CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：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.
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.
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研究发现了 USP7 的功能和机制，并强调了其在宫颈癌发展中的致癌作用。
宫颈癌是最常见的妇科恶性肿瘤之一。EZH2在多种肿瘤中发生失调，并作为癌基因促进癌症发展。然而，其在宫颈癌中的上游调节因子和下游靶点仍不清楚。PD-L1是癌细胞的表面标志物，可形成免疫抑制性微环境，使肿瘤逃避免疫攻击。亟需探究宫颈癌PD-L1表达升高的分子机制。
通过qRT-PCR和组织病理染色检测宫颈癌患者样本及细胞系中USP7、EZH2和TIMP2表达。敲低或过表达目标基因后，采用MTT、细胞迁移和侵袭实验评估USP7、EZH2和TIMP2功能。通过检测PD-L1表达及与NK-92细胞共培养时的细胞毒性分析肿瘤微环境。采用异种移植模型测试USP7体内功能。
研究数据显示，宫颈癌中USP7和EZH2上调，TIMP2下调。抑制USP7或EZH2，或过表达TIMP2，可抑制宫颈癌细胞增殖、迁移、侵袭和免疫逃逸能力。USP7可提高EZH2水平，后者通过其启动子甲基化抑制TIMP2表达。TIMP2可通过NF-κB信号通路调节PD-L1表达。敲低USP7可在体内抑制宫颈癌发展。
本研究发现USP7的功能和作用机制，并凸显其在宫颈癌发展中的致癌作用。结果提示，靶向USP7可能成为治疗宫颈癌的策略。
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.
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.
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.
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.
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