Bioinformatics analysis of the microRNA genes associated with type 2 cardiorenal syndrome.

BACKGROUND: MicroRNAs (miRNAs) are important regulatory factors in the normal developmental stages of the heart and kidney. However, it is currently unclear how miRNA is expressed in type 2 cardiorenal syndrome (CRS). This study aimed to detect the differential expression of miRNAs and to clarify the main enrichment pathways of differentially expressed miRNA target genes in type 2 CRS. METHODS: Five cases of healthy control (Group 1), eight of chronic heart failure (CHF, Group 2) and seven of type 2 CRS (Group 3) were enrolled, respectively. Total RNA was extracted from the peripheral blood of each group. To predict the miRNA target genes and biological signalling pathways closely related to type 2 CRS, the Agilent miRNA microarray platform was used for miRNA profiling and bioinformatics analysis of the isolated total RNA samples. RESULTS: After the microarray analysis was done to screen for differentially expressed circulating miRNAs among the three different groups of samples, the target genes and bioinformatic pathways of the differential miRNAs were predicted. A total of 38 differential miRNAs (15 up- and 23 down-regulated) were found in Group 3 compared with Group 1, and a total of 42 differential miRNAs (11 up- and 31 down-regulated) were found in Group 3 compared to Group 2. According to the Gene Ontology (GO) function and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway analysis, the top 10 lists of molecular functions, cellular composition and biological processes, and the top 30 signalling pathways of predicted gene targets of the differentially expressed miRNAs were discriminated among the three groups. CONCLUSION: Between the patients with CHF and type 2 CRS, miRNAs were differentially expressed. Prediction of target genes of differentially expressed miRNAs and the use of GO function and KEGG pathway analysis may reveal the molecular mechanisms of CRS. Circulating miRNAs may contribute to the diagnosis of CRS, and further and larger studies are needed to enhance the robustness of our findings.

Clinical Significance of Apela in Acute Cardiorenal Insuffiency of Chronic Heart Failure.

INTRODUCTION: Apela has a wide range of biological effects on the cardiovascular system, but the changes and significance of endogenous Apela in patients with chronic heart failure (CHF) and acute deterioration of cardiac and renal function are unclear. METHODS: A total of 69 patients with stable CHF combined with well-preserved renal function were enrolled and followed for 12 months. The effects of Apela on human renal glomerular endothelial cells (hRGEC), human glomerular mesangial cells (hMC), and human renal tubular epithelial cells (HK-2) were observed. RESULTS: Serum Apela concentration was positively correlated with NYHA class (r = 0.711) and N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration (r = 0.303) but negatively correlated with left ventricular ejection fraction (LVEF) (r = -0.374) and 6-min walk distance (r = -0.860) in patients with stable CHF. Twenty-one patients experiencing deterioration of renal and cardiac function were diagnosed with cardiorenal syndrome (CRS) during the follow-up period. In addition, the serum Apela, as well as the difference in Apela between stable and worsening phases (ΔApela), was correlated with the estimated glomerular filtration rate (eGFR) and ΔeGFR in patients with CRS. Apela significantly inhibited the upregulated expression of MCP-1 and TNF-α induced by angiotensin II (AngII) in hRGEC, hMC, and HK-2 cells. Apela inhibited the adhesion of THP-1 cells to hRGEC and promoted the tubular formation of hRGEC. Moreover, Apela enhanced the expression of MMP-9 in hMC but inhibited the upregulated expression of α-SMA and vimentin in HK-2 cells by AngII. CONCLUSION: This study suggests that the level of Apela can be used to diagnose heart failure and assess the severity of cardiac dysfunction in patients with stable CHF, and its dynamic changes can be used to evaluate the damage to renal function in patients with CRS. Apela plays multiple protective effects on renal cells, highlighting its clinical application prospect in the prevention and treatment of CRS.

PSMD8 can serve as potential biomarker and therapeutic target of the PSMD family in ovarian cancer: based on bioinformatics analysis and in vitro validation.

