ST14 interacts with TMEFF1 and is a predictor of poor prognosis in ovarian cancer.

TMEFF1 is a new protein involved in the physiological functions of the central nervous system, and we previously reported TMEFF1 can promote ovarian cancer. ST14 was determined to be involved in the processes of epidermal differentiation, epithelial cell integrity, and vascular endothelial cell migration, etc. The relationship between ST14 and TMEFF1 in the ovary remains unknown. In this study, we detected the expression of ST14 and TMEFF1 in 130 different ovarian cancer tissues through immunohistochemistry. We determined ST14 and TMEFF1 were highly expressed in ovarian cancer, indicating a higher degree of tumor malignancy and a worse prognosis. Tissues significantly expressing ST14 also highly expressed TMEFF1, and the expression of the two proteins was positively correlated. Consistently, immunofluorescence double staining demonstrated the co-localization of ST14 and TMEFF1 in the same region, and immunoprecipitation confirmed the interaction between ST14 and TMEFF1. TMEFF1 expression was also reduced after knocking down ST14 through Western blot. MTT, wound healing and Transwell assays results determined that knockdown of ST14 inhibited proliferation, migration and invasion of ovarian cancer cells in vitro, but the inhibitory effect was restored after adding TMEFF1 exogenous protein. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways analysis showed that ST14 and its related genes were enriched in the processes of epithelial formation, intercellular adhesion, protein localization, and mitosis regulation. We also clarified the kinase, microRNA, and transcription factor target networks and the impact of genetic mutations on prognosis. Overall, high expression of ST14 and TMEFF1 in ovarian cancer predicts higher tumor malignancy and a worse prognosis. ST14 and TMEFF1 co-localize and interact with each other in ovarian cancer. ST14 can regulate TMEFF1 expression to promote proliferation, migration and invasion of ovarian cancer cells. We speculate that the relationship between ST14 and TMEFF1 in ovarian cancer could become a potential target for anti-cancer therapy.

Glycolysis: A fork in the path of normal and pathological pregnancy.

Glucose metabolism is vital to the survival of living organisms. Since the discovery of the Warburg effect in the 1920s, glycolysis has become a major research area in the field of metabolism. Glycolysis has been extensively studied in the field of cancer and is considered as a promising therapeutic target. However, research on the role of glycolysis in pregnancy is limited. Recent evidence suggests that blastocysts, trophoblasts, decidua, and tumors all acquire metabolic energy at specific stages in a highly similar manner. Glycolysis, carefully controlled throughout pregnancy, maintains a dynamic and coordinated state, so as to maintain the homeostasis of the maternal-fetal interface and ensure normal gestation. In the present review, we investigate metabolic remodeling and the selective propensity of the embryo and placenta for glycolysis. We then address dysregulated glycolysis that occurs in the cellular interactive network at the maternal-fetal interface in miscarriage, preeclampsia, fetal growth restriction, and gestational diabetes mellitus. We provide new insights into the field of maternal-fetal medicine from a metabolic perspective, thus revealing the mystery of human pregnancy.

Mechanism of human chorionic gonadotropin in endometrial receptivity via the miR-126-3p/PI3K/Akt/eNOS axis.

Human chorionic gonadotropin (hCG) might affect endometrial receptivity, exerting integral roles in embryo implantation. This study explored the action of hCG in endometrial receptivity via the miR-126-3p/PIK3R2/PI3K/Akt/eNOS axis. The embryo implantation dysfunction (EID) mouse models were established by administrating mifepristone and human endometrial epithelial cells (EECs) were used for in vivo experiments, both followed by hCG treatment. Expression level of CD105 and protein levels of cadherin CD144 and CD146 in mice were determined by immunohistochemistry and Western blot. The levels of miR-126-3p and PIK3R2 mRNA and PIK3R2, p-PI3K p85 α, PI3K p110 α, p-Akt, Akt, p-eNOS, and eNOS protein levels were measured. Cell proliferation was evaluated by CCK-8 and EdU assays. The binding sites of miR-126-3p and PIK3R2 were predicted and verified. hCG-treated EECs were further transfected with miR-126-inhibitor for functional rescue experiments. hCG ameliorated endometrial receptivity in EID mice. Moreover, hCG promoted miR-126-3p and suppressed PIK3R2 in EID mice and EECs. miR-126-3p targeted PIK3R2. EEC proliferation was enhanced after hCG treatment but inhibited by miR-126-3p downregulation. Both in vivo and in vitro experiments validated that hCG activated the PI3K/Akt/eNOS pathway through the miR-126-3p/PIK3R2 axis. Collectively, hCG improves endometrial receptivity by activating the PI3K/Akt/eNOS pathway via regulating miR-126-3p/PIK3R2.

