Construction and analysis of a survival-associated competing endogenous RNA network in breast cancer

BackgroundRecently, increasing studies have shown that non-coding RNAs are closely associated with the progression and metastasis of cancer by participating in competing endogenous RNA (ceRNA) networks. However, the role of survival-associated ceRNAs in breast cancer (BC) remains unknown.MethodsThe Gene Expression Omnibus database and The Cancer Genome Atlas BRCA_dataset were used to identify differentially expressed RNAs. Furthermore, circRNA-miRNA interactions were predicted based on CircInteractome, while miRNA-mRNA interactions were predicted based on TargetScan, miRDB, and miRTarBase. The survival-associated ceRNA networks were constructed based on the predicted circRNA-miRNA and miRNA-mRNA pairs. Finally, the mechanism of miRNA-mRNA pairs was determined. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of survival-related mRNAs were performed using the hypergeometric distribution formula in R software.The prognosis of hub genes was confirmed using gene set enrichment analysis.ResultsBased on the DE-circRNAs of the top 10 initial candidates, 162 DE-miRNAsand 34 DE-miRNAs associated with significant overall survival were obtained. The miRNA target genes were then identified using online tools and verified using the Cancer Genome Atlas (TCGA) database. Overall, 46 survival-associated DE-mRNAs were obtained. The results of GO and KEGG pathway enrichment analyses implied that up-regulated survival-related DE-mRNAs were mostly enriched in the “regulation of cell cycle” and “chromatin” pathways, while down-regulated survival-related DE-mRNAs were mostly enriched in “negative regulation of neurotrophin TRK receptor signaling” and “interleukin-6 receptor complex” pathways. Finally, the survival-associated circRNA-miRNA-mRNA ceRNA network was constructed using 34 miRNAs, 46 mRNAs, and 10 circRNAs. Based on the PPI network, two ceRNA axes were identified. These ceRNA axescould be considered biomarkers for BC.GSEA results revealed that the hub genes were correlated with “VANTVEER_BREAST_CANCER_POOR_PROGNOSIS”, and the hub genes were verified using BC patients' tissues.ConclusionsIn this study, we constructed a circRNA-mediated ceRNA network related to BC. This network provides new insight into discovering potential biomarkers for diagnosing and treating BC

Calcium-binding protein S100P promotes tumor progression but enhances chemosensitivity in breast cancer

Background: Chemoresistance remains one of the obstacles to overcome in the treatment of breast cancer. S100 calcium-binding protein P (S100P) has been observed to be overexpressed in several cancers and has been associated with drug resistance, metastasis, and prognosis. However, the role of S100P in chemoresistance in breast cancer has not been thoroughly determined. Methods: Immunohistochemistry was used to evaluate the expression level of S100P protein in 22 pairs (pre-chemo and post-chemo) of breast cancer tissue from patients who underwent neoadjuvant chemotherapy. The influence of S100P on the biological behavior and chemosensitivity of breast cancer cells was then investigated. Results: The protein level of S100P in breast cancer tissue was significantly higher than in benign fibroadenoma (p<0.001). The S100P expression level was shown to be decreased by 46.55% after neoadjuvant chemotherapy (p=0.015). Subgroup analysis revealed that S100P reduction (57.58%) was mainly observed in the HER2+ tumors (p=0.027). Our in-vitro experiments showed that the knockdown of S100P suppressed the proliferation, adhesion, migration and invasion abilities of T47D and SK-BR-3 breast cancer cells. We further demonstrated that this knockdown increased the chemoresistance to paclitaxel and cisplatin in SK-BR-3 cells. We found that S100P exerted its function by activating NF-κB, CCND1 and Vimentin, but downregulating E-cadherin. Conclusions: S100P promotes the aggressive properties of breast cancer cells and may be considered as a promising therapeutic target. Moreover, S100P can be used to predict the therapeutic effect of chemotherapy in HER2+ breast cancer patients

Tim-3 promotes cell aggressiveness and paclitaxel resistance through the NF-κB /STAT3 signalling pathway in breast cancer cells

