BackgroundHypoxia is one driving factor of gastric cancer. It causes a series of immunosuppressive processes and malignant cell responses, leading to a poor prognosis. It is clinically important to identify the molecular markers related to hypoxia.MethodsWe screened the prognostic markers related to hypoxia in The Cancer Genome Atlas database, and a risk score model was developed based on these markers. The relationships between the risk score and tumor immune microenvironment were investigated. An independent validation cohort from Gene Expression Omnibus was applied to validate the results. A nomogram of risk score model and clinicopathological factor was developed to individually predict the prognosis.ResultsWe developed a hypoxia risk score model based on SERPINE1 and EFNA3. Quantified real-time PCR was further applied to verified gene expressions of SERPINE1 and EFNA3 in gastric cancer patients and cell lines. A high-risk score is associated with a poor prognosis through the immunosuppressive microenvironment and immune escape mechanisms, including infiltration of immunosuppressive cells, expression of immune checkpoint molecules, and enrichment of signal pathways related to cancer and immunosuppression. The nomogram basing on the hypoxia-related risk score model showed a good ability to predict prognosis and high clinical net benefits.ConclusionsThe hypoxia risk score model revealed a close relationship between hypoxia and tumor immune microenvironment. The current study potentially provides new insights of how hypoxia affects the prognosis, and may provide a new therapeutic target for patients with gastric cancer.
Background
LncRNAs are known to play a crucial role in the initiation and progression of human diseases, especially cancers. Our previous study demonstrated that dysregulation of LINC02532 facilitated the malignant phenotype of gastric cancer (GC). However, the potential molecular mechanisms regarding the upstream and downstream regulation of LINC02532 in GC progression remain unclear.
Methods
RNA-Seq and clinical data from public databases were used for gene expression and clinical analyses. The subcellular location of LINC02532 was predicted by the bioinformatics tools and further validated by the RNA-Fluorescence in situ hybridization (FISH) assay. The effect of FOXF2/LINC02532/SOX7 axis in GC cell migration and invasion was evaluated using in vitro and in vivo assays. The transcriptional regulation role of FOXF2 and the mRNA stability of SOX7 were explored by dual-luciferase reporter assay and Actinomycin-D drug assay.
Results
We found that high LINC02532 expression was associated with poor prognosis of GC. Furthermore, a Cox regression model indicated that LINC02532 was an independent prognostic factor for GC patients. Using in vitro and in vivo assays, we found that LINC02532 promoted GC cell migration and invasion, as well as tumour growth and metastasis in nude mice. Mechanistically, LINC02532 decreased SOX7 mRNA stability by binding to its 3’UTR, resulting in reduced SOX7 expression. In addition, FOXF2 was identified as a transcriptional factor of LINC02532 and was shown to repress LINC02532 expression by negative transcriptional regulation.
Conclusions
Together, these findings show that LINC02532 promotes GC progression through epithelial–mesenchymal transition (EMT). Cross-talk between the FOXF2/LINC02532/SOX7 axis may provide a novel target for the treatment and prognostic prediction of GC.
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