Regulation of protein corona on liposomes using albumin-binding peptide for targeted tumor therapy.

Nanocarriers entering the body are usually coated by plasma protein, leading to a protein "corona" easily recognized by tissues and cells. Adjusting the composition of protein coronas may be an efficient way to change the properties and behavior of nanoparticles in vivo. In this study, we modified doxorubicin-loaded liposomes (Lip/DOX) with an albumin-binding domain (ABD) to prepare nanoparticles (ABD-Lip/DOX) that can specifically bind to albumin and form albumin-based protein coronas in vivo for targeted tumor therapy. The prepared liposomes were spherical with a particle size of about 100 nm. After incubating the liposomes with rat serum, the albumin content was eight times higher on ABD-Lip than on control liposomes. ABD-Lip significantly inhibited adsorption of IgG and complement activation in rat serum in vitro, while corona-coated ABD-Lip was internalized to a significantly greater extent than corona-coated control liposomes. In addition, ABD-Lip showed longer blood circulation time, higher tumor accumulation and greater antitumor efficacy than control liposomes in mice bearing 4 T1 tumors, while both liposome formulations showed similar biocompatibility. These results confirm that adjusting the component of protein coronas around nanoparticles can improve their therapeutic efficacy.

Maleimide-Functionalized Liposomes: Prolonged Retention and Enhanced Efficacy of Doxorubicin in Breast Cancer with Low Systemic Toxicity.

Cell surface thiols can be targeted by thiol-reactive groups of various materials such as peptides, nanoparticles, and polymers. Here, we used the maleimide group, which can rapidly and covalently conjugate with thiol groups, to prepare surface-modified liposomes (M-Lip) that prolong retention of doxorubicin (Dox) at tumor sites, enhancing its efficacy. Surface modification with the maleimide moiety had no effect on the drug loading efficiency or drug release properties. Compared to unmodified Lip/Dox, M-Lip/Dox was retained longer at the tumor site, it was taken up by 4T1 cells to a significantly greater extent, and exhibited stronger inhibitory effect against 4T1 cells. The in vivo imaging results showed that the retention time of M-Lip at the tumor was significantly longer than that of Lip. In addition, M-Lip/Dox also showed significantly higher anticancer efficacy and lower cardiotoxicity than Lip/Dox in mice bearing 4T1 tumor xenografts. Thus, the modification strategy with maleimide may be useful for achieving higher efficient liposome for tumor therapy.

RAD21 Confers Poor Prognosis and Affects Ovarian Cancer Sensitivity to Poly(ADP-Ribose)Polymerase Inhibitors Through DNA Damage Repair.

