ARL4C might serve as a prognostic factor and a novel therapeutic target for gastric cancer: bioinformatics analyses and biological experiments.
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ABSTRACT:
SUBMITTER: Xie N
PROVIDER: S-EPMC8051716 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundOur previous studies demonstrate that ARL4C is the most critical clinical biomarker for gastric cancer (GC) patients among ARL family members (ARLs) and functions as an oncogene in GC. However, its underlying mechanisms in GC need to be further illustrated. In this study, we aim to explore the upstream and downstream molecular mechanisms of ARL4C in GC cells.MethodsThe genetic alteration of ARL4C in GC is analyzed by cBioPortal database. Potential ARL4C-targeted microRNAs (miRs) are predicted by three databases. The high-throughput RNA sequencing is performed to explore the underlying mechanisms of ARL4C in GC cells. The effects of predicted microRNAs on ARL4C, the RNA-sequencing results validation and the biological functions of ARL4C in GC cells are illustrated by in vitro experiments.ResultsGenetic analyses indicate that ARL4C is significantly upregulated in GC, which is not caused by gene amplification. MicroRNAs prediction shows the high relevance between ARL4C and miR-302 members. Moreover, miR-302c or miR-302d transfection reduces ARL4C protein expression in GC cells. Based on the high-throughput RNA sequencing of ARL4C-knockdown cells, enrichment analyses demonstrate that ARL4C is closely related to cell growth and involved in p53 signaling. Moreover, there are strong gene-gene interactions between ARL4C and genes in p53 signaling, and ARL4C downregulation could inhibit the protein expression of MDM2, a critical gene in p53 pathway. Further functional experiments demonstrate that ARL4C silencing leads to cell cycle arrest and increased cell apoptosis in AGS and MKN45 cells.ConclusionOur data suggest that miR-302c and miR-302d may function as the upstream regulators of ARL4C. And, ARL4C might promote GC cell cycle progression via regulating p53 signaling. Our findings provide novel insights into the key role of ARL4C and the underlying mechanisms in GC progression, thus facilitating the development of ARL4C-targeted therapy.
| S-EPMC8053516 | biostudies-literature
Project description:BackgroundGastric carcinoma (GC) is one of the most aggressive primary digestive cancers. It has unsatisfactory therapeutic outcomes and is difficult to diagnose early.AimTo identify prognostic biomarkers for GC patients using comprehensive bioinformatics analyses.MethodsDifferentially expressed genes (DEGs) were screened using gene expression data from The Cancer Genome Atlas and Gene Expression Omnibus databases for GC. Overlapping DEGs were analyzed using univariate and multivariate Cox regression analyses. A risk score model was then constructed and its prognostic value was validated utilizing an independent Gene Expression Omnibus dataset (GSE15459). Multiple databases were used to analyze each gene in the risk score model. High-risk score-associated pathways and therapeutic small molecule drugs were analyzed and predicted, respectively.ResultsA total of 95 overlapping DEGs were found and a nine-gene signature (COL8A1, CTHRC1, COL5A2, AADAC, MAMDC2, SERPINE1, MAOA, COL1A2, and FNDC1) was constructed for the GC prognosis prediction. Receiver operating characteristic curve performance in the training dataset (The Cancer Genome Atlas-stomach adenocarcinoma) and validation dataset (GSE15459) demonstrated a robust prognostic value of the risk score model. Multiple database analyses for each gene provided evidence to further understand the nine-gene signature. Gene set enrichment analysis showed that the high-risk group was enriched in multiple cancer-related pathways. Moreover, several new small molecule drugs for potential treatment of GC were identified.ConclusionThe nine-gene signature-derived risk score allows to predict GC prognosis and might prove useful for guiding therapeutic strategies for GC patients.
| S-EPMC7509999 | biostudies-literature
Project description:The role of HCK expression in the prognosis of breast cancer patients is unclear. Thus, this study aimed to explore the clinical implications of HCK expression in breast cancer. We assessed HCK expression and genetic variations in breast cancer using Oncomine, GEPIA, UALCAN, and cBioPortal databases. Then, immunochemistry was used to analyze HCK expression in breast cancer specimens, non-cancer tissues and metastatic cancer tissues. Consequently, we evaluated the effect of HCK expression on survival outcomes set as disease-free survival (DFS) and overall survival (OS). Finally, STRING, Coexpedia, and TISIDB database were explored to identify the molecular functions and regulation pathways of HCK. We found that breast cancer tissues have more HCK mRNA transcripts than non-cancer tissues. Patients with HCK expression had significantly shorter DFS and OS. The ratio of HCK expression was higher in cancer tissues than in non-cancer tissues. These results from STRING database, FunRich software, and TISIDB database showed that HCK was involved in mediating multiple biological processes including immune response-regulating signaling pathway, cell growth and maintenance through multiple signaling pathways including epithelial to mesenchymal transition, PI3K/AKT signaling pathway, and focal adhesion. Overall, HCK may be an oncogene in the development of breast cancer and thus may as a novel biomarker and therapeutic target for breast cancer.