BACKGROUND: The ubiquity-proteasome system is an indispensable mechanism for regulating intracellular protein degradation, thereby affecting human antigen processing, signal transduction, and cell cycle regulation. We used bioinformatics database to predict the expression and related roles of all members of the PSMD family in ovarian cancer. Our findings may provide a theoretical basis for early diagnosis, prognostic assessment, and targeted therapy of ovarian cancer. METHODS: GEPIA, cBioPortal, and Kaplan-Meier Plotter databases were used to analyze the mRNA expression levels, gene variation, and prognostic value of PSMD family members in ovarian cancer. PSMD8 was identified as the member with the best prognostic value. The TISIDB database was used to analyze the correlation between PSMD8 and immunity, and the role of PSMD8 in ovarian cancer tissue was verified by immunohistochemical experiments. The relationship of PSMD8 expression with clinicopathological parameters and survival outcomes of ovarian cancer patients was analyzed. The effects of PSMD8 on malignant biological behaviors of invasion, migration, and proliferation of ovarian cancer cells were studied by in vitro experiments. RESULTS: The expression levels of PSMD8/14 mRNA in ovarian cancer tissues were significantly higher than those in normal ovarian tissues, and the expression levels of PSMD2/3/4/5/8/11/12/14 mRNA were associated with prognosis. Up-regulation of PSMD4/8/14 mRNA expression was associated with poor OS, and the up-regulation of PSMD2/3/5/8 mRNA expression was associated with poor PFS in patients with ovarian serous carcinomas. Gene function and enrichment analysis showed that PSMD8 is mainly involved in biological processes such as energy metabolism, DNA replication, and protein synthesis. Immunohistochemical experiments showed that PSMD8 was mainly expressed in the cytoplasm and the expression level was correlated with FIGO stage. Patients with high PSMD8 expression had poor prognosis. Overexpression of PSMD8 significantly enhanced the proliferation, migration, and invasion abilities in ovarian cancer cells. CONCLUSION: We observed different degrees of abnormal expression of members of PSMD family in ovarian cancer. Among these, PSMD8 was significantly overexpressed in ovarian malignant tissue, and was associated with poor prognosis. PSMDs, especially PSMD8, can serve as potential diagnostic and prognostic biomarkers and therapeutic targets in ovarian cancer.

Apela gene therapy alleviates pulmonary hypertension in rats.

Pulmonary artery hypertension (PAH) is a common disease that threatens human health. At present, no treatment can cure PAH, and the prognosis is poor. Therefore, it is important to determine new targets for PAH treatment. Recently, a novel endogenous ligand Apela (ELABELA/Toddler/ELA32) of apelin peptide jejunum (APJ) receptor was identified as a possible PAH target. This study explored the potential effect of Apela gene therapy on rats with PAH. An AAV-ELA32 recombinant expression vector was constructed by molecular cloning. Purified adeno-associated virus (AAV) was injected into monocrotaline (MCT)-induced PAH rats via tail vein 1 and 2 weeks after modeling. Apela gene therapy significantly reduced the increased right ventricular systolic pressure and N-terminal pro-brain natriuretic peptide (NT-proBNP) in PAH rats. The results of histopathology and immunofluorescence showed that Apela gene therapy not only reduced the rate of pulmonary arteriole muscularization and media thickening in PAH rats but also inhibited the endothelial-to-mesenchymal transition of the pulmonary arteriole. Western blotting showed that Apela gene therapy up-regulated the expression of KLF2/eNOs and BMPRII/SMAD4 in pulmonary arterioles of PAH rats. Overall, the results show that Apela gene therapy can inhibit pulmonary arteriolar vascular remodeling and reduce pulmonary artery pressure in PAH rats. These effects may be related to KLF2/eNOs and BMPRII/SMAD4 signaling pathways. The apelinergic system may be a potential new target for the prevention and treatment of PAH.

Genome-wide association study of dilated cardiomyopathy-induced heart failure associated with renal insufficiency in a Chinese population.