Background: Poly(ADP-ribose)polymerase (PARP) inhibitors are a class of molecular-targeted cancer drugs. Synthetic lethality is a phenomenon that renders homologous recombination repair defective cells more sensitive to PARP inhibitors. As a component of the cohesin complex, RAD21 regulates DNA damage repair. However, the biological roles of RAD21 in ovarian cancer and their underlying mechanisms remain unclear. Methods: An immunohistochemical assay was used to validate the expression of RAD21 in ovarian cancer and its correlation with prognosis. The effects of RAD21 were evaluated through Cell Counting Kit-8 (CCK8), wound-healing, and invasion assays in vitro and the tumor growth in vivo. Furthermore, CCK8 assay and immunofluorescence assay were used to detect the effect of RAD21 on cell sensitivity to PARP inhibitors and their mechanism. The pathway changes were detected by Western blotting. Results: RAD21 was markedly upregulated in ovarian cancer samples. High RAD21 expression was correlated with poor differentiation and poor prognosis in patients with ovarian cancer. Functionally, RAD21 overexpression promoted cancer cell proliferation, migration, and invasion. Moreover, RAD21 knockdown increased the sensitivity of ovarian cancer cells to three kinds of PARP inhibitors by affecting DNA damage repair. In vivo experiments indicated that RAD21 promoted tumor growth. Mechanistically, the overexpression of RAD21 led to increased phosphorylation levels of Akt and mTOR. Blocking the Akt/mTOR signaling pathway reversed RAD21 overexpression-induced cancer progression and drug resistance. Conclusions: RAD21 can serve as a valuable prognostic marker for ovarian cancer and has the potential as a therapeutic target that can expand the utility of PARP inhibitors.

Identification and clinical validation of NUSAP1 as a novel prognostic biomarker in ovarian cancer.

BACKGROUND: Nucleolar and spindle-associated protein 1 (NUSAP1) was shown to be involved in cell cycle regulation in cancer. However, its prognostic value and underlying mechanism in ovarian cancer remain unclear. METHODS: Oncomine, TCGA, CCLE, and UALCAN databases were used to analyze the expression level of NUSAP1 in ovarian cancer. The Kaplan-Meier plotter database was used to evaluate its prognostic value. The results from these analyses were further validated using immunohistochemical assay. The potential molecular mechanism of NUSAP1 in ovarian cancer was assessed with respect to homologous recombination repair, mismatch repair, and immunology using different databases. RESULTS: Database analyses and experimental results demonstrated that NUSAP1 was highly expressed in ovarian cancer, its levels being correlated with the FIGO stage. High NUSAP1 expression was an independent risk factor affecting the prognosis of patients with epithelial ovarian cancer. Moreover, NUSAP1 was associated with cell cycle, DNA replication, homologous recombination, and p53 signaling pathway. A positive correlation was identified between the expression of NUSAP1 and BRCA1/2 in ovarian cancer. In addition, NUSAP1 was associated with the expression of DNA mismatch repair genes and immune cell infiltration. CONCLUSIONS: NUSAP1 may be a valuable prognostic marker, as well as a novel biomarker for evaluating the response to immunotherapy of patients with ovarian cancer.

Exosomal ANXA2 derived from ovarian cancer cells regulates epithelial-mesenchymal plasticity of human peritoneal mesothelial cells.

Ovarian cancer, one of the malignant gynaecological tumours with the highest mortality rate among female reproductive system, is prone to metastasis, recurrence and chemotherapy resistance, causing a poor prognosis. Exosomes can regulate the epithelial-mesenchymal plasticity of tumour cells, remodel surrounding tumour microenvironment, and affect tumour cell proliferation, invasion and metastasis. However, the function and mechanism of exosomes in the intraperitoneal implantation of ovarian cancer remain unclear. In this study, exosomal annexin A2 (ANXA2) derived from ovarian cancer cells was co-cultured with human peritoneal mesothelial (HMrSV5) cells; functional experiments were conducted to explore the effects of exosomal ANXA2 on the biological behaviour of HMrSV5 and the related mechanisms. This study showed that ANXA2 in ovarian cancer cells can be transferred to HMrSV5 cells through exosomes, exosomal ANXA2 can not only promote the migration, invasion and apoptosis of HMrSV5 cells, but also regulates morphological changes and fibrosis of HMrSV5 cells. Furthermore, ANXA2 promotes the mesothelial-mesenchymal transition (MMT) and degradation of the extracellular matrix of HMrSV5 cells through PI3K/AKT/mTOR pathway, finally affects pre-metastasis microenvironment of ovarian cancer, which provides a new theoretical basis for the mechanism of intraperitoneal implantation and metastasis of ovarian cancer.