| S-EPMC7645343 | biostudies-literature
Project description:This study aims to investigate the prognostic power of carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) in gastric cancer (GC) and its potential role in cancer development and progression. Data mining results show that CEACAM6 is overexpressed in gastric cancer and is correlated with lymph node metastasis. Subsequently, immunohistochemical staining was performed to determine CEACAM6 protein levels in paraffin gastric tumor specimens. Real-time reverse-transcription-polymerase chain reaction (RT-PCR) was conducted to detect CEACAM6 mRNA levels in fresh GC samples. CEACAM6 protein and mRNA levels were significantly up regulated in GC compared with paired normal mucosa. The IHC staining intensity of CEACAM6 was positively correlated with tumor size, Lauren's classification, vascular invasion, lymph node metastasis, distant metastasis, and TNM stage. CEACAM6 expression was inversely correlated with the five-year survival rate of GC patients. Cox multivariate analysis results demonstrated that the overall survival was independently correlated with CEACAM6 expression. A significant association was observed between CEACAM6 and distant metastases. Network analysis of downstream gene signatures revealed several hub genes such as SRC and DNM1L etc. which may mediating tumor promoting functions of CEACAM6. Further data mining discovered that Tamoxifen etc. could be therapeutic alternatives for gastric patients with CEACAM6 overexpression. Collectively, CEACAM6 overexpression is a common characteristic of GC and is associated with poor 5 year survival rate in GC. Besides, potential molecular mechanisms and treatment options were also provided.
| S-EPMC5663545 | biostudies-literature
Project description:Lung adenocarcinoma is the most common histological type of lung cancer and is classified into adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and invasive adenocarcinoma (IA). Atypical adenomatous hyperplasia (AAH) lesions are possible precursors to adenocarcinoma. However, the mechanism underlying the stepwise continuum of lung adenocarcinoma is unclear. In this study, the involvement of ADP-ribosylation factor (ARF)-like (ARL) 4C (ARL4C), a member of the small GTP-binding protein family, in the progression of lung adenocarcinoma and the possibility of ARL4C as a molecular target for lung cancer therapy were explored. ARL4C was frequently expressed in AAH and ARL4C expression in immortalized human small airway epithelial cells promoted cell proliferation and suppressed cell death. In addition, ARL4C was expressed with increased frequency in AIS, MIA and IA in a stage-dependent manner, and the expression was correlated with histologic grade, fluorine-18 fluorodeoxyglucose uptake and poor prognosis. An anti-sense oligonucleotide (ASO) against ARL4C (ARL4C ASO-1316) inhibited RAS-related C3 botulinum toxin substrate activity and nuclear import of Yes-associated protein and transcriptional coactivator with PDZ-binding motif, and suppressed in vitro proliferation and migration of lung cancer cells with KRAS or epidermal growth factor receptor (EGFR) mutations. In addition, transbronchial administration of ARL4C ASO-1316 suppressed orthotopic tumor formation induced by these cancer cells. Thus, ARL4C is involved in the initiation of the premalignant stage and is associated with the stepwise continuum of lung adenocarcinoma. ARL4C ASO-1316 would be useful for lung adenocarcinoma patients expressing ARL4C regardless of the KRAS or EGFR mutation.
| S-EPMC7060486 | biostudies-literature
Project description:Adamantinomatous craniopharyngioma (ACP) is considered a benign intracranial tumor, but it can also exhibit aggressive characteristics. Due to its unique location in the suprasellar, which brings it close to important nerves and vascular structures, ACP can often lead to significant neuroendocrine diseases. The current treatments primarily include surgical intervention, radiation therapy or a combination of the two, but these can lead to serious complications and adversely affect the quality of life of patients. Thus, it is important to identify effective and safe alternatives. Recently, studies have focused on the tumor genome, transcriptome and proteome in an attempt to identify potential therapeutic targets for clinical use. However, studies on this region of the CP are limited; thus, the present study focused on this region. The GSE94349 and GSE68015 datasets were downloaded from the Gene Expression Omnibus database and analyzed. In the in vitro studies, the effect of the matrix metalloproteinase (MMP)12 inhibitor, MMP408, on cell proliferation and protein expression was assessed. The results demonstrated that MMP408 effectively inhibited cell proliferation and migration of ACP cells, and decreased the expression levels of the related proteins. Thus, MMP12 may be used as a potential therapeutic target for the treatment of ACP.