BACKGROUND: As it is unclear whether there is genetic susceptibility to cardiorenal syndrome (CRS), we conducted a genome-wide association study of dilated cardiomyopathy (DCM)-induced heart failure (HF) associated with renal insufficiency (RI) in a Chinese population to identify putative susceptibility variants and culprit genes. METHODS: A total of 99 Han Chinese patients with DCM-induced chronic HF were selected and divided into one of three groups, namely, HF with normal renal function (Group 1), HF with mild RI (Group 2) and HF with moderate to severe RI (Group 3). Genomic DNA was extracted from each subject for genotyping. RESULTS: According to Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, top 10 lists of molecular function, cell composition and biological process of differential target genes and 15 signalling pathways were discriminated among the three groups. Additionally, sequencing results identified 26 significantly different single-nucleotide polymorphisms (SNPs) in the 15 signalling pathways, including three SNPs (rs57938337, rs6683225 and rs6692782) in ryanodine receptor 2 (RYR2) and two SNPs (rs12439006 and rs16958069) in RYR3. The genotype and allele frequencies of the five SNPs in RYR2 and RYR3 were significantly differential between HF (Group 1) and CRS (Group 2 + 3) patients. CONCLUSION: Twenty-six significantly different SNP loci in 17 genes of the 15 KEGG pathways were found in the three patient groups. Among these variants, rs57938337, rs6683225 and rs6692782 in RYR2 and rs12439006 and rs16958069 in RYR3 are associated with RI in Han Chinese patients with heart failure, suggesting that these variants may be used to identify patients susceptible to CRS in the future.

First case of endometrial cancer after yolk sac tumor in a patient with Li-Fraumeni syndrome.

BACKGROUND: Li-Fraumeni syndrome (LFS) is a rare autosomal dominant disease with high penetrance caused by a germline variant of TP53 gene. We report the first case of endometrial cancer after yolk sac tumor with LFS. CASE PRESENTATION: The presented female patient underwent right adnexectomy at age 23 because of a yolk sac tumor of the ovary. At the age of 27, the patient was diagnosed with endometrial adenocarcinoma, received cytoreductive surgery and chemotherapy. Given that her personal cancer history along with a strong family history of cancer, her father passing away from lung cancer at age 48 and her grandmother dying of ovarian cancer at age 50, the patient was referred for genetic counseling and testing. Genetic screening revealed a heterozygous pathogenic TP53 c.844C > T, p.( R282 W) with NM_000546.5 variant, a class 5 (C5) variant. This is the first reported case of a yolk sac tumor accompanied by subsequent endometrial cancer that is associated with LFS. CONCLUSIONS: We reported a first case of an endometrial cancer after yolk sac tumor patient with a tumor family history of harboring the germline TP53 pathogenic variation which expanded types of tumor that can be presented in patients with LFS. This case highlights the importance of genetic testing for patients with malignant tumors, as well as patients with a family history of malignant tumors. And our case highlights the necessity of screening for gynecologic tumor in LFS patients.

Acuminatums E and F, two new cyclic lipopeptides from Fusarium lateritium HU0053 and their antifungal activity.

Two new cyclic lipopeptides, acuminatums E (1) and F (2), together with four known cyclic lipopeptides, acuminatums A-D (3-6) were isolated from the corn culture of endophytic Fusarium lateritium HU0053. Their structures were elucidated by spectroscopic and advanced Marfey's amino acid analysis. All compounds were found to exhibit antifungal activities against Penicillium digitatum. Acuminatum F (2), a new cyclic lipopeptide containing an unusual 3, 4-dihydroxy-phenylalanine unit exhibited the strongest antifungal activities with inhibition zone of 6.5 mm at the dose of 6.25 µg. Therefore, acuminatum F might be a potential environmental-friendly preservative for citrus fruits.

miRNA-651-3p regulates EMT in ovarian cancer cells by targeting ZNF703 and via the MEK/ERK pathway.