Keratin 80 regulated by miR-206/ETS1 promotes tumor progression via the MEK/ERK pathway in ovarian cancer.

Introduction: Keratin 80 (KRT80) is a type II epithelial keratin protein that plays an important role in cell differentiation and tumor progression. However, its role and mechanisms in ovarian cancer remain unclear. Methods: The effect of KRT80 on the survival and prognosis of patients with ovarian cancer was determined using immunohistochemistry. Cell lines overexpressing KRT80 and with KRT80 knockdown were established to study its effect on the malignant behavior of ovarian cancer cells. Western blotting was used to detect changes in related molecules, and in the MEK/ERK signal transduction pathway. ChIP assay was used to confirm that ETS1 regulates KRT80 at the transcriptional level. A double luciferase assay was used to confirm the target of miR-206. Results: The expression levels of KRT80 were high in ovarian cancer tissue, and were related to survival and prognosis. KRT80 expression is an independent prognostic factor in patients with ovarian cancer. KRT80 overexpression promotes the proliferation of ovarian cancer cells, the transition from G1 phase to S phase, invasion, and migration. KRT80 overexpression increased the expression of BCL2/BAX, CyclinD1, MMP2, MMP9, and N-cadherin, decreased the expression of E-cadherin, and increased the phosphorylation of MEK and ERK. ETS1 binds to the upstream promoter sequence of KRT80 and regulates KRT80 expression at the transcriptional level. ETS1 is a direct target of miR-206 in ovarian cancer cells. Conclusion: KRT80 regulated by miR-206/ETS1 promotes tumor progression via the MEK/ERK pathway in ovarian cancer, and KRT80 may have applications as a screening biomarker and potential therapeutic target for ovarian cancer.

Development of a seven-gene tumor immune microenvironment prognostic signature for high-risk grade III endometrial cancer.

Uterine corpus endometrial carcinoma locally infiltrates numerous immune cells and other tumor immune microenvironment components. These cells are involved in malignant tumor growth and proliferation and the process of resistance toward immunotherapies. Here, we aimed to develop a tumor immune microenvironment-related prognostic signature for high-risk grade III endometrial carcinoma based on The Cancer Genome Atlas. The signature was systematically correlated with immune infiltration characteristics of the tumor microenvironment. The seven-gene Riskscore signature was robust and performed well in training, testing, and Gene Expression Omnibus-independent cohorts. A nomogram comprising the gene signature accurately predicted patient prognosis, with our model performing better than other endometrial cancer-related signatures. Analysis of the IMvigor210 immunotherapy cohort revealed that subgroups with a low Riskscore had a better prognosis than subgroups with a high Riskscore. Subgroups with a low Riskscore exhibited immune cell infiltration and inflammatory profiles, whereas subgroups with a high Riskscore experienced progressive disease. The receiver operating characteristic curve indicated that risk score, neoantigen, and tumor mutation burden models together accurately predicted treatment response. Taken together, we developed a tumor microenvironment-based seven-gene prognostic stratification system to predict the prognosis of patients with high-risk endometrial cancer and guide more effective immunotherapy strategies.

Identification of the prognostic value of a 2-gene signature of the WNT gene family in UCEC using bioinformatics and real-world data.

