Manhua Cui

UBP43 promotes epithelial ovarian carcinogenesis via activation of β‐catenin signaling pathway

AbstractDysregulation of the deubiquitinating protease, UBP43, has been implicated in many human diseases, including cancer. Here, we evaluated the functional significance and mechanism of action of UBP43 in epithelial ovarian cancer. We found that UBP43 was significantly upregulated in the tumor tissues of patients with epithelial ovarian cancer. Similar results were observed in OVCAR‐3, Caov‐3, TOV‐112D, A2780, and SK‐OV‐3 cells. Furthermore, in vitro functional assays of A2780 and TOV‐112D cells demonstrated that UBP43 overexpression promoted cell proliferation, migration, and invasion. Upregulation of UBP43 might result in epithelial–mesenchymal transition by inducing the nuclear transport of β‐catenin, which was accompanied by enhanced N‐cadherin but decreased E‐cadherin expression. These malignant phenotypes were reversed by UBP43 silencing. Further investigation revealed that the knockdown of UBP43 inhibited cell proliferation by inducing a cell cycle arrest at the G2/M phase. The oncogenic characteristics of UBP43 were validated in a subcutaneous xenograft mouse model. In vivo, tumor growth was delayed in the UBP43‐silenced group but accelerated after UBP43 overexpression. Finally, we demonstrated that β‐catenin is a key protein in the UBP43‐mediated malignant development of epithelial ovarian cancer. Specifically, overexpression of UBP43 decreased the ubiquitination degradation of β‐catenin and enhanced its protein stability. Also, we observed that the downstream genes of beta‐catenin such as cyclin D1, MMP2, and MMP9 were upregulated due to UBP43 overexpression. Thus, we concluded that UBP43 promoted epithelial ovarian cancer tumorigenesis and metastasis through activation of the β‐catenin pathway, suggesting that UBP43 may be a potential therapeutic target for this intractable disease.

Effect of BRCA1 on the Concurrent Chemoradiotherapy Resistance of Cervical Squamous Cell Carcinoma Based on Transcriptome Sequencing Analysis

Background. Cervical squamous cell carcinoma (CSCC) is the main pathological type of cervical cancer, accounting for 80%–85% of cervical cancer. Owing to concurrent chemoradiotherapy (CCRT) resistance in a subset of CSCC patients, the treatment response is often unsatisfactory. Identifying predictors and therapeutic targets related to cisplatin‐based CCRT resistance in CSCC is critical. Methods. We reanalyzed GSE56363, an mRNA dataset from the GEO database with 21 patients with locally advanced CSCC, to identify differentially expressed genes (DEGs) related to CCRT resistance. The hub genes were screened from the protein‐protein interaction network of DEGs using cytoHubba plug‐in of Cytoscape software. Transcriptome sequencing technology was used to compare differential expression between SiHa cells overexpressing BRCA1 compared with control SiHa cells. Functional annotation for DEGs and gene set enrichment analysis (GSEA) was performed to identify DEG‐enriched relative signaling pathways to examine the molecular mechanisms of BRCA1 in CCRT resistance of CSCC. qPCR was used to verify the expression of key genes in SiHa/DDP cells. Results. A total of 609 DEGs including 223 upregulated DEGs and 386 downregulated DEGs were identified between the complete response to CCRT (CR) and noncomplete response to CCRT (NCR) CSCC patients based on the GSE56363 dataset. Ten hub genes with the highest degrees were identified via the plug‐in CytoHubba in Cytoscape: BRCA1, CDCA8, ASPM, CDC45, RAD51, HMMR, CENPF, EXO1, DTL, and ZWINT genes, and BRCA1 ranked first. Through transcriptome sequencing analysis based on GSE141558, 1344 DEGs were identified in BRCA1‐overexpressing SiHa cells, including 824 upregulated DEGs and 520 downregulated DEGs. GSEA results showed that CCRT‐resistance related signaling pathways, such as the JAK/STAT signaling pathway and the WNT signaling pathway, were differentially enriched in BRCA1‐expressing SiHa cells. STAT1, STAT2, and CCND1 were screened as the differentially expressed target genes of BRCA1 and may correlate with resistance of CSCC. qPCR results showed that only STAT1 was significantly increased in SiHa cells with GV230‐BRCA1 plasmid transfection. Conclusion. BRCA1 overexpression in SiHa cells may upregulate STAT1 to activate the JAK/STAT signaling pathway, suggesting a mechanism for enhanced CCRT resistance.

MCM10: An effective treatment target and a prognostic biomarker in patients with uterine corpus endometrial carcinoma

AbstractMolecular profiling has been applied for uterine corpus endometrial carcinoma (UCEC) management for many years. The aim of this study was to explore the role of MCM10 in UCEC and construct its overall survival (OS) prediction models. Data from TCGA, GEO, cbioPotal and COSMIC databases and the methods, such as GO, KEGG, GSEA, ssGSEA and PPI, were employed to bioinformatically detect the effects of MCM10 on UCEC. RT‐PCR, Western blot and immunohistochemistry were used to validate the effects of MCM10 on UCEC. Based on Cox regression analysis using the data from TCGA and our clinical data, two OS prediction models for UCEC were established. Finally, the effects of MCM10 on UCEC were detected in vitro. Our study revealed that MCM10 was variated and overexpressed in UCEC tissue and involved in DNA replication, cell cycle, DNA repair and immune microenvironment in UCEC. Moreover, silencing MCM10 significantly inhibited the proliferation of UCEC cells in vitro. Importantly, based on MCM10 expression and clinical features, the OS prediction models were constructed with good accuracy. MCM10 could be an effective treatment target and a prognostic biomarker for UCEC patients. The OS prediction models might help establish the strategies of follow‐up and treatment for UCEC patients.