Gene Regulation Network of Prognostic Biomarker YAP1 in Human Cancers: An Integrated Bioinformatics Study.

Background: Yes-associated protein 1 (YAP1) is the main downstream effector of the Hippo signaling pathway, which is involved in tumorigenesis. This study aimed to comprehensively understand the prognostic performances of YAP1 expression and its potential mechanism in pan-cancers by mining databases. Methods: The YAP1 expression was evaluated by the Oncomine database and GEPIA tool. The clinical significance of YAP1 expression was analyzed by the UALCAN, GEPIA, and DriverDBv3 database. Then, the co-expressed genes with YAP1 were screened by the LinkedOmics, and annotated by the Metascape and DAVID database. Additionally, by the MitoMiner 4.0 v tool, the YAP1 co-expressed genes were screened to obtain the YAP1-associated mitochondrial genes that were further enriched by DAVID and analyzed by MCODE for the hub genes. Results: YAP1 was differentially expressed in human cancers. Higher YAP1 expression was significantly associated with poorer overall survival and disease-free survival in adrenocortical carcinoma (ACC), brain Lower Grade Glioma (LGG), and pancreatic adenocarcinoma (PAAD). The LinkedOmics analysis revealed 923 co-expressed genes with YAP1 in adrenocortical carcinoma, LGG and PAAD. The 923 genes mainly participated in mitochondrial functions including mitochondrial gene expression and mitochondrial respiratory chain complex I assembly. Of the 923 genes, 112 mitochondrial genes were identified by MitoMiner 4.0 v and significantly enriched in oxidative phosphorylation. The MCODE analysis identified three hub genes including CHCHD1, IDH3G and NDUFAF5. Conclusion: Our findings showed that the YAP1 overexpression could be a biomarker for poor prognosis in ACC, LGG and PAAD. Specifically, the YAP1 co-expression genes were mainly involved in the regulation of mitochondrial function especially in oxidative phosphorylation. Thus, our findings provided evidence of the carcinogenesis of YAP1 in human cancers and new insights into the mechanisms underlying the role of YAP1 in mitochondrial dysregulation.

RNA sequencing analysis of FGF2-responsive transcriptome in skin fibroblasts.

BACKGROUND: Fibroblast growth factor 2 (FGF2) is a highly pleiotropic cytokine with antifibrotic activity in wound healing. During the process of wound healing and fibrosis, fibroblasts are the key players. Although accumulating evidence has suggested the antagonistic effects of FGF2 in the activation process of fibroblasts, the mechanisms by which FGF2 hinders the fibroblast activation remains incompletely understood. This study aimed to identify the key genes and their regulatory networks in skin fibroblasts treated with FGF2. METHODS: RNA-seq was performed to identify the differentially expressed mRNA (DEGs) and lncRNA between FGF2-treated fibroblasts and control. DEGs were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Furthermore, the networks between mRNAs and lncRNAs were constructed by Pearson correlation analysis and the networkanalyst website. Finally, hub genes were validated by real time-PCR. RESULTS: Between FGF2-treated fibroblasts and control fibroblasts, a total of 1475 DEGs was obtained. These DEGs were mainly enriched in functions such as the ECM organization, cell adhesion, and cell migration. They were mainly involved in ECM-receptor interaction, PI3K-Akt signaling, and the Hippo pathway. The hub DEGs included COL3A1, COL4A1, LOX, PDGFA, TGFBI, and ITGA10. Subsequent real-time PCR, as well as bioinformatics analysis, consistently demonstrated that the expression of ITGA10 was significantly upregulated while the other five DEGs (COL3A1, COL4A1, LOX, PDGFA, TGFBI) were downregulated in FGF2-treated fibroblasts. Meanwhile, 213 differentially expressed lncRNAs were identified and three key lncRNAs (HOXA-AS2, H19, and SNHG8) were highlighted in FGF2-treated fibroblasts. CONCLUSION: The current study comprehensively analyzed the FGF2-responsive transcriptional profile and provided candidate mechanisms that may account for FGF2-mediated wound healing.