BACKGROUND: The WNT gene family plays an important role in the occurrence and development of malignant tumors, but its involvement has not been systematically analyzed in uterine corpus endometrial carcinoma (UCEC). This study aimed to evaluate the prognostic value of the WNT gene family in UCEC. METHODS: Pan-cancer transcriptome data of the UCSC Xena database and Genotype-Tissue Expression (GTEx) normal tissue data were downloaded to analyze the expression and prognosis of 19 WNT family genes in UCEC. A cohort from The Cancer Genome Atlas-Uterine Corpus Endometrial Carcinoma (TCGA-UCEC) was used to analyze the expression of the WNT gene family in different immune subtypes and clinical subgroups. The STRING database was used to analyze the interaction of the WNT gene family and its biological function. Univariate Cox regression analysis and Lasso cox analysis were used to identify the genes associated with significant prognosis and to construct multi signature prognosis model. An immunohistochemical assay was used to verify the predictive ability of the model. Risk score and the related clinical features were used to construct a nomogram. RESULTS: The expression levels of WNT2, WNT3, WNT3A, WNT5A, WNT7A, and WNT10A were significantly different among different immune subtypes and correlated with TP53 mutation. According to the WNT family genes related to the prognosis of UCEC, UCEC was classified into two subtypes (C1, C2). The prognosis of subtype C1 was significantly better than that of subtype C2. A 2-gene signature (WNT2 and WNT10A) was constructed and the two significantly prognostic groups can be divided based on median Risk score. These results were verified using real-world data, and the nomogram constructed using clinical features and Risk score had good prognostic ability. CONCLUSIONS: The 2-gene signature including WNT2 and WNT10A can be used to predict the prognosis of patients with UCEC, which is important for clinical decision-making and individualized therapy for patients with UCEC.

PGK1 Is a Key Target for Anti-Glycolytic Therapy of Ovarian Cancer: Based on the Comprehensive Analysis of Glycolysis-Related Genes.

Reprogramming of energy metabolism is a key hallmark of cancer, which provides a new research perspective for exploring the development of cancer. However, the most critical target of anti-glycolytic therapy for ovarian cancer remains unclear. Therefore, in the present study, Oncomine, GEPIA, and HPA databases, combined with clinical specimens of different histological types of ovarian cancer were used to comprehensively evaluate the expression levels of glycolysis-related metabolite transporters and enzymes in ovarian cancer. We selected phosphoglycerate kinase 1 (PGK1), which showed the greatest prognostic value in the Kaplan-Meier Plotter database, for subsequent validation. Immunochemistry assays confirmed that PGK1 was highly expressed in ovarian cancer. The PGK1 expression level was an independent risk factor for the survival and prognosis of patients with ovarian cancer. Functional analysis showed that the PGK1 expression level was positively correlated with the infiltration of neutrophils. Cell experiments confirmed that inhibiting PGK1 expression in ovarian cancer cells could reduce the epithelial-mesenchymal transition (EMT) process, resulting in loss of cell migration and invasion ability. The small molecule NG52 dose-dependently inhibited the proliferation of ovarian cancer cells. In addition, NG52 reduced the EMT process and reversed the Warburg effect by inhibiting PGK1 activity. Therefore, PGK1 is an attractive molecular target for anti-glycolytic therapy of ovarian cancer.

YWHAE as an HE4 interacting protein can influence the malignant behaviour of ovarian cancer by regulating the PI3K/AKT and MAPK pathways.

BACKGROUND: Malignant tumours of the female reproductive system threaten the lives and health of women worldwide, with ovarian cancer having the highest mortality rate. Based on previous work, this study analysed the expression and role of YWHAE in ovarian epithelial tumours. METHODS: The interaction between YWHAE and HE4 was evaluated via immunoprecipitation, western blot analysis, and cellular immunofluorescence. Immunohistochemistry was used to address the relationship between YWHAE expression, clinicopathological parameters, and patient prognosis. Changes in cell invasion, epithelial-mesenchymal transition, migration, proliferation, apoptosis, and cell cycle before and after differential expression of YWHAE were also explored in ovarian cancer cell lines and via in vivo experiments. RESULTS: YWHAE was found to interact with HE4, and its expression was positively correlated with HE4 expression. Moreover, YWHAE upregulation was associated with advanced stages of ovarian cancer and poor patient prognosis. In addition, YWHAE enhanced invasion, migration, and proliferation, but inhibited the apoptosis of ovarian cancer cells. These biological effects were found to be mediated by the AKT and MAPK signalling pathways. CONCLUSIONS: Altogether, this study demonstrates that YWHAE is substantially upregulated in ovarian cancer tissues, representing a risk factor for the prognosis of ovarian cancer that is positively correlated with HE4 expression. Furthermore, YWHAE and its downstream pathways may represent new therapeutic targets for ovarian cancer.