miRNAs are non-coding single-stranded RNA molecules with many functions. Several miRNAs have been found to be dysregulated in ovarian cancer; however, the role of miR-651-3p in ovarian cancer remains unknown. Here, the expression level of miR-651-3p in ovarian tissue samples was determined via qRT-PCR, and then miR-651-3p was overexpressed and downregulated to study the functional changes in ovarian cancer cells. Based on previous research and database predictions, we analyzed the binding and regulatory effects of miR-651-3p on zinc finger protein 703 (ZNF703). We additionally evaluated the effect of miR-651-3p on epithelial-mesenchymal transition (EMT) and mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathways in ovarian cancer cells. We found that miR-651-3p was downregulated in ovarian cancer tissues. miR-651-3p expression was associated with inhibited proliferation, invasion, and migration of ovarian cancer cells and promoted cell cycle arrest. Additionally, miR-651-3p was found to target ZNF703 and affect EMT in ovarian cancer by activating the MEK/ERK signaling pathway. MiR-651-3p was downregulated in ovarian cancer, and suppressed the malignant biological behavior of ovarian cancer by inhibiting ZNF703 and the MEK/ERK pathway. Our findings on miR-651-3p provided new insights for the diagnosis and treatment of ovarian cancer.

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.

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.

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.

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.

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 immune-enhanced molecular subtype associated with BRCA1 mutations, immune checkpoints and clinical outcome in ovarian carcinoma.

Ovarian carcinoma has the highest mortality among the malignant tumours in gynaecology, and new treatment strategies are urgently needed to improve the clinical status of ovarian carcinoma patients. The Cancer Genome Atlas (TCGA) cohort were performed to explore the immune function of the internal environment of tumours and its clinical correlation with ovarian carcinoma. Finally, four molecular subtypes were obtained based on the global immune-related genes. The correlation analysis and clinical characteristics showed that four subtypes were all significantly related to clinical stage; the immune scoring results indicated that most immune signatures were upregulated in C3 subtype, and the majority of tumour-infiltrating immune cells were upregulated in both C3 and C4 subtypes. Compared with other subtypes, C3 subtype had a higher BRCA1 mutation, higher expression of immune checkpoints, and optimal survival prognosis. These findings of the immunological microenvironment in tumours may provide new ideas for developing immunotherapeutic strategies for ovarian carcinoma.

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.

Identification of long noncoding RNA RP11-89K21.1 and RP11-357H14.17 as prognostic signature of endometrial carcinoma via integrated bioinformatics analysis.

BACKGROUND: Endometrial carcinoma (EC) is one of the most common malignant tumors in gynecology. The potential functions and mechanisms of long noncoding RNAs (lncRNAs) in the occurrence and progression of EC remains unclear. It's meaningful to explore lncRNAs signature for providing prognostic value of EC. METHODS: The differentially expressed lncRNAs and their prognostic values in EC were investigated based on The Cancer Genome Atlas (TCGA) database; the transcriptional factors (TFs), the competing endogenous RNA (ceRNA) mechanism, functional regulatory network and immune infiltration of RP11-89K21.1 and RP11-357H14.17 were further explored by various bioinformatics tools and databases. RESULTS: We firstly identified high expression of RP11-89K21.1 and RP11-357H14.17 were closely associated with shorten overall survival (OS) and poor prognosis in patients with EC. We also elucidated the networks of transcription factor and co-expression genes associated with RP11-89K21.1 and RP11-357H14.17. Furthermore, the ceRNA network mechanism was successfully constructed through 2 lncRNAs (RP11-89K21.1 and RP11-357H14.17), 11 miRNAs and 183 mRNAs. Functional enrichment analysis revealed that the targeting genes of RP11-89K21.1 and RP11-357H14.17 were strongly associated with microRNAs in cancer, vessel development, growth regulation, growth factor and cell differentiation, and involved in pathways including pathways in cancer, microRNAs in cancer and apoptotic signaling pathway. CONCLUSIONS: We demonstrated for the first time that RP11-89K21.1 and RP11-357H14.17 may play crucial roles in the occurrence, development and malignant biological behavior of EC, and can be regarded as potential prognostic biomarkers for EC.

Identification of molecular marker associated with ovarian cancer prognosis using bioinformatics analysis and experiments.

