USP7 通过上调 EZH2 的表达抑制 TIMP2，激活 NF-κB/PD-L1 轴，从而促进宫颈癌的发展。

USP7 inhibits TIMP2 by up-regulating the expression of EZH2 to activate the NF-κB/PD-L1 axis to promote the development of cervical cancer.

机构信息

Department of Obstetrics and Gynecology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China.

出版信息

Cell Signal. 2022 Aug;96:110351. doi: 10.1016/j.cellsig.2022.110351. Epub 2022 May 29.

DOI:10.1016/j.cellsig.2022.110351

PMID:35523402

Abstract

BACKGROUND

Cervical cancer belongs to the most common gynecological malignant cancers. EZH2 has been found to be dysregulated in different kinds of tumors and acts as an oncogene to promote cancer development. However, its upstream regulators and downstream targets in cervical cancer remain unclear. PD-L1 is a surface marker of cancer cells, facilitating the immunosuppressive microenvironment for escape from immunity attack. The molecular mechanism of increased PD-L1 expression in cervical cancer is needed to be explored.

METHODS

The expression levels of USP7, EZH2 and TIMP2 in cervical cancer patients' samples and cell lines were detected by qRT-PCR and histopathology staining. The functions of USP7, EZH2 and TIMP2 were evaluated by MTT, cell migration and invasion assays after knocking down or overexpression of indicated genes. The tumor microenvironment was determined by testing of PD-L1 expression and cytotoxicity when co-cultured with NK-92 cells. Xenograft model was used to test the function of USP7 in vivo.

RESULTS

Our data demonstrated that USP7 and EZH2 were upregulated in cervical cancer, while TIMP2 was downregulated. Inhibition of USP7 and EZH2, or overexpression of TIMP2 suppressed proliferation, migration, invasion and immune escape ability of cervical cancer cells. USP7 could increase EZH2 level, which in turn inhibited TIMP2 expression via methylation in its promoter. TIMP2 was able to mediate PD-L1 expression via NF-κB signaling pathway. Knocking down of USP7 could inhibit tumor development in vivo of cervical cancer.

CONCLUSIONS

The study discovered the function and mechanism of USP7 and highlighted its oncogenic role in cervical cancer development. Our results indicated that targeting USP7 could be a therapeutic strategy the treatment of cervical cancer.

摘要

背景

宫颈癌属于最常见的妇科恶性肿瘤之一。EZH2 在不同类型的肿瘤中被发现失调，作为一种癌基因促进癌症的发展。然而，其在宫颈癌中的上游调节因子和下游靶标尚不清楚。PD-L1 是癌细胞的表面标志物，有助于肿瘤细胞逃避免疫攻击的免疫抑制微环境。需要探索宫颈癌中 PD-L1 表达增加的分子机制。

方法

通过 qRT-PCR 和组织病理学染色检测宫颈癌患者样本和细胞系中 USP7、EZH2 和 TIMP2 的表达水平。通过敲低或过表达指定基因后的 MTT、细胞迁移和侵袭测定评估 USP7、EZH2 和 TIMP2 的功能。通过与 NK-92 细胞共培养时检测 PD-L1 表达和细胞毒性来确定肿瘤微环境。使用异种移植模型在体内测试 USP7 的功能。

结果

我们的数据表明，USP7 和 EZH2 在宫颈癌中上调，而 TIMP2 下调。抑制 USP7 和 EZH2 或过表达 TIMP2 抑制了宫颈癌细胞的增殖、迁移、侵袭和免疫逃逸能力。USP7 可以增加 EZH2 水平，进而通过其启动子的甲基化抑制 TIMP2 的表达。TIMP2 能够通过 NF-κB 信号通路介导 PD-L1 的表达。敲低 USP7 可抑制宫颈癌的体内肿瘤发展。