Identification of a five-gene signature of the RGS gene family with prognostic value in ovarian cancer.

The RGS (regulator of G protein signaling) gene family, which includes negative regulators of G protein-coupled receptors, comprises important drug targets for malignant tumors. It is thus of great significance to explore the value of RGS family genes for diagnostic and prognostic prediction in ovarian cancer. The RNA-seq, immunophenotype, and stem cell index data of pan-cancer, The Cancer Genome Atlas (TCGA) data, and GTEx data of ovarian cancer were downloaded from the UCSC Xena database. In the pan-cancer database, the expression level of RGS1, RGS18, RGS19, and RGS13 was positively correlated with stromal and immune cell scores. Cancer patients with high RGS18 expression were more sensitive to cyclophosphamide and nelarabine, whereas those with high RGS19 expression were more sensitive to cladribine and nelarabine. The relationship between RGS family gene expression and overall survival (OS) and progression-free survival (PFS) of ovarian cancer patients was analyzed using the KM-plotter database, RGS17, RGS16, RGS1, and RGS8 could be used as diagnostic biomarkers of the immune subtype of ovarian cancer, and RGS10 and RGS16 could be used as biomarkers to predict the clinical stage of this disease. Further, Lasso cox analysis identified a five-gene risk score (RGS11, RGS10, RGS13, RGS4, and RGS3). Multivariate COX analysis showed that the risk score was an independent prognostic factor for patients with ovarian cancer. Immunohistochemistry and the HPA protein database confirmed that the five-gene signature is overexpressed in ovarian cancer. GSEA showed that it is mainly involved in the ECM-receptor interaction, TGF-beta signaling pathway, Wnt signaling pathway, and chemokine signaling pathway, which promote the occurrence and development of ovarian cancer. The prediction model of ovarian cancer constructed using RGS family genes is of great significance for clinical decision making and the personalized treatment of patients with ovarian cancer.

Interaction of CD147 and human epididymis protein 4 promotes invasion and metastasis of ovarian cancer.

Background: Ovarian cancer is one of the most common malignant tumors in female reproductive system. The expression of CD147 and human epididymis protein 4 (HE4) are both upregulated and associated with malignant progression in ovarian cancer. However, the important role of interaction between CD147 and HE4 in the invasion and metastasis of ovarian cancer remains unclear. Methods: The co-expression and co-localization of CD147 and HE4 in cells and tissues of ovarian cancer were detected by co-immunoprecipitation, immunohistochemistry and immunocytochemistry, double-labeling immunofluorescence method. The interaction between CD147 and annexin A2 (ANXA2) was also investigated. Furthermore, we detect the regulatory relationship between CD147 and HE4 by Western blot. Transwell assay and scratch test were conducted to explore the effect of CD147-HE4 interaction on migration and invasion of ovarian cancer. Results: The protein CD147 and HE4 were co-immunoprecipitated and co-located in the cytoplasm and membrane of ovarian cancer tissues and cells. Both of two proteins were highly expressed and positively associated with advanced FIGO stages, poor differentiation degree and poor prognosis of ovarian cancer, and HE4 was confirmed as an independent risk factor for CD147 in ovarian cancer tissues. What's more, AXNA2 was also identified as a CD147 interacting protein in ovarian cancer. It is further confirmed that interaction between CD147 and HE4 can affect the invasion and metastasis of ovarian cancer. Conclusion: This study demonstrated that HE4 and ANXA2 were both CD147 interacting proteins, the expression of CD147 and HE4 can affect each other, and HE4 could promote the invasion and metastasis of ovarian cancer by regulating the expression of CD147, which may provide novel thought for early diagnosis and therapeutic target of ovarian cancer.

ZNF703 promotes tumor progression in ovarian cancer by interacting with HE4 and epigenetically regulating PEA15.

