Abstract
Gastric cancer (GC) is a common tumor-associated lethal disease, and invasiveness and metastasis are primary challenges in its clinical treatment. Hypoxia microenvironment cannot be ignored in the process of metastasis. Hypoxia inducible factor-1α (HIF-1α) is the core component of the hypoxia signaling pathway. The aim of this study was to identify potential hub genes and signaling pathways associated with HIF-1α. We explored the invasiveness- and metastasis-associated phenotype of GC via bioinformatics analysis and molecular studies. Differentially expressed genes (DEGs) were identified in GC cells and HIF-1α-knockdown GC cells. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed, and a protein-protein interaction (PPI) network was constructed. Hub genes were identified via centrality analysis and Molecular Complex Detection (MCODE) module analysis. The findings suggested that prolyl 4-hydroxylase beta polypeptide (P4HB) has strong associations with HIF-1α. Further, we observed that HIF-1α and P4HB were upregulated in SGC-7901 and BGC-823 cells. In addition, inhibition of HIF-1α expression reduced invasion and metastasis in GC cells; this effect was partially reversed by P4HB overexpression. Our results confirm that P4HB plays a significant role in the regulatory network of HIF-1α. Therefore, HIF-1α and P4HB may be considered potential biomarkers of GC.
Highlights
Gastric cancer (GC) is the most common malignant tumor of the digestive system
Western blot and Reverse TranscriptionPolymerase Chain Reaction (RT-PCR) results showed that both Hypoxia induction factors (HIFs)- α and P HB were overexpressed in GC cells compared to their levels in GES1 cells (Figures 5(a)–5(d), P < 0.05) under 1% O2
The results showed that reduction of HIF- α inhibited the invasion and metastasis of GC cells (Figures 7 and 8, P < 0.01); this decrease was partially rescued by the overexpression of P HB
Summary
Gastric cancer (GC) is the most common malignant tumor of the digestive system. progress has been reported in terms of treatment, it is still the second leading cause of cancer-related death [1]. Recent gene expression profiling studies of GC in the last decade have revealed differentially expressed genes (DEGs) related to different signaling pathways. Based on these results, a plethora of molecular targeted drugs have been approved in the last ten years and used in clinical practice. High levels of PDIs are associated with lymphatic metastases of cancers, as confirmed by proteomic and protein functional studies [21]. These studies confirm the potential carcinogenicity of P HB. The present findings indicated that HIF- α suppresses the expression of P HB and promotes GC invasion and metastasis
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