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
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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.

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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
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