BACKGROUND: It is known that the transcription factor zinc finger protein 703 (ZNF703) plays an important role in physiological functions and the occurrence and development of various tumors. However, the role and mechanism of ZNF703 in ovarian cancer are unclear. MATERIALS AND METHODS: Immunohistochemistry was used to analyze the expression of ZNF703 in ovarian cancer patients and to assess the effect of ZNF703 expression on the survival and prognosis of ovarian cancer patients. ZNF703 overexpression and suppression expression experiments were used to evaluate the effect of ZNF703 on malignant biological behavior of ovarian cancer cells in vitro. Detecting the interaction between HE4 and ZNF703 by immunofluorescence colocalization and coprecipitation, and nuclear translocation. Chromatin immunoprecipitation-sequencing (ChIP-Seq), dual luciferase reporter assay, ChIP-PCR, in vivo model were applied to study the molecular mechanism of ZNF703 affecting the development of ovarian cancer. RESULTS: ZNF703 was highly expressed in ovarian cancer tissues, and its expression level is related to the prognosis of ovarian cancer patients. In vivo and in vitro experiments confirmed that ZNF703 overexpression/inhibition expression will promoted/inhibited the malignant biological behavior of ovarian cancer. Mechanically, ZNF703 interacted with HE4, and HE4 promoted nuclear translocation of ZNF703. ChIP-Seq identified multiple regulatory targets of ZNF703, of which ZNF703 directly binds to the enhancer region of PEA15 to promote the transcription of PEA15 and thereby promoted the proliferation of cancer cells. CONCLUSION: The results showed that ZNF703 as an oncogene played an important role in the epigenetic modification of ovarian cancer proliferation, and suggested that ZNF703 as a transcription factor may become a prognostic factor and a potential therapeutic target for ovarian cancer.

Identification of KIF23 as a prognostic signature for ovarian cancer based on large-scale sampling and clinical validation.

The purpose of this study is to explore the expression and clinical significance of KIF23 in ovarian cancer (OV) and identify potential targets for clinical treatment. Oncomine, GEO, and TCGA databases were used to analysis the expression of KIF23 in OV. The prognostic value of KIF23 gene was analyzed by the Kaplan-Meier plotter database. The molecular mechanism of KIF23 activity was analyzed from the perspective of immunology, gene mutation, copy number variation (CNV). Finally, immunohistochemistry was conducted to validate the expression of KIF23, univariable and multivariate cox analysis were used to determine its relationship with clinical characteristics and OV prognosis. It showed that highly expressed KIF23 is an adverse independent prognostic biomarker for OV patients. Genomics analysis showed that KIF23 expression was associated with mutations such as FLG2 and TTN, and was significantly enriched in DNA replication and the cell cycle tumor-related signaling pathways. Immunology analysis showed that KIF23 is closely related to the immune infiltration. KIF23 can not only performed as a prognosis signature in OV but also as a target of immune molecular therapeutics.

Down-regulation of TRIB3 inhibits the progression of ovarian cancer via MEK/ERK signaling pathway.

BACKGROUND: Tribbles pseudokinase 3 (TRIB3) protein is a pseudokinase which plays an important role in cellular stress, metabolism, and tumor progression. However, the expression and function of TRIB3 in ovarian cancer is unknown. METHODS: TRIB3 expression was detected by immunohistochemistry in the ovarian tissue samples. Following down-regulation of TRIB3 by siRNA, multiple aspects of ovarian cancer cells were detected by the MTT assay, flow cytometry, scratch test and Transwell. Additionally, changes in related molecules and the MEK/ERK pathway were detected by western blotting. Finally, many bioinformatic methods, websites and databases, such as gene set enrichment analysis (GSEA), DVAID, Genemania, TISIDB and cBioPortal were used to study the TRIB3. RESULTS: The expression level of TRIB3 was higher in ovarian epithelial malignant tumors as compared to other groups. Patients with a high expression level of TRIB3 had significantly shorter survival times,which was consistent with the results of analysis of the KM-plot database. Down-regulation of TRIB3 expression significantly inhibited the proliferation, invasion, and migration capabilities of ovarian cancer cells, and induced apoptosis and cell cycle arrest. Following TRIB3 siRNA transfection, expression levels of relative proteins were found to be decreased. Additionally, analysis in DAVID website and GSEA revealed that TRIB3 expression was associated with multiple biological processes. Protein phosphorylation levels of MEK and ERK also decreased following TRIB3-siRNA transfection. The Genemania website was used to analyze the proteins that interact with TRIB3. Analysis of TRIB3 in the TISIDB database and cBioPortal website showed that ovarian cancer patients with high levels of mutation in TRIB3 had poor prognosis, and that the expression of TRIB3 was related to immunomodulation. CONCLUSIONS: The TRIB3 was highly expressed and promoting the malignant behavior of ovarian cancer cells by activating the MEK-ERK signaling pathway. It was also found to be associated with genetic variations and immune modulators.

