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鉴定和验证 MMP 家族成员（MMP2、MMP9、MMP12 和 MMP16）作为肾透明细胞癌（KIRC）的治疗靶点和生物标志物。

Identifying and validating MMP family members (MMP2, MMP9, MMP12, and MMP16) as therapeutic targets and biomarkers in kidney renal clear cell carcinoma (KIRC).

机构信息

The Second Affiliated Hospital of Harbin Medical University, Harbin Medical University, Harbin, China.

Department of Pharmaceutical Engineering, Jiangsu Ocean University, Lianyungang, China.

出版信息

Oncol Res. 2024 Mar 20;32(4):737-752. doi: 10.32604/or.2023.042925. eCollection 2024.

DOI:10.32604/or.2023.042925
PMID:38560573
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10972725/
Abstract

Kidney Renal Clear Cell Carcinoma (KIRC) is a malignant tumor that carries a substantial risk of morbidity and mortality. The MMP family assumes a crucial role in tumor invasion and metastasis. This study aimed to uncover the mechanistic relevance of the MMP gene family as a therapeutic target and diagnostic biomarker in Kidney Renal Clear Cell Carcinoma (KIRC) through a comprehensive approach encompassing both computational and molecular analyses. STRING, Cytoscape, UALCAN, GEPIA, OncoDB, HPA, cBioPortal, GSEA, TIMER, ENCORI, DrugBank, targeted bisulfite sequencing (bisulfite-seq), conventional PCR, Sanger sequencing, and RT-qPCR based analyses were used in the present study to analyze MMP gene family members to accurately determine a few hub genes that can be utilized as both therapeutic targets and diagnostic biomarkers for KIRC. By performing STRING and Cytohubba analyses of the 24 MMP gene family members, MMP2 (matrix metallopeptidase 2), MMP9 (matrix metallopeptidase 9), MMP12 (matrix metallopeptidase 12), and MMP16 (matrix metallopeptidase 16) genes were denoted as hub genes having highest degree scores. After analyzing MMP2, MMP9, MMP12, and MMP16 via various TCGA databases and RT-qPCR technique across clinical samples and KIRC cell lines, interestingly, all these hub genes were found significantly overexpressed at mRNA and protein levels in KIRC samples relative to controls. The notable effect of the up-regulated MMP2, MMP9, MMP12, and MMP16 was also documented on the overall survival (OS) of the KIRC patients. Moreover, targeted bisulfite-sequencing (bisulfite-seq) analysis revealed that promoter hypomethylation pattern was associated with up-regulation of hub genes (MMP2, MMP9, MMP12, and MMP16). In addition to this, hub genes were involved in various diverse oncogenic pathways. The MMP gene family members (MMP2, MMP9, MMP12, and MMP16) may serve as therapeutic targets and prognostic biomarkers in KIRC.

摘要

肾透明细胞癌（KIRC）是一种恶性肿瘤，具有较高的发病率和死亡率。MMP 家族在肿瘤侵袭和转移中起着关键作用。本研究旨在通过综合计算和分子分析方法，揭示 MMP 基因家族作为肾透明细胞癌（KIRC）治疗靶点和诊断生物标志物的机制相关性。本研究使用 STRING、Cytoscape、UALCAN、GEPIA、OncoDB、HPA、cBioPortal、GSEA、TIMER、ENCORI、DrugBank、靶向亚硫酸氢盐测序（bisulfite-seq）、常规 PCR、Sanger 测序和基于 RT-qPCR 的分析，分析 MMP 基因家族成员，以准确确定几个可作为 KIRC 治疗靶点和诊断生物标志物的枢纽基因。通过对 24 个 MMP 基因家族成员进行 STRING 和 Cytohubba 分析，MMP2（基质金属蛋白酶 2）、MMP9（基质金属蛋白酶 9）、MMP12（基质金属蛋白酶 12）和 MMP16（基质金属蛋白酶 16）基因被标记为具有最高度数评分的枢纽基因。通过对各种 TCGA 数据库和 RT-qPCR 技术进行分析，以及对临床样本和 KIRC 细胞系进行分析，有趣的是，所有这些枢纽基因在 KIRC 样本中的 mRNA 和蛋白水平均显著高于对照组。上调的 MMP2、MMP9、MMP12 和 MMP16 对 KIRC 患者的总生存期（OS）也有显著影响。此外，靶向亚硫酸氢盐测序（bisulfite-seq）分析显示，启动子低甲基化模式与枢纽基因（MMP2、MMP9、MMP12 和 MMP16）的上调有关。除此之外，枢纽基因还参与了各种不同的致癌途径。MMP 基因家族成员（MMP2、MMP9、MMP12 和 MMP16）可作为 KIRC 的治疗靶点和预后生物标志物。

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