BACKGROUND: Ovarian cancer is one of the three major malignant tumors of the female reproductive system, and the mortality associated with ovarian cancer ranks first among gynecologic malignant tumors. The pathogenesis of ovarian cancer is not yet clearly defined but elucidating this process would be of great significance for clinical diagnosis, prevention, and treatment. For this study, we used bioinformatics to identify the key pathogenic genes and reveal the potential molecular mechanisms of ovarian cancer; we used immunohistochemistry to validate them. METHODS: We analyzed and integrated four gene expression profiles (GSE14407, GSE18520, GSE26712, and GSE54388), which were downloaded from the Gene Expression Omnibus (GEO) database, with the aim of obtaining a common differentially expressed gene (DEG). Then, we performed Gene Ontology (GO) analysis and Kyoto Encyclopedia of Gene and Genome (KEGG) pathway analysis using the Database for Annotation, Visualization, and Integrated Discovery (DAVID). We then established a protein-protein interaction (PPI) network of the DEGs through the Search Tool for the Retrieval of Interacting Genes (STRING) database and selected hub genes. Finally, survival analysis of the hub genes was performed using a Kmplotter online tool. RESULTS: A total of 226 DEGs were detected after the analysis of the four gene expression profiles; of these, 87 were upregulated genes and 139 were downregulated. GO analysis results showed that DEGs were significantly enriched in biological processes including the G2/M transition of the mitotic cell cycle, the apoptotic process, cell proliferation, blood coagulation, and positive regulation of the canonical Wnt signaling pathway. KEGG analysis results showed that DEGs were particularly enriched in the cell cycle, the p53 signaling pathway, the Wnt signaling pathway, the Ras signaling pathway, the Rap1 signaling pathway, and tyrosine metabolism. We selected 50 hub genes from the PPI network, which had 147 nodes and 655 edges, and 30 of them were associated with the prognosis of ovarian cancer. We performed immunohistochemistry on phosphoserine aminotransferase 1 (PSAT1). PSAT1 was highly expressed in cancer tissues, and its expression level was related to clinical stage and tissue differentiation in ovarian cancer. A Cox proportional risk model suggested that high expression of PSAT1 and late clinical stage were independent risk factors for survival and prognosis of ovarian cancer patients. CONCLUSION: The detection of DEGs using bioinformatics analysis might be crucial to understanding the pathogenesis of ovarian cancer, especially the molecular mechanisms of its development. The association between PSAT1 expression and the occurrence, development, and prognosis of ovarian cancer was further verified by immunohistochemistry. The PSAT1 expression can be used as a prognostic marker to provide a potential target for the diagnosis and treatment of ovarian cancer.

Annexin A8 can serve as potential prognostic biomarker and therapeutic target for ovarian cancer: based on the comprehensive analysis of Annexins.

BACKGROUND: Annexins are involved in vesicle trafficking, cell proliferation and apoptosis, but their functional mechanisms in ovarian cancer remain unclear. In this study, we analyzed Annexins in ovarian cancer using different databases and selected Annexin A8 (ANXA8), which showed the greatest prognostic value, for subsequent validation in immunohistochemical (IHC) assays. METHODS: The mRNA expression levels, genetic variations, prognostic values and gene-gene interaction network of Annexins in ovarian cancer were analyzed using the Oncomine, Gene Expression Profiling Interactive Analysis (GEPIA), cBioPortal, Kaplan-Meier plotter and GeneMANIA database. ANXA8 was selected for analyzing the biological functions and pathways of its co-expressed genes, and its correlation with immune system responses via the Database for Annotation, Visualization, and Integrated Discovery (DAVID) and the TISIDB database, respectively. We validated the expression of ANXA8 in ovarian cancer via IHC assays and analyzed its correlation with clinicopathological parameters and prognosis. RESULTS: ANXA2/3/8/11 mRNA expression levels were significantly upregulated in ovarian cancer, and ANXA5/6/7 mRNA expression levels were significantly downregulated. Prognostic analysis suggested that significant correlations occurred between ANXA2/4/8/9 mRNA upregulation and poor overall survival, and between ANXA8/9/11 mRNA upregulation and poor progression-free survival in patients with ovarian serous tumors. Taken together, results suggested that ANXA8 was most closely associated with ovarian cancer tumorigenesis and progression. Further analyses indicated that ANXA8 may be involved in cell migration, cell adhesion, and vasculature development, as well as in the regulation of PI3K-Akt, focal adhesion, and proteoglycans. Additionally, ANXA8 expression was significantly correlated with lymphocytes and immunomodulators. The IHC results showed that ANXA8 expression was higher in the malignant tumor group than in the borderline and benign tumor groups and normal ovary group, and high ANXA8 expression was an independent risk factor for survival and prognosis of ovarian cancer patients (P = 0.013). CONCLUSIONS: Members of the Annexin family display varying degrees of abnormal expressions in ovarian cancer. ANXA8 was significantly highly expressed in ovarian cancer, and high ANXA8 expression was significantly correlated with poor prognosis. Therefore, ANXA8 is a high candidate as a novel biomarker and therapeutic target for ovarian cancer.

