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ZNF750 exerted its Antitumor Action in Oral Squamous Cell Carcinoma by regulating E2F2.

ABSTRACT: Cell cycle activator E2F transcription factor 2 (E2F2) play a key role in tumor development and metastasis. Previous RNA sequence analysis (GSE134835) revealed E2F2 was significantly reduced by Zinc-finger protein 750 (ZNF750) in oral squamous cell carcinoma (OSCC). This study was aimed to determine the involvement of E2F2 in antitumor action of ZNF750. The nude mouse xenograft model was established by subcutaneously injection of stable cell line CAL-27^oeZNF750 or CAL-27^shZNF750. Xenograft tumor volume and tumor weight was measured. The expression of E2F2, transcriptional repressors such as enhancer of zeste 2 (Ezh2), PHD finger protein 19 (PHF19), and the genes related to cell proliferation or metastasis was studied in vivo or in vitro. Luciferase assay was performed to investigate regulation effect of ZNF750 on E2F2 luciferase activity. The involvement of E2F2 in the antitumor action of ZNF750 was studied by cotransduced ZNF750 with E2F2 lentivirus. The tumor growth and metastasis was repressed by ZNF750 manifested by reduced tumor size, tumor weight and the genes related to cell proliferation and metastasis. However, all of these were reversed by knockdown of the ZNF750 gene. Furthermore, E2F2 luciferase activity was inhibited by ZNF750. E2F2 partly blocked the antitumor action of ZNF750 manifested by increased self-renewal, invasion, migration, elevated Ezh2 and MMP13 protein expression in ZNF750 + E2F2 groups. However, silenced E2F2 further enhanced the antitumor action of ZNF750. ZNF750 depressed E2F2 activity and played a critical role in regulating transcriptional repressors for inhibiting the OSCC growth and metastasis in OSCC.

SUBMITTER: Yang HL

PROVIDER: S-EPMC8734408 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Periodontitis is closely related to oral cancer, but the molecular mechanism of periodontal pathogens involved in the occurrence and development of oral cancer is still inconclusive. Here, we demonstrate that, in vitro, the cell proliferation ability and S phase cells of the periodontitis group (colonized by Porphyromonas gingivalis and Fusobacterium nucleatum, P+) significantly increased, but the G1 cells were obviously reduced. The animal models with an in situ oral squamous cell carcinoma (OSCC) and periodontitis-associated bacteria treatment were constructed, and micro-CT showed that the alveolar bone resorption of mice in the P+ group (75.3 ± 4.0 μm) increased by about 53% compared with that in the control group (48.8 ± 1.3 μm). The tumor mass and tumor growth rate in the P+ group were all higher than those in the blank control group. Hematoxylin-eosin (H&E) staining of isolated tumor tissues showed that large-scale flaky necrosis was found in the tumor tissue of the P+ group, with lots of damaged vascular profile and cell debris. Immunohistochemistry (IHC) of isolated tumor tissues showed that the expression of Ki67 and the positive rate of cyclin D1 were significantly higher in tumor tissues of the P+ group. The qRT-PCR results of the expression of inflammatory cytokines in oral cancer showed that periodontitis-associated bacteria significantly upregulated interleukin (IL)-6, tumor necrosis factor (TNF)-α, IL-18, apoptosis-associated speck-like protein containing a CARD (ASC) (up to six times), and caspase-1 (up to four times), but it downregulated nuclear factor (NF)-κB, NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3), and IL-1β (less than 0.5 times). In addition, the volume of spleen tissue and the number of CD4+ T cells, CD8+ T cells, and CD206+ macrophages in the P+ group increased significantly. IHC and Western blotting in tumor tissues showed that expression levels of γ-H2AX, p-ATR, RPA32, CHK1, and RAD51 were upregulated, and the phosphorylation level of CHK1 (p-chk1) was downregulated. Together, we identify that the periodontitis-related bacteria could promote tumor growth and proliferation, initiate the overexpressed NLRP3, and activate upstream signal molecules of ATR-CHK1. It is expected to develop a new molecular mechanism between periodontitis-related bacteria and OSCC.

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ZNF750 exerted its Antitumor Action in Oral Squamous Cell Carcinoma by regulating E2F2.

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