Based on the findings of this meta-analysis, ever use of OC is associated with lower risk of CRC. Additionally, there is a statistically significant nonlinear inverse association between the duration of OC use and CRC risk.

PurposeTo analyze the role of six human epididymis protein 4 (HE4)‐related mitochondrial ribosomal proteins (MRPs) in ovarian cancer and selected MRPL15, which is most closely related to the tumorigenesis and prognosis of ovarian cancer, for further analyses.MethodsUsing STRING database and MCODE plugin in Cytoscape, six MRPs were identified among genes that are upregulated in response to HE4 overexpression in epithelial ovarian cancer cells. The Cancer Genome Atlas (TCGA) ovarian cancer, GTEX, Oncomine, and TISIDB were used to analyze the expression of the six MRPs. The prognostic impact and genetic variation of these six MRPs in ovarian cancer were evaluated using Kaplan‐Meier Plotter and cBioPortal, respectively. MRPL15 was selected for immunohistochemistry and GEO verification. TCGA ovarian cancer data, gene set enrichment analysis, and Enrichr were used to explore the mechanism of MRPL15 in ovarian cancer. Finally, the relationship between MRPL15 expression and immune subtype, tumor‐infiltrating lymphocytes, and immune regulatory factors was analyzed using TCGA ovarian cancer data and TISIDB.ResultsSix MRPs (MRPL10, MRPL15, MRPL36, MRPL39, MRPS16, and MRPS31) related to HE4 in ovarian cancer were selected. MRPL15 was highly expressed and amplified in ovarian cancer and was related to the poor prognosis of patients. Mechanism analysis indicated that MRPL15 plays a role in ovarian cancer through pathways such as the cell cycle, DNA repair, and mTOR 1 signaling. High expression of MRPL15 in ovarian cancer may be associated with its amplification and hypomethylation. Additionally, MRPL15 showed the lowest expression in C3 ovarian cancer and was correlated with proliferation of CD8+ T cells and dendritic cells as well as TGFβR1 and IDO1 expression.ConclusionMRPL15 may be a prognostic indicator and therapeutic target for ovarian cancer. Because of its close correlation with HE4, this study provides insights into the mechanism of HE4 in ovarian cancer.

Purpose: To identify key pathogenic genes and reveal the potential molecular mechanisms of endometrial cancer (EC) using bioinformatics analysis and immunohistochemistry validation. Materials and Methods: Through weighted gene co-expression network analysis (WGCNA), a co-expression network was constructed based on the top 25% variant genes in the GSE50830 dataset downloaded from gene expression omnibus (GEO). GO and KEGG pathway enrichment analyses were performed using the DAVID online tool. Candidate genes were selected using the cytoHubba plug-in of Cytoscape, mRNA expression levels and prognostic values in EC were analyzed by Oncomine, GEPIA, and Kaplan-Meier Plotter database to determine hub genes. One hub gene was validated by immunohistochemical (IHC) staining of 116 paraffin-embedded endometrial tissues and TCGA-UCEC cohort. Genes co-expressed with this hub gene were identified by LinkedOmics. Finally, its correlation with immune infiltration was evaluated by TIMER. Results: Three co-expression modules and five candidate genes in each module were obtained by WGCNA; four hub genes were identified (LGR5, SST, ZNF558, and PTGDS). The mRNA levels of LGR5 and SST were significantly upregulated in EC, whereas those of ZNF558 and PTGDS were significantly downregulated; the expression of all four genes was associated with EC prognosis. Further validation demonstrated that PTGDS was significantly downregulated in the EC group compared with the atypical hyperplasia and normal endometrial groups, and its low expression was an independent risk factor for worse prognosis of EC. Biological function analysis indicated that PTGDS might be involved in the adaptive immune response, leukocyte migration, as well as in the regulation of cell adhesion molecules and chemokine signaling. Additionally, PTGDS expression was positively correlated with immune infiltration status of B cells, CD4 + T cells and macrophages. Conclusion:LGR5, SST, ZNF558, and PTGDS may participate in the development, progression, and prognosis of EC, in which PTGDS may be a novel biomarker and therapeutic target for EC.

Inadequate trophoblast invasion and increased trophoblast apoptosis cause serious pregnancy complications. Pleckstrin homology-like domain, family A, member 2 (PHLDA2) has been linked to fetal size at birth and growth restriction in a number of studies. However, the impact of PHLDA2 on trophoblast function had not been studied previously, to the best of our knowledge. In the present study, immunofluorescence staining demonstrated that primary trophoblasts isolated from placental villous tissues were positive for cytokeratin 18 (CK18), vimentin and human placental lactogen (hPL). JEG-3 cells and primary trophoblasts were infected with lentivirus overexpressing PHLDA2. RT-qPCR and western blot analysis detected high levels of PHLDA2. A Cell Counting Kit-8 (CCK-8) assay showed that PHLDA2 overexpression inhibited trophoblast proliferation. In addition, PHLDA2 significantly induced apoptosis, as evidenced by Annexin V-FITC/propidium iodide (PI) and Hoechst staining, along with activation of Bax and caspase-3 and also decreased Bcl-2 expression. Further investigation showed that PHLDA2 effectively induced reactive oxygen species (ROS) generation, caused cytochrome c release from the mitochondria into the cytosol and decreased mitochondrial membrane potential. PHLDA2 likely induced apoptosis through the mitochondrial pathway. Wound healing and Transwell assays indicated that PHLDA2 overexpression efficiently suppressed cell migration and invasion. These data suggest that PHLDA2 plays an important role in the occurrence and development of pregnancy complications by promoting trophoblast apoptosis and suppressing cell invasion.