Xiuwei Chen

PRMT3‐Mediated Arginine Methylation of METTL14 Promotes Malignant Progression and Treatment Resistance in Endometrial Carcinoma

AbstractProtein arginine methyltransferase (PRMT) plays essential roles in tumor initiation and progression, but its underlying mechanisms in the treatment sensitivity of endometrial cancer (EC) remain unclear and warrant further investigation. Here, a comprehensive analysis of the Cancer Genome Atlas database and Clinical Proteomic Tumor Analysis Consortium database identifies that PRMT3 plays an important role in EC. Specifically, further experiments show that PRMT3 inhibition enhances the susceptibility of EC cells to ferroptosis. Mechanistically, PRMT3 interacts with Methyltransferase 14 (METTL14) and is involved in its arginine methylation. In addition, PRMT3 inhibition‐mediated METTL14 overexpression promotes methylation modification via an m6A‐YTHDF2‐dependent mechanism, reducing Glutathione peroxidase 4 (GPX4) mRNA stability, increasing lipid peroxidation levels, and accelerating ferroptosis. Notably, combined PRMT3 blockade and anti‐PD‐1 therapy display more potent antitumor effects by accelerating ferroptosis in cell‐derived xenograft models. The specific PRMT3 inhibitor SGC707 exerts the same immunotherapeutic sensitizing effect in a patient‐derived xenograft model. Notably, blocking PRMT3 improves tumor suppression in response to cisplatin and radiation therapy. Altogether, this work demonstrates that PRMT3 depletion is a promising target for EC.

ATAD2 Upregulation Promotes Tumor Growth and Angiogenesis in Endometrial Cancer and Is Associated with Its Immune Infiltration

Background. Endometrial cancer is one of the three major gynecologic malignancies, and its incidence continues to rise. ATPase family AAA structural domain-containing protein 2 (ATAD2) is an ATPase protein, which is an independent factor for poor prognosis in endometrial cancer. However, its role in the disease is yet to be determined. Methods. The Tumor IMmune Estimation Resource (TIMER) database was used to assess ATAD2 expression in pan-cancer, and the relevance of ATAD2 expression in Uterine Corpus Endometrial Carcinoma (UCEC) in clinical settings was obtained using Gene Expression Profiling Interactive Analysis (GEPIA) and UALCAN analysis. In addition, the Human Protein Atlas database was used to assess ATAD2 protein expression in UCEC. Furthermore, in vitro molecular biology and in vivo functional experiments were employed to ascertain the effect of ATAD2 expression on tumor angiogenesis and tumor growth. UALCAN was used to screen for ATAD2 coexpressed genes, and Sangerbox was utilized to perform Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of these coexpressed genes. Finally, the TIMER, Tumor Immune System Interaction and Drug Bank (TISIDB), and GEPIA databases were used to analyze the relationship between ATAD2 and immune infiltration. Results. ATAD2 is highly expressed in a variety of tumors, and in UCEC, it plays the role of a protooncogene. Basic experiments revealed that ATAD2 promotes vascular endothelial growth factor expression in endometrial cancer and affects tumor growth and angiogenesis. In addition, GO and KEGG enrichment analyses showed that ATAD2-associated genes were chiefly enriched in certain signaling pathways, such as herpes simplex virus 1 infection and that ATAD2 was associated with immune infiltration in UCEC. Conclusion. Our findings suggest that ATAD2 promotes tumor growth and angiogenesis in endometrial cancer. Furthermore, ATAD2 is associated with immune infiltration and is a potential diagnostic and therapeutic target.

