Matrix metalloproteinase 9 implication during colorectal carcinogenesis. Effect of doxycycline

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology Pub Date : 2025-04-24 DOI:10.1111/fcp.70012

Abdelkader Bounaama, Bahia Djerdjouri

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引用次数: 0

Abstract

Background

Matrix metalloproteinases (MMPs), including MMP9, play a significant role in colorectal cancer (CRC) progression, mainly by extracellular matrix remodeling. However, little is known about MMP9 role in aberrant crypt foci (ACF) cluster formation, the earliest colon preneoplastic lesions.

Aims and methods

We conducted a bioinformatics analysis of MMPs expression in CRC using Gene Expression Profiling Interactive Analysis2 (GEPIA2). Subsequently, we investigated MMP9 expression during the early stage of colon carcinogenesis in mice and assessed the effect of doxycycline (DOX), a global inhibitor of MMPs, on ACF cluster formation. Thus, NMRI mice received two weekly injections of 1,2-Dimethylhydrazine (DMH, 20 mg/kg, subcutaneously), followed or not by DOX (100 mg/kg, orally, from the 4th to the 6th week).

Results

GEPIA2 analysis indicated that among the 28 identified MMPs with collagenase and doxycycline-sensitive activities, MMPs 1, 3, 7, 9, and 13 were overexpressed in CRC tissues. Moreover, only MMP1 and MMP9 correlated well with collagen expression in colorectal tumors. In vivo, methylene blue-stained DMH-treated colons revealed multiple ACF clusters at week 6, associated with mucosa remodeling and sustained nitrosative stress as attested by enhanced collagen fibers, malondialdehyde level, and nitrotyrosine deposits. Pyrosequencing showed increased methylation at the tenth CpG site of the MMP9 promoter, which was associated with increased MMP9 expression. Interestingly, DOX attenuated the number and size of ACF clusters and mucosa remodeling without rebalancing nitrosative stress.

Conclusion

Overexpression of MMP9 occurs early during colorectal carcinogenesis, and doxycycline may control the pathological remodeling of colon mucosa into ACF clusters by attenuating MMP9 activity.

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基质金属蛋白酶9在结直肠癌发生中的意义。强力霉素的作用

基质金属蛋白酶（MMPs），包括MMP9，主要通过细胞外基质重塑在结直肠癌（CRC）的进展中发挥重要作用。然而，关于MMP9在异常隐窝病灶（ACF）簇形成（最早的结肠肿瘤前病变）中的作用知之甚少。目的和方法我们使用基因表达谱交互分析2 （GEPIA2）对CRC中MMPs的表达进行了生物信息学分析。随后，我们研究了小鼠结肠癌发生早期MMP9的表达，并评估了多西环素（DOX）对ACF簇形成的影响，多西环素是一种全球性的MMPs抑制剂。因此，NMRI小鼠每周注射两次1,2-二甲肼（DMH, 20 mg/kg，皮下注射），随后或不注射DOX （100 mg/kg，口服，从第4周到第6周）。结果GEPIA2分析显示，在鉴定的28个具有胶原酶和多西环素敏感活性的MMPs中，MMPs 1、3、7、9和13在结直肠癌组织中过表达。此外，在结直肠肿瘤中，只有MMP1和MMP9与胶原蛋白表达有良好的相关性。在体内，亚甲基蓝染色的dmh处理的结肠在第6周显示多个ACF簇，与粘膜重塑和持续的亚硝化应激有关，胶原纤维、丙二醛水平和硝基酪氨酸沉积的增强证明了这一点。焦磷酸测序显示MMP9启动子第10 CpG位点甲基化增加，这与MMP9表达增加有关。有趣的是，DOX减少了ACF簇的数量和大小以及粘膜重塑，而没有重新平衡亚硝化应激。结论MMP9的过表达发生在结直肠癌早期，强力霉素可能通过降低MMP9的活性控制结肠黏膜的病理重塑，使其形成ACF簇。

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

Fundamental & Clinical Pharmacology 医学-药学

CiteScore

5.30

自引率

6.90%

发文量

111

审稿时长

6-12 weeks

期刊介绍： Fundamental & Clinical Pharmacology publishes reports describing important and novel developments in fundamental as well as clinical research relevant to drug therapy. Original articles, short communications and reviews are published on all aspects of experimental and clinical pharmacology including: Antimicrobial, Antiviral Agents Autonomic Pharmacology Cardiovascular Pharmacology Cellular Pharmacology Clinical Trials Endocrinopharmacology Gene Therapy Inflammation, Immunopharmacology Lipids, Atherosclerosis Liver and G-I Tract Pharmacology Metabolism, Pharmacokinetics Neuropharmacology Neuropsychopharmacology Oncopharmacology Pediatric Pharmacology Development Pharmacoeconomics Pharmacoepidemiology Pharmacogenetics, Pharmacogenomics Pharmacovigilance Pulmonary Pharmacology Receptors, Signal Transduction Renal Pharmacology Thrombosis and Hemostasis Toxicopharmacology Clinical research, including clinical studies and clinical trials, may cover disciplines such as pharmacokinetics, pharmacodynamics, pharmacovigilance, pharmacoepidemiology, pharmacogenomics and pharmacoeconomics. Basic research articles from fields such as physiology and molecular biology which contribute to an understanding of drug therapy are also welcomed.