Differential proteomic analysis of serum exosomes reveals alterations in progression of Parkinson disease.

Exosomes are nanometer-sized vesicles with intercellular communication functions, and their encapsulated proteins may participate in the pathological process of neurodegenerative disorders. The aim of this study was to identify the protein changes of serum exosomes in Parkinson disease (PD) patients with different disease progress types, and to identify potential biomarkers. The exosomes of PD patients with different severity and healthy control group were isolated from serum. The exosome proteins were analyzed by mass spectrometry with label-free quantitative proteomics. A total of 429 proteins were identified, of which 14 were significantly different in mild and severe PD patients. The expression levels of 7 proteins, including pigmented epithelium-derived factor, afamin, apolipoprotein D and J, were significantly increased in PD patients. The expression levels of 7 proteins, including complement C1q and protein Immunoglobulin Lambda Variable 1-33 (IGLV1-33)Cluster -33, were decreased in PD patients. These differentially expressed proteins were analyzed by gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis, which confirmed that the interaction between prion diseases and ECM receptors was the most significant pathways of enrichment. The changes of proteins and pathways may be related to the pathophysiological mechanism of PD. Therefore, some of these proteins could be considered as potential biomarkers for early PD diagnosis.

Realization and Technology Acceptance Test of a Wearable Cardiac Health Monitoring and Early Warning System with Multi-Channel MCGs and ECG.

In this work, a wearable smart clothing system for cardiac health monitoring with a multi-channel mechanocardiogram (MCG) has been developed to predict the myo-cardiac left ventricular ejection fraction (LVEF) function and to provide early risk warnings to the subjects. In this paper, the realization of the core of this system, i.e., the Cardiac Health Assessment and Monitoring Platform (CHAMP), with respect to its hardware, firmware, and wireless design features, is presented. The feature values from the CHAMP system have been correlated with myo-cardiac functions obtained from actual heart failure (HF) patients. The usability of this MCG-based cardiac health monitoring smart clothing system has also been evaluated with technology acceptance model (TAM) analysis and the results indicate that the subject shows a positive attitude toward using this wearable MCG-based cardiac health monitoring and early warning system.

Expression of RACGAP1 in high grade meningiomas: a potential role in cancer progression.

Recently, Rac GTPase-activating protein 1 (RACGAP1) has been shown to have a critical role in various tumors. The aim of the present study was to investigate the expression of RACGAP1 in human meningiomas and to compare these results with the clinicopathological parameters. Thirty-two cases, classified as 13 World Health Organization grade I (40.6 %), 10 grade II (31.3 %) and 9 grade III (28.1 %) primary meningiomas, were selected from our pathological files. Clinico-pathological data, including survival data, were also available. RACGAP1 expression in the meningiomas was measured by real-time quantitative PCR and western blot. Our results showed the level of RACGAP1 expression in grade III meningioma is higher than that of grade I. Higher levels of RACGAP1 mRNA were significantly correlated with tumor size, higher Simpson grade, histological type and clinical course (P < 0.05). Furthermore, the level of RACGAP1 expression mRNA was positively correlated with MIB-1 labeling index in different meningiomas tissue (r(2) = 0.3237, P = 0.0007). Additionally, Kaplan-Meier curves demonstrated a significantly worse survival in patients with high levels of RACGAP1 mRNA (P = 0.008). In conclusion, these findings suggest that RACGAP1 may be used as a potential predictor for tumor proliferative and patient prognosis in meningiomas.

Association between laminin γ1 expression and meningioma grade, recurrence, and progression-free survival.

