MRPL15 is a novel prognostic biomarker and therapeutic target for epithelial ovarian cancer.

PURPOSE: To 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. METHODS: Using 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. RESULTS: Six 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 TGFßR1 and IDO1 expression. CONCLUSION: MRPL15 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.

Eukaryotic initiation factor 3B is overexpressed and correlates with larger tumor size, advanced FIGO stage, and shorter overall survival in epithelial ovarian cancer patients.

BACKGROUND: This study aimed to detect the eukaryotic initiation factor 3B (EIF3B) expression and explore its correlation with clinical features and prognosis in epithelial ovarian cancer (EOC) patients. METHODS: A total of 230 primary EOC patients underwent surgery treatment were retrospectively reviewed. Immunohistochemical (IHC) assay was used to determine EIF3B expression in tumor and adjacent tissue specimens of all patients. According to the total IHC score, the expression of EIF3B was classified as low expression and high expression, and the latter was further divided into 3 grades: high+, high++, and high+++ expressions. Overall survival (OS) was calculated. RESULTS: Eukaryotic initiation factor 3B expression was increased in tumor tissue compared with adjacent tissue. Tumor EIF3B high expression correlated with larger tumor size (>10 cm), lymphatic metastasis, and advanced International Federation of Gynecology and Obstetrics stage (FIGO) (III/IV). Besides, OS was decreased in patients with tumor EIF3B high expression compared with patients with tumor EIF3B low expression, and further analysis showed that the OS was shortest in patients with tumor EIF3B high+++ expression, followed by patients with tumor EIF3B high++ expression and patients with tumor EIF3B high + expression, and the longest in patients with tumor EIF3B low expression. Additionally, higher tumor EIF3B expression, peritoneal cytology (positive), ascites volume (>100 mL), differentiation (poor vs. well/moderate), tumor size (>10 cm), FIGO stage (III/IV vs. I/II), and cancer antigen 125 (>1000 U/mL) independently predicted shorter OS. CONCLUSION: Eukaryotic initiation factor 3B exhibits a clinical value for monitoring disease progression and predicting prognosis in EOC patients.

SFRP1 inhibited the epithelial ovarian cancer through inhibiting Wnt/ß-catenin signaling.

BACKGROUND: Epithelial ovarian cancer is the most malignant gynecologic neoplasm accounting for 90% of the ovarian cancer patients. OBJECTIVE: Researchers proved that epigenetic alterations could disrupt gene expression as often as genetic alterations. Secreted frizzed related protein (SFRP1), a Wnt antagonist, exerts a significant effect on ovarian cancer. The aim of this research was to investigate the effects and the mechanism of action of SFRP1 on epithelial ovarian cancer. METHODS: Clinical specimens (including fallopian tubes epithelium from 60 epithelial ovarian cancer patients' and 20 healthy subjects who were undergoing surgical treatments), transgenic mice (overexpressing SFRP1 gene), and 4 epithelial ovarian cancer cell lines (including OVCAR4, SKOV3, COV644, TOV21G) were used in this study. Overexpression of SFRP1 in cells was carried out on OVCAR4 cells by transfection using Lipofectamine 2000. Gene transcription was analyzed by qRT-PCR. The methylation of SFRP1 gene was quantified by methylation-specific PCR. The level of protein expression was measured by Western blot or immunohistochemistry analysis. Cell proliferation was analyzed by CCK8 methods. The ability of cell migration and invasion were measured by wound healing assay and transwell assay. RESULTS: Abnormal expression level and hypermethylation status of SFRP1 were found in clinical epithelial ovarian cancer samples and cell lines. We observed that SFRP1 knockdown could promote proliferation, migration and invasion abilities of epithelial ovarian cancer cells. Additionally, we discovered a potential inhibitory effect of SFRP1 on Wnt/ß-catenin signaling pathway in epithelial ovarian cancer cells. Furthermore, the anti-tumor effect of SFRP1 was tested in SFRP1 transgenic mice. CONCLUSION: SFRP1 inhibited epithelial ovarian cancer through inhibiting Wnt/ß-catenin pathway, suggesting that SFRP1 could be considered as a potential therapeutic target in epithelial ovarian cancer.

Chemical Analysis of Morphological Changes in Lysophosphatidic Acid-Treated Ovarian Cancer Cells.

Ovarian cancer (OvCa) cells are reported to undergo biochemical changes at the cell surface in response to treatment with lysophosphatidic acid (LPA). Here we use scanning electron microscopy (SEM) and multiplex coherent anti-Stokes Raman scattering (CARS) imaging via supercontinuum excitation to probe morphological changes that result from LPA treatment. SEM images show distinct shedding of microvilli-like features upon treatment with LPA. Analysis of multiplex CARS images can distinguish between molecular components, such as lipids and proteins. Our results indicate that OvCa429 and SKOV3ip epithelial ovarian cancer cells undergo similar morphological and chemical responses to treatment with LPA. The microvilli-like structures on the surface of multicellular aggregates (MCAs) are removed by treatment with LPA. The CARS analysis shows a distinct decrease in protein and increase in lipid composition on the surface of LPA-treated cells. Importantly, the CARS signals from cellular sheddings from MCAs with LPA treatment are consistent with cleavage of proteins originally present. Mass spectrometry on the cellular sheddings show that a large number of proteins, both membrane and intracellular, are present. An increased number of peptides are detected for the mesenchymal cell line relative to the epithelial cell indicating a differential response to LPA treatment with cancer progression.