| S-EPMC8161407 | biostudies-literature
Project description:OBJECTIVE:To explore the pathogenesis of gastric cancer through a bioinformatic approach to provide evidence for the prevention and treatment of gastric cancer. METHODS:The differentially expressed genes (DEGs) in gastric cancer and normal gastric mucosa in GSE79973 dataset were analyzed using GEO2R online tool. GO analysis and KEGG pathway enrichment analysis of the DEGs in DAVID database were performed. The protein interaction network was constructed using STRING database, and the key genes (Hub genes) were screened and their functional modules were analyzed using Cytoscape software. The GEPIA database was used to validate the Hub genes, and the Target Scan database was used to predict the microRNAs that regulate the target genes; OncomiR was used to analyze the expressions of the microRNAs in gastric cancer tissues and their relationship with the survival outcomes of the patients. RESULTS:A total of 181 DEGs were identified in gastric cancer, and 10 hub genes were screened by the protein- protein interaction network. Functional analysis showed that these DEGs were involved mainly in protein digestion and absorption, PI3K-Akt signaling pathway, ECM-receptor interaction and platelet activation signal pathway. GEPIA database validation showed that COL1A1 was highly expressed in gastric cancer tissues and was associated with a poor prognosis of patients with gastric cancer. MiR-129-5p was found to bind to the 3'UTR of COL1A1 mRNA, and compared with that in normal tissues, miR-129-5p expression was obviously down-regulated in gastric cancer tissues, and was correlated with the prognosis of the patients. CONCLUSIONS:COL1A1 under regulation by MiR-129-5p is a potential therapeutic target for gastric cancer.
| S-EPMC6743932 | biostudies-literature
Project description:Prefoldin subunits (PFDN), primarily known for co-chaperone function associated with cytoskeletal rearrangement, have been found involved in epithelial-mesenchymal transition (EMT) and cancer progression. However, studies focusing on the roles of PFDN in gastric cancer (GC) remain limited. The present study aims to evaluate the prognostic values of PFDN in GC. Prognostic roles of PFDNs were analyzed via the Kaplan-Meier platform, followed by subset analysis within various clinical parameters. High mRNA expression of PFDN2, PFDN3 and PFDN4 displayed poor overall survival (OS) while PFDN5 displayed favorable OS. In HER2+ subset, PFDN2, PFDN3, PFDN4 and PFDN6 displayed poor OS. In human epidermal growth factor receptor 2 (HER2-) subset, PFDN2, PFDN3 and PFDN4 displayed poor OS. In intestinal type subset, PFDN1 and PFDN2 displayed poor OS. In diffuse-type subset, PFDN2 and PFDN6 displayed poor OS. In moderate differentiation type subset, PFDN1 displayed poor OS. In poor differentiation type subset, PFDN2 and PFDN6 displayed poor OS. In metastasis negative subset, PFDN1, PFDN2 and PFDN6 displayed poor OS. In lymph node (LN) positive subset, PFDN2 and PFDN5 displayed poor OS. The present study provided insightful clues into the poor prognostic values of PFDNs in GC patients.
| S-EPMC7024841 | biostudies-literature
Project description:BackgroundAnnexins 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.MethodsThe 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.ResultsANXA2/3/8/11 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).ConclusionsMembers 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.
| S-EPMC6717992 | biostudies-literature
Project description:Gastric cancer (GC) is a common cancer and the leading cause of cancer-related death worldwide. To improve the diagnosis and treatment of GC, it is necessary to identify new biomarkers by investigating the cellular and molecular mechanisms. In this study, miR-30c-5p expression was significantly down-regulated in GC tissues by comprehensive analysis using multiple databases. The target genes of miR-30c-5p with up-regulated expression level in GC were identified, including ADAM12 (a disintegrin and metalloproteinase12), EDNRA (the Endothelin receptor type A), STC1 (stanniocalcin 1), and CPNE8 (the calcium-dependent protein, copine 8). The expression level of ADAM12 was significantly related to depth of invasion (p = 0.036) in GC patients. The expression level of EDNRA was significantly related to grade (P = 0.003), depth of invasion (P = 0.019), and lymphatic metastasis (P = 0.001). The expression level of CPNE8 was significantly related to grade (P = 0.043) and TNM stage (P = 0.027).Gene set enrichment analysis showed that they might participate in GC progression through cancer-related pathways. CIBERSORT algorithm analysis showed that their expressions were related to a variety of tumor-infiltrating immune cells. The higher expression of those target genes might be the independent risk factor for poor survival of GC patients, and they might be potential prognostic markers in GC patients.
| S-EPMC8523699 | biostudies-literature