Application and reflection of genomic scar assays in evaluating the efficacy of platinum salts and PARP inhibitors in cancer therapy.

Defective DNA repair is one of the most important features of tumors. BRCA1/2 participates in homologous recombination repair as a key tumor suppressor gene. BRCA1/2 mutation is an important biomarker for predicting the sensitivity of platinum salts and Poly (ADP-ribose) polymerase (PARP) inhibitors in breast cancer, ovarian cancer, and other cancers. However, epigenetic modifications and other mutations in homologous recombination repair (HRR) genes can also cause homologous recombination deficiency (HRD). Patients with no BRCA1/2 mutations, but bearing similar molecular phenotypes (BRCAness) can still obtain clinical benefits from treatment with platinum salts or PARP inhibitors. Therefore, an accurate assessment of HRD is essential for the formulation of personalized treatments. However, methods to identify HRD in tumors vary and are controversial. Currently, genomic scar assays have been used in multiple clinical trials to assess patient clinical benefit. This review summarizes the therapeutic effects of platinum salts and PARP inhibitors in breast and ovarian cancer, clarifies the predictive value of genomic scar assays in evaluating the clinical benefit of different patient groups and treatment options, and proposes the limitations and optimization of current HRD scoring methods. Using and optimizing genomic scar assays can help to accurately screen the population with the most benefit, expand the scope of drug application, and make the most suitable clinical decision based on individual differences.

High expression and potential synergy of human epididymis protein 4 and Annexin A8 promote progression and predict poor prognosis in epithelial ovarian cancer.

Epithelial ovarian cancer (EOC) is the most common cause of gynecological cancer-related deaths. Aberrant expression of human epididymis protein 4 (HE4) and Annexin A8 (ANXA8) plays crucial roles in some malignancies; however, their functions in EOC remain unclear. In this study, we utilized immunohistochemistry, real-time PCR, western blotting, immunofluorescence labeling, and gene interaction and enrichment pathway analyses to explore the roles of HE4 and ANXA8 in EOC. They were highly expressed in EOC tissues, which significantly correlated with higher tumor burden, advanced FIGO stages, poor differentiation, presence of > 1 cm residual tumor, and tumor recurrence. The expression patterns of HE4 and ANXA8 were similar, and Spearman's correlation analysis showed that they were positively correlated (r=0.671, P < 0.001). Large sample database analyses also showed significant positive correlation between their mRNA expression (R=0.304, 0.321, and 0.304 in TCGA, CCLE and GTEx, respectively, all P < 0.001). Kaplan-Meier survival analysis demonstrated that advanced FIGO stages, lymph node metastasis, residual tumor size > 1 cm, and high HE4 and ANXA8 expression were significantly associated with poor overall survival (all P < 0.05). Moreover, multivariate Cox analysis showed that advanced FIGO stages and HE4 expression were independent factors for poor survival (P < 0.001, 0.012, respectively). Interaction network analysis of genes associated with ANXA8, expressed in response to HE4, revealed that these genes participated in TP53 expression, autophagy regulation, and the PID FOXO pathway. In conclusion, the potential synergy between HE4 and ANXA8 may exacerbate the disease condition. Thus, targeting HE4 and ANXA8 could be a novel therapeutic strategy for ovarian cancer.