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MMP 家族基因的上调表达与食管鳞状细胞癌患者的不良预后相关,通过调节增殖和上皮-间充质转化。

Upregulated expression of MMP family genes is associated with poor survival in patients with esophageal squamous cell carcinoma via regulation of proliferation and epithelial‑mesenchymal transition.

机构信息

School of Pharmaceutical Sciences, Shenzhen University Health Science Center, Shenzhen, Guangdong 518060, P.R. China.

Department of Pharmacy, The Second Clinical Medical College (Shenzhen People's Hospital), Jinan University, Shenzhen 518020, P.R. China.

出版信息

Oncol Rep. 2020 Jul;44(1):29-42. doi: 10.3892/or.2020.7606. Epub 2020 May 7.

Abstract

Matrix metalloproteinases (MMPs) are involved in the cleavage of several components of the extracellular matrix and serve important roles in tumor growth, metastasis and invasion. Previous studies have focused on the expression of one or several MMPs in esophageal squamous cell carcinoma (ESCC); however, in the present study, the transcriptomics of all 23 MMPs were systematically investigated with a focus on the prognostic value of the combination of MMPs. In this study, 8 overlapping differentially expressed genes of the MMP family were identified based on data obtained from Gene Expression Omnibus and The Cancer Genome Atlas. The prognostic value of these MMPs were investigated; the receiver operating characteristic curves, survival curves and nomograms showed that the combination of 6 selected MMPs possessed a good predictive ability, which was more accurate than the prediction model based on Tumor‑Node‑Metastasis stage. Gene set enrichment analysis and gene co‑expression analysis were performed to investigate the potential mechanism of action of MMPs in ESCC. The MMP family was associated with several signaling pathways, such as epithelial‑mesenchymal transition (EMT), Notch, TGF‑β, mTOR and P53. Cell Counting Kit‑8, colony formation, wound healing assays and western blotting were used to determine the effect of BB‑94, a pan‑MMP inhibitor, on proliferation and migration of ESCC cells. BB‑94 treatment decreased ESCC cell growth, migration and EMT. Therefore, MMPs may serve both as diagnostic and prognostic biomarkers of ESCC, and MMP inhibition may be a promising preventive and therapeutic strategy for patients with ESCC.

摘要

基质金属蛋白酶(MMPs)参与细胞外基质的多种成分的裂解,在肿瘤生长、转移和侵袭中发挥重要作用。先前的研究集中在食管鳞状细胞癌(ESCC)中一种或几种 MMP 的表达;然而,在本研究中,系统地研究了 23 种 MMP 的转录组学,重点是 MMP 组合的预后价值。在这项研究中,根据从基因表达综合数据库和癌症基因组图谱获得的数据,确定了 MMP 家族的 8 个重叠差异表达基因。研究了这些 MMP 的预后价值;受试者工作特征曲线、生存曲线和列线图表明,6 种选定 MMP 的组合具有良好的预测能力,比基于肿瘤-淋巴结-转移分期的预测模型更准确。进行了基因集富集分析和基因共表达分析,以研究 MMP 在 ESCC 中的潜在作用机制。MMP 家族与几个信号通路有关,如上皮-间充质转化(EMT)、Notch、TGF-β、mTOR 和 P53。细胞计数试剂盒-8、集落形成、划痕愈合试验和 Western blot 用于确定泛 MMP 抑制剂 BB-94 对 ESCC 细胞增殖和迁移的影响。BB-94 处理降低了 ESCC 细胞的生长、迁移和 EMT。因此,MMP 可能既是 ESCC 的诊断和预后生物标志物,也是 MMP 抑制可能是 ESCC 患者有希望的预防和治疗策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ea88/7251684/10ba21cd6765/OR-44-01-0029-g00.jpg

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