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Overexpressing PLOD family genes predict poor prognosis in gastric cancer.

ABSTRACT: Procollagen-lysine, 2-oxoglutarate 5-dioxygenases (PLODs) are a set of enzymes involved in the hydroxylation of lysine and stabilization of collagen by crosslinks. Previous studies have highlighted that overexpressing PLOD genes were related to the progression, migration and progression of different human cancers. However, the diverse expression patterns and prognostic values of PLOD genes remain to be elucidated in gastric cancer (GC). In this study, we mined the expression and survival data in GC patients through ONCOMINE, UALCAN and Kaplan-Meier Plotter database. STRING portal couple with DAVID was used to establish a functional protein interaction network of PLOD family genes and analyze the GO and KEGG enriched pathways. Differential gene expression correlated with PLOD family genes was identified with LinkedOmics. We found that PLOD1, 2 and 3 were up-regulated in GC patients compared with normal tissues. High expression levels of PLOD1 and PLOD3 were associated with shorter overall survival (OS), first progression (FP) and post progression survival (PPS) while high expression level of PLOD2 was only associated with shorter FP in all GC patients. Specifically, only high PLOD2 expression had significant correlation with shorter OS, FP and PPS in the diffuse type GC patients. Furthermore, combinatorial use of expressions of all PLOD genes was a superior prognostic indicator for GC patients. Pathway analysis confirmed that PLOD family genes mainly participate in regulating the collagen metabolism and extracellular matrix constitution, and the cellular adaptor protein SHC1, which helps to transduce an extracellular signal into an intracellular signal, could be the regulatory module mediating PLOD's effect on GC. Therefore, we propose that individual PLOD genes or PLOD family genes as a whole could be potential prognostic biomarkers for GC.

SUBMITTER: Li SS

PROVIDER: S-EPMC6930397 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Overexpressing PLOD family genes predict poor prognosis in gastric cancer.

Li Shan-Shan SS Lian Yi-Fan YF Huang Yan-Lin YL Huang Yue-Hua YH Xiao Jian J

Journal of Cancer 20200101 1

Procollagen-lysine, 2-oxoglutarate 5-dioxygenases (PLODs) are a set of enzymes involved in the hydroxylation of lysine and stabilization of collagen by crosslinks. Previous studies have highlighted that overexpressing PLOD genes were related to the progression, migration and progression of different human cancers. However, the diverse expression patterns and prognostic values of PLOD genes remain to be elucidated in gastric cancer (GC). In this study, we mined the expression and survival data in ...[more]

PMID: 31892979

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Project description:BackgroundKinesin superfamily proteins (KIFs) can transport membranous organelles and protein complexes in an ATP-dependent manner. Kinesin family member 15 (KIF15) is overexpressed in various cancers. However, the function of KIF15 in gastric cancer (GC) is still unclear.MethodsGC patients' data from The Cancer Genome Atlas (TCGA) were analyzed by bioinformatics methods. The expression of KIF15 was examined in GC and paracarcinoma tissues from 41 patients to verify the analysis results. The relationship between KIF15 expression and clinical characteristics were also observed by bioinformatics methods. Kaplan-Meier survival analysis of 122 GC patients in our hospital was performed to explore the relationship between KIF15 expression levels and GC patients' prognosis. KIF15 was downregulated in GC cell lines AGS and SGC-7901 by transfecting a lentivirus-mediated shRNA plasmid targeting KIF15. In vitro, GC cell proliferation and apoptosis were detected by MTT assay, colony formation assay, and Annexin V-APC staining. In vivo, xenograft experiments were used to verify the in vitro results. Furthermore, Human Apoptosis Antibody Array kit was used to screen possible targets of KIF15 in GC cell lines.ResultsThe bioinformatics results showed that KIF15 expression levels were higher in GC tissues than in normal tissues. IHC showed same results. High expression of KIF15 was statistical correlated with high age and early histologic stage. Kaplan-Meier curves indicated that high KIF15 expression predict poor prognosis in patients with GC. MTT assay and colony formation assay showed that KIF15 promote GC cell proliferation. Annexin V-APC staining found that KIF15 can inhibit GC cell apoptosis. Xenograft experiments reveal that downregulating KIF15 can inhibit GC tumor growth and promote GC apoptosis. Through detection of 43 anti-apoptotic proteins by the Human Apoptosis Antibody Array kit, it was confirmed that knocking down KIF15 can reduce seven anti-apoptotic proteins expression.ConclusionsTaken together, our study revealed a critical role for KIF15 to inhibit GC cell apoptosis and promote GC cell proliferation. KIF15 may decrease anti-apoptotic proteins expression by regulating apoptosis pathways. High expression of KIF15 predicts a poor prognosis in patients with GC. KIF15 might be a novel prognostic biomarker and a therapeutic target for GC.

Project description:Background:Ranking fourth in the world in tumor incidence and second in cancer-related death worldwide, gastric cancer (GC) is one of the major malignant tumors, and has a very complicated pathogenesis. In the present study, we aimed to identify new biomarkers to predict the survival rate of GC patients. Methods:The differentially expressed genes (DEGs) between GC tissues and normal stomach tissues were obtained by using GEO2R, and overlapped DEGs were acquired with Venn diagrams. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were conducted with R software. Then, the protein-protein interaction (PPI) of these DEGs was visualized by Cytoscape. Gene Expression Profiling Interactive Analysis (GEPIA) was used to verify the expression differences of hub genes in gastric adenocarcinoma tissues and normal tissues. Overall survival (OS) of hub genes was calculated by Kaplan-Meier plotter. Results:There were a total of 128 consistently expressed genes in the two datasets: 85 upregulated genes were enriched in extra-cellular matrix (ECM)-receptor interaction, protein digestion and absorption, focal adhesion, gastric acid secretion, mineral absorption, systemic lupus erythematosus, amoebiasis, and PI3K-Akt signaling pathway, and 43 downregulated genes were enriched in palate development, blood coagulation, positive regulation of transcription from RNA polymerase II promoter, axonogenesis, receptor internalization, negative regulation of transcription from RNA polymerase II promoter, and in no significant signaling pathways. From the PPI network analyzed by Molecular Complex Detection (MCODE) plug-in, all 27 upregulated genes were selected. Furthermore, to analyze the OS among these genes, Kaplan-Meier analysis was conducted, and 25 genes were associated with remarkably worse survival. For validation in GEPIA, 11 of 25 genes were discovered to be highly expressed in GC tissues compared to normal OS tissues. Furthermore, in the re-analysis of the Database for Annotation, Visualization and Integrated Discovery (DAVID), three genes [G2/miotic-specific cyclin B1 (CCNB1), polo-like kinases 1 (PLK1), and pituitary tumor-transforming gene-1 (PTTG1)] were markedly enriched in the cell cycle pathway, particulary the G1-G1/S phase. Conclusions:Three remarkably upregulated DEGs with poor prognosis in GC were identified and may serve as new prognostic biomarkers and targets in GC therapy.

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Overexpressing PLOD family genes predict poor prognosis in gastric cancer.

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Overexpressing PLOD family genes predict poor prognosis in gastric cancer.

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