Objective: Although T-cell immunoglobulin and mucin-domain containing molecule-3 (Tim-3) has been recognized as a promising target for cancer immunotherapy, its exact role in breast cancer has not been fully elucidated. Methods: Tim-3 gene expression in breast cancer and its prognostic significance were analyzed. Associated mechanisms were then explored in vitro by establishing Tim-3-overexpressing breast cancer cells. Results: In a pooled analysis of The Cancer Genome Atlas (TCGA) database, Tim-3 gene expression levels were significantly higher (P<0.001) in breast cancer tissue, compared with normal tissues. Tim-3 was a prognosis indicator in breast cancer patients [relapse-free survival (RFS), P=0.004; overall survival (OS), P=0.099]. Tim-3 overexpression in Tim-3low breast cancer cells promoted aggressiveness of breast cancer cells, as evidenced by enhanced proliferation, migration, invasion, tight junction deterioration and tumor-associated tubal formation. Tim-3 also enhanced cellular resistance to paclitaxel. Furthermore, Tim-3 exerted its function by activating the NF-κB/STAT3 signalling pathway and by regulating gene expression [cyclin D1 (CCND1), C-Myc, matrix metalloproteinase-1(MMP1), TWIST, vascular endothelial growth factor (VEGF) upregulation, concomitant with E-cadherin downregulation). Lastly, Tim-3 downregulated tight junction-associated molecules zona occludens (ZO)-2, ZO-1 and occludin, which may further facilitate tumor progression. Conclusions: Tim-3 plays an oncogenic role in breast cancer and may represent a potential target for antitumor therapy

Corporate Social Responsibility and the Long-Term Performance of Mergers and Acquisitions: Do Regions and Related-Party Transactions Matter?

This study investigates the effects of geographical regions and related-party transactions on corporate social responsibility (CSR) and long-term mergers and acquisitions (M&amp;A) performance linkage. We conduct a Heckman two-stage model analysis, using data from listed firms in the Shanghai and Shenzhen stock exchange markets in China. The results indicate that: (1) buyers&rsquo; CSR performance has a significant and positive effect on long-term M&amp;A performance. (2) Significant differences exist across geographical regions in the links between CSR and long-term M&amp;A performance. In our study, the effects of CSR on long-term M&amp;A performance were positive and significant in a sub-sample of firms located in the eastern region, but the effects were negative and insignificant in a sub-sample of firms located in regions other than in the east. (3) Related-party M&amp;A transactions experience more positive and significant CSR long-term M&amp;A performance linkage, compared to non-related party M&amp;A transactions. Our findings might provide more robust evidence to CSR performance linkage, as we have examined the linkage in a special context of M&amp;A activities, using a Heckman two-stage model to alleviate endogeneity bias. We also bring further insights into the effects of two contingent factors (geographical regions and related-party transactions) on the CSR-performance linkage. The findings of this article suggest that it is reasonable for firms to act socially responsibly when generating economic benefits. Policy makers should consider how to encourage firms to better fulfill CSR through improving the market environment and by enhancing their levels of supervision

Condensation Dripping Water Detection and Its Control Method from Exhaust Pipe of Gasohol Vehicle under Low Environmental Temperature Conditions: A Case Study in Harbin, China

Gasohol is one of renewable clean alternative energies, which is widely used around the world. Gasohol had been raised to be used in 9 provinces of China since 2001. However, its closed use was merely promoted in Heilongjiang province since November 1, 2004. Moreover, this issue aroused extensive discussions and controversies. One of them is the condensation dripping water issue from exhaust pipe in cold winter. Does the ethanol cause the road freezing in cold winter? To deal with this issue, taking the Harbin city as a case study, this work designs detection experiments of the condensation dripping water from exhaust pipe. Moreover, the amount of the condensation dripping water from exhaust pipe for gasohol and gasoline vehicles with the same working condition is obtained and measured, and their results are compared and analyzed. Simultaneously, the method of reducing the condensation dripping water is proposed. The results illustrate the effectiveness of the proposed method

Integrated transcriptome analysis identifies APPL1/RPS6KB2/GALK1 as immune-related metastasis factors in breast cancer