Systematic profiling of alternative splicing signature reveals prognostic predictor for cervical cancer.

AIM: Cervical cancer is a common malignant carcinoma of the gynecological tract with high morbidity and mortality. Therefore, it is crucial to elucidate the pathogenesis, prevention, diagnosis and prognosis of cervical cancer by searching for the involved key genes. METHOD: In this study, the alternative splicing (AS) events of 253 patients with cervical cancer were analyzed, and 41,766 AS events were detected in 9961 genes. Univariate analysis was performed to screen prognostic AS events. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was used to identify the pathways in which these AS events were involved. RESULTS: We found that exon skip (ES) is the main AS event in patients with cervical cancer. There was pronounced consistency between the genes involved in overall survival and those involved in recurrence. At the same time, we found that a gene may exhibit several different types of AS events, and these different AS events may be related to prognosis. Four characteristic genes, HSPA14, SDHAF2, CAMKK2 and TM9SF1, that can be used as prognostic markers for cervical cancer were selected. CONCLUSION: The importance of AS events in the development of cervical cancer and prediction of prognosis was revealed by a large amount of data at the whole genome level, which may provide a potential target for cervical cancer treatment. We also provide a new method for exploring the pathogenesis of cervical cancer to determine clinical treatment and prognosis more accurately.

Photothermal treatment with EGFRmAb-AuNPs induces apoptosis in hypopharyngeal carcinoma cells via PI3K/AKT/mTOR and DNA damage response pathways.

Hypopharyngeal carcinoma (HC) is one of the most malignant tumors in the upper aerodigestive tract. Currently, there are no effective treatments for HC. Gold nanoparticles (AuNPs) are a promising tool that can be used for plasmonic photothermal therapy (PPTT), which refers to the use of electromagnetic radiation, most often in near infrared (NIR) region, for the treatment of various medical conditions including cancer. AuNPs have been proved to be a promising tool for NIR spectroscopy-mediated photothermal therapies. In this study, we chemically conjugated AuNPs with a monoclonal antibody (mAb) targeting the epidermal growth factor receptor (EGFR), a cell-surface receptor that is overexpressed in many cancers. We then assessed the effect of NIR photothermal treatment with the EGFRmAb-AuNPs in FaDu HC cells. Our data showed that nanoparticle conjugation with the EGFRmAb improved the specific targeting towards FaDu cells and reduced cytotoxicity towards normal (293 T) cells which do not overexpress the EGFR. A significant amount of our EGFRmAb-conjugated AuNPs could enter the nucleus. Moreover, the expression levels of double strand DNA break repair proteins, including p-ATR, p-CHK1, and p-CHK2 were increased following AuNPs treatment, indicating the presence of DNA damage. These findings suggest that the AuNPs can potentially disrupt genome integrity and induce apoptosis. In addition, EGFRmAb-AuNPs+NIR could induce FaDu cell apoptosis, accompanied by the inhibition of the PI3K/AKT/mTOR pathway and stimulation of DNA damage response. Based on these data, PPTT using the EGFRmAb-AuNPs could be a new promising treatment for HC.