KDM4B, a potential prognostic biomarker revealed by large-scale public databases and clinical samples in uterine corpus endometrial carcinoma

Abstract Background: Uterine corpus endometrial carcinoma (UCEC) is the fourth most common cancer among women worldwide. The 5 year survival rate for patients with advanced UCEC is only 17%. Lysine-specific demethylase 4B (KDM4B), a histone demethylase, is overexpressed or dysregulated in various cancers and is associated with tumor progression and poor prognosis. We performed bioinformatics analysis and in vitro assays to assess the role of KDM4B in UCEC. Additionally, the role of KDM4B in the tumor immune microenvironment was explored. Methods: The mRNA and protein levels of KDM4B in UCEC were evaluated using The Cancer Genome Atlas (TCGA), The Human Protein Atlas (HPA), and Gene Expression Omnibus (GEO) databases. Immunohistochemistry and western blotting were performed to verify the protein expression level of KDM4B in two batches of clinical samples. Kaplan–Meier survival, univariate, and multivariate analyses were performed to assess the correlation between KDM4B expression and the prognosis of patients with UCEC. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to predict the function and mechanism of KDM4B, and four immune-related databases (TIMER, CIBERSORT, TISIDB, and EPIC) were used to explore their relevance in a tumor immune microenvironment. Results: First, KDM4B was significantly overexpressed in UCEC tissues at the mRNA and protein levels. Immunohistochemistry and western blotting confirmed the abnormal overexpression of KDM4B. Additionally, upregulation of KDM4B was associated with different clinicopathological prognostic factors. Second, the overexpression of KDM4B was also associated with shorter overall survival (OS) and progression-free survival (PFS). Univariate and multivariate analyses confirmed that KDM4B was an independent prognostic factor for poor survival. Then, GO and KEGG analysis revealed that KDM4B is enriched in biological processes and cellular signaling pathways closely related to the immune response. Finally, KDM4B expression was closely associated with immune cell infiltration and expression of immune checkpoint molecules, indicating that it may be a new immune-related potential oncogene in UCEC. Conclusions: KDM4B may be a new potential oncogene that is clinically significant in patients with UCEC. KDM4B may not only be used to assess the clinical prognosis of patients with UCEC but may also be a target for immunotherapy or targeted gene therapy.

UBE2S promotes the development of ovarian cancer by promoting PI3K/AKT/mTOR signaling pathway to regulate cell cycle and apoptosis

Abstract Background Ovarian cancer is one of the important factors that seriously threaten women's health and its morbidity and mortality ranks eighth among female cancers in the world. It is critical to identify potential and promising biomarkers for prognostic evaluation and molecular therapy of OV. Ubiquitin-conjugating enzyme E2S (UBE2S), a potential oncogene, regulates the malignant progression of various tumors; however, its role in OV is still unclear. Methods The expression and prognostic significance of UBE2S at the pan-cancer level were investigated through high-throughput gene expression analysis and clinical prognostic data from TCGA, GEPIA, and GEO databases. 181 patients with OV were included in this study. Cell culture and cell transfection were performed on OV cell lines (SKOV3 and A2780) and a normal ovarian cell line (IOSE80). The expression level and prognostic significance of UBE2S in OV were verified by western blot, immunohistochemistry, and Kaplan–Meier survival analysis. Through cell transfection, CCK-8, Ki-67 immunofluorescence, wound healing, Transwell, clonogenic, and flow cytometry assays, the effect and detailed mechanism of UBE2S knockdown on the malignant biological behavior of OV cells were explored. Results UBE2S exhibited abnormally high expression at the pan-cancer level. The results of RT-qPCR and Western blotting indicated that UBE2S was significantly overexpressed in ovarian cancer cell lines compared with normal cell lines (P < 0.05). Kaplan–Meier survival analysis and Immunohistochemistry indicated that overexpression of UBE2S was related to poor prognosis of OV (HR > 1, P < 0.05). Results of in vitro experiments indicated that UBE2S gene knockdown might inhibit the proliferation, invasion, and prognosis of OV cells by inhibiting the PI3K/AKT/mTOR signaling pathway, thereby blocking the cell cycle and promoting apoptosis (P < 0.05). Conclusion UBE2S is a potential oncogene strongly associated with a poor prognosis of OV patients. Knockdown of UBE2S could block the cell cycle and promote apoptosis by inhibiting the PI3K/AKT/mTOR pathway and ultimately inhibit the proliferation, migration and prognosis of ovarian cancer, which suggested that UBE2S might be used for molecular therapy and prognostic evaluation of ovarian cancer.