BACKGROUND: Laminins are central components of basement membranes and play important roles in cell adhesion, proliferation, and migration. However, the role of laminins in tumor progression has not been thoroughly investigated in meningiomas. OBJECTIVE: The aim of the present study is to evaluate the expression of laminin γ1 in various grades of meningiomas in Chinese patients. METHODS: In the current study, clinical and pathological data for 32 meningioma patients with various tumor grades were collected. The expression of laminin γ1 in each tumor was assessed by using quantitative real-time polymerase chain reaction (qPCR), Western blot and immunohistochemical analysis and was correlated with the meningioma grade, tumor recurrence and patient survival. Patient prognoses were attained and the progression-free survival was calculated based on the Kaplan-Meier method. A two-sided probability cutoff of 0.05 was chosen for statistical significance. RESULTS: A total of 32 meningioma patients with various pathological subtypes (WHO grade I: 13, grade II: 10 and grade III: 9) were enrolled in this study. The qPCR results showed that laminin γ1 mRNA expression was significantly higher in grade III meningiomas than in grade I meningiomas (p < 0.05), although there was no significant difference in laminin γ1 expression between grade II and grade I meningiomas (p > 0.05). Western blot and immunohistochemistry analysis confirmed that the expression of laminin γ1 protein was relatively higher in grade III meningiomas when compared with grade I meningiomas. Higher levels of laminin γ1 expression in meningiomas are associated with a significantly shorter tumor recurrence time (p < 0.05) and a decreased patient survival time (p < 0.05). CONCLUSIONS: Our results suggest that laminin γ1 is associated with meningioma grades and could play a role in enhancing tumor invasion. Laminin γ1 could be used as a predictor for meningioma recurrence and patient survival. Furthermore, laminin γ1 may represent a druggable molecular target for future therapies for tumors that overexpress this marker.

PI3K expression and PIK3CA mutations are related to colorectal cancer metastases.

AIM: To assess the significance of phosphatidylinositol 3-kinase (PI3K) in colorectal cancer (CRC) and toxicity of LY294002 in CRC cells with different metastatic abilities. METHODS: Sixty formalin-fixed and paraffin-embedded CRC tumor specimens were investigated. Adjacent normal colonic mucosa specimens from 10 of these cases were selected as controls. PI3K protein was detected by immunohistochemistry and PIK3CA mutations were investigated by gene sequencing analysis. A flow-cytometry-based apoptosis detection kit was used to determine PI3K inhibitor-induced apoptosis in CRC cell lines SW480 and SW620. Expression of phosphorylated protein kinase B in CRC cell lines was detected by Western blotting. RESULTS: There was a significant difference in the proportion of primary lesions (30%, 18/60) vs metastatic lesions (46.7%, 28/60) that were positive for PI3K (P < 0.05). Mutations were detected in exon 9 (13.3%) and exon 20 (8.3%). Out of 60 cases, seven mutations were identified: two hotspot mutations, C.1633G>A resulting in E545A, and C.3140A>G resulting in H1047R; two novel missense mutations C.1624G>A and C.3079G>A; and three synonymous mutations (C.1641G>A, C.1581C>T and C.3027T>A). Exposure of SW480 cells to PI3K inhibitor for 48 h resulted in a significant increase of apoptotic cells in a dose-dependent manner [3.2% apoptotic cells in 0 µmol/L, 4.3% in 5 µmol/L, 6.3% in 10 µmol/L (P < 0.05), and 6.7% in 20 µmol/L (P < 0.05)]. Moreover, PI3K inhibitor induced a similar significant increase of apoptotic cells in the SW620 cell line for 48 h [3.3% apoptotic cells in 0 µmol/L, 13.3% in 5 µmol/L (P < 0.01), 19.2% in 10 µmol/L (P < 0.01), and 21.3% in 20 µmol/L (P < 0.01)]. CONCLUSION: High PI3K expression is associated with CRC metastasis. PI3K inhibitor induced apoptosis in CRC cells and displayed strong cytotoxicity for highly metastatic cells. PI3K inhibition may be an effective treatment for CRC.