲,下调结肠中的 HB-EGF 和表皮生长因子受体抑制了 miR-221 的表达,并通过激活增强子结合蛋白 2 alpha 增强了 miR-126 的表达。重新引入 miR-126 可减少肿瘤的发展和 HB-EGF 的表达。miR-126靶向特定的HB-EGF活性蛋白酶,但不靶向ADAM17,重新引入miR-126与MMP抑制剂(如Batimastat或Marimastat)相结合可有效抑制肿瘤生长。这种组合可使蛋白酶表达正常化,并平衡发育中和生长中肿瘤的 miR-126 和 miR-221 水平。这些研究结果表明,抑制 HB-EGF 和表皮生长因子受体 (EGFR1) 会将致癌的 miR-221 作用平衡转移到抑制肿瘤的 miR-126 作用上。因此,miR-126表达的正常化可为治疗CAC和CRC患者开辟新的途径,而这种正常化与MMP抑制剂的抗癌功效息息相关。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Heparin-binding EGF-like growth factor via miR-126 controls tumor formation/growth and the proteolytic niche in murine models of colorectal and colitis-associated cancers.

MicroRNAs, including the tumor-suppressor miR-126 and the oncogene miR-221, regulate tumor formation and growth in colitis-associated cancer (CAC) and colorectal cancer (CRC). This study explores the impact of the epithelial cytokine heparin-binding epidermal growth factor (HB-EGF) and its receptor epidermal growth factor receptor (EGFR) on the pathogenesis of CAC and CRC, particularly in the regulation of microRNA-driven tumor growth and protease expression. In murine models of CRC and CAC, lack of miR-126 and elevated miR-221 expression in colonic tissues enhanced tumor formation and growth. MiR-126 downregulation in colon cells established a pro-tumorigenic proteolytic niche by targeting HB-EGF-active metalloproteinase-7, -9 (MMP7/MMP9), disintegrin, and metalloproteinase domain-containing protein 9, and modulating chemokine-mediated recruitment of HB-EGF-loaded inflammatory cells. Mechanistically, downregulation of HB-EGF and EGFR in the colon suppressed miR-221 and enhanced miR-126 expression via activating enhancer-binding protein 2 alpha. Reintroducing miR-126 reduced tumor development and HB-EGF expression. Combining miR-126 reintroduction, which targets specific HB-EGF-active proteases but not ADAM17, with MMP inhibitors like Batimastat or Marimastat effectively suppressed tumor growth. This combination normalized protease expression and balanced miR-126 and miR-221 levels in developing and growing tumors. These findings demonstrate that suppressing HB-EGF and EGFR1 shifts the balance from oncogenic miR-221 to tumor-suppressive miR-126 action. Consequently, normalizing miR-126 expression could open new avenues for treating patients with CAC and CRC, and this normalization is intertwined with the anticancer efficacy of MMP inhibitors.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Cell Death & Disease
Cell Death & Disease CELL BIOLOGY-
CiteScore
15.10
自引率
2.20%
发文量
935
审稿时长
2 months
期刊介绍: Brought to readers by the editorial team of Cell Death & Differentiation, Cell Death & Disease is an online peer-reviewed journal specializing in translational cell death research. It covers a wide range of topics in experimental and internal medicine, including cancer, immunity, neuroscience, and now cancer metabolism. Cell Death & Disease seeks to encompass the breadth of translational implications of cell death, and topics of particular concentration will include, but are not limited to, the following: Experimental medicine Cancer Immunity Internal medicine Neuroscience Cancer metabolism
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信