首页|USP7 inhibits TIMP2 by up-regulating the expression of EZH2 to activate the NF-?B/PD-L1 axis to promote the development of cervical cancer
USP7 inhibits TIMP2 by up-regulating the expression of EZH2 to activate the NF-?B/PD-L1 axis to promote the development of cervical cancer
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NSTL
Elsevier
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 kappa B 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.
NSTL
Elsevier