The aim of this study is to investigate the prognostic immune-related factors in breast cancer (BC) metastasis. The gene expression chip GSE159956 was downloaded from the gene expression omnibus database. Differentially expressed genes (DEGs) were selected using GEO2R online tools based on lymph node and metastasis status. The intersected survival-associated DEGs were screened from the Kaplan–Meier curve. Gene ontology (GO) and Kyoto Encyclopedia of Gene and Genome (KEGG) annotation analyses were performed to determine the survival-associated DEGs. Immune-related prognostic factors were screened based on immune infiltration. The screened prognostic factors were verified by the Cancer Genome Atlas (TCGA) database and single-sample gene set enrichment analysis (ssGSEA). As a result, twenty-eight upregulated and three downregulated genes were generated by the survival analysis. The enriched GO and KEGG pathways were mostly correlated with “regulation of cellular amino acid metabolic process,” “proteasome complex,” “endopeptidase activity,” and “proteasome.” Six of 19 (17 upregulated and 2 downregulated) immune-related prognostic factors were verified by the TCGA database. Four immune-related factors were obtained after ssGSEA, and three significant immune-related factors were selected after univariate and multivariate analyses. Based on the risk score receiver operating characteristic, the three immune-related prognosis factors could be potential biomarkers of BC metastasis. In conclusion, APPL1, RPS6KB2, and GALK1 may play a pivotal role as potential biomarkers for prediction of BC metastasis

Tim-3 promotes tube formation and decreases tight junction formation in vascular endothelial cells

As a negative immune checkpoint molecule, T cell immunoglobulin domain and mucin domain containing molecule-3 (Tim-3) has been found to serve a crucial role in immune escape and tumour progression. Previous studies have reported that Tim-3 is important to endothelial cells and it has also been demonstrated to be involved in numerous types of human disease, including melanoma, lymphoma, rickettsial infection and atherosclerosis; however, its exact mechanism of action remains largely unknown. In the present study, Tim-3 was overexpressed in vascular endothelial HMVECs and HUVECs and in vitro assays were used to determine that Tim-3 promoted cell proliferation, migration, invasion and tube formation through activating cyclin D1, Ras homolog gene family member A and vascular endothelial growth factor receptor 2 (VEGFR2). Additionally, Tim-3 decreased tight junction (TJ) formation and the transepithelial resistance of endothelial cells by decreasing the expression levels of TJ protein 2, Occludin and claudin 1. In conclusion, these findings suggested that Tim-3 may exert a positive role in angiogenesis and a negative role in TJ formation in vascular endothelial cells, which may provide novel strategies for the treatment of Tim-3 associated diseases

Datasheet5_Construction and analysis of a survival-associated competing endogenous RNA network in breast cancer.zip

BackgroundRecently, increasing studies have shown that non-coding RNAs are closely associated with the progression and metastasis of cancer by participating in competing endogenous RNA (ceRNA) networks. However, the role of survival-associated ceRNAs in breast cancer (BC) remains unknown.MethodsThe Gene Expression Omnibus database and The Cancer Genome Atlas BRCA_dataset were used to identify differentially expressed RNAs. Furthermore, circRNA-miRNA interactions were predicted based on CircInteractome, while miRNA-mRNA interactions were predicted based on TargetScan, miRDB, and miRTarBase. The survival-associated ceRNA networks were constructed based on the predicted circRNA-miRNA and miRNA-mRNA pairs. Finally, the mechanism of miRNA-mRNA pairs was determined. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of survival-related mRNAs were performed using the hypergeometric distribution formula in R software.The prognosis of hub genes was confirmed using gene set enrichment analysis.ResultsBased on the DE-circRNAs of the top 10 initial candidates, 162 DE-miRNAsand 34 DE-miRNAs associated with significant overall survival were obtained. The miRNA target genes were then identified using online tools and verified using the Cancer Genome Atlas (TCGA) database. Overall, 46 survival-associated DE-mRNAs were obtained. The results of GO and KEGG pathway enrichment analyses implied that up-regulated survival-related DE-mRNAs were mostly enriched in the “regulation of cell cycle” and “chromatin” pathways, while down-regulated survival-related DE-mRNAs were mostly enriched in “negative regulation of neurotrophin TRK receptor signaling” and “interleukin-6 receptor complex” pathways. Finally, the survival-associated circRNA-miRNA-mRNA ceRNA network was constructed using 34 miRNAs, 46 mRNAs, and 10 circRNAs. Based on the PPI network, two ceRNA axes were identified. These ceRNA axescould be considered biomarkers for BC.GSEA results revealed that the hub genes were correlated with “VANTVEER_BREAST_CANCER_POOR_PROGNOSIS”, and the hub genes were verified using BC patients' tissues.ConclusionsIn this study, we constructed a circRNA-mediated ceRNA network related to BC. This network provides new insight into discovering potential biomarkers for diagnosing and treating BC.</p