NF-κB 抑制剂 BAY11-7082 通过 miR-30a/NF-κB/Snail 信号通路抑制膀胱癌细胞中 M2 肿瘤相关巨噬细胞诱导的 EMT 潜能。

NF-κB inhibitor, BAY11-7082, suppresses M2 tumor-associated macrophage induced EMT potential via miR-30a/NF-κB/Snail signaling in bladder cancer cells.

机构信息

Department of Urology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310014, China; Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Hangzhou 310014, China.

Department of Urology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310014, China.

出版信息

Gene. 2019 Aug 20;710:91-97. doi: 10.1016/j.gene.2019.04.039. Epub 2019 Apr 16.

DOI:10.1016/j.gene.2019.04.039

PMID:31002892

Abstract

BACKGROUND

Chronic inflammatory microenvironment has been shown to play a key role in initiating tumorigenesis and facilitating malignant progression. Primary tumors surrounded with and infiltrated by tumor-associated macrophages (TAMs) significantly promote the epithelial-to-mesenchymal transition (EMT) and distant metastasis in urothelial bladder cancer.

METHODS

In this study, we aimed to explore the potential of targeting TAMs for the treatment of malignant bladder cancer.

RESULTS

First, we found a higher number of TAMs, CD68 (pan-macrophage marker), and clever-1 (M2 macrophage marker) was associated with a higher pT category and grade in a cohort of 108 patients. In vitro assays showed that the co-culture of TAMs promoted the metastatic potential in HTB-1 and T24 by up-regulating EMT markers including Snail, VEGF and Vimentin, as well as oncogenic markers such as β-catenin and NF-κB. More importantly, M2 co-cultured HTB-1 and T24 showed an increased level of metastatic microRNA, miR-30. Silencing of miR-30 resulted in the reduced metastatic potential, migration/invasion, in association with the decreased expression of Twist1 and Vimentin. The addition of BAY11-7082 into the TAM/cancer co-culture system significantly reduced the M2 phenotype and tumorigenic properties. Coincidentally, miR-30a level was significantly lowered in the presence of BAY11-7082.

CONCLUSION

Our study demonstrated that AMs promoted metastatic potential of bladder cancer cells via promoting EMT through the increase of miR-30a. BAY11-7082 treatment suppressed both oncogenic and metastatic potential in bladder cancer cells while preventing the M2 polarization of TAMs.

摘要

背景

慢性炎症微环境已被证明在启动肿瘤发生和促进恶性进展中起着关键作用。原发性肿瘤周围和浸润肿瘤相关巨噬细胞（TAMs）显著促进了尿路上皮膀胱癌的上皮间质转化（EMT）和远处转移。

方法

在这项研究中，我们旨在探索针对 TAMs 治疗恶性膀胱癌的潜力。

结果

首先，我们在 108 名患者的队列中发现，TAMs、CD68（泛巨噬细胞标志物）和 clever-1（M2 巨噬细胞标志物）数量较多与较高的 pT 分期和分级相关。体外实验表明，TAMs 的共培养通过上调 EMT 标志物，包括 Snail、VEGF 和 Vimentin 以及癌基因标志物，如β-catenin 和 NF-κB，促进了 HTB-1 和 T24 的转移潜能。更重要的是，M2 共培养的 HTB-1 和 T24 显示出转移性 microRNA，miR-30 的水平增加。沉默 miR-30 导致转移潜能、迁移/侵袭减少，与 Twist1 和 Vimentin 的表达降低有关。在 TAM/癌细胞共培养系统中添加 BAY11-7082 可显著降低 M2 表型和致瘤特性。巧合的是，BAY11-7082 的存在显著降低了 miR-30a 的水平。