Abstract
BackgroundUnfolded protein response (UPR)-mediated tumor-promoting functions have been identified in multiple cancers, and this study focused on investigating the role and molecular mechanisms of UPR in modulating gastric cancer (GC) pathogenesis.MethodsThe bioinformatics analysis was performed to examine the expression status of cancer associated genes in patients with stomach adenocarcinoma (STAD) and predict the targeting sites of miR-224-5p with LncRNA MIR503HG and TUSC3. Genes expressions were quantified by Real-Time qPCR, Western Blot and immunohistochemistry (IHC). Cell proliferation, viability, apoptosis and mobility were evaluated by MTT assay, trypan blue staining assay, flow cytometer and transwell assay, respectively. The binding sites were validated by dual-luciferase reporter gene system assay.ResultsLncRNA MIR503HG and TUSC3 were downregulated, but miR-224-5p was upregulated in GC tissues and cells, in contrast with their normal counterparts. Further gain- and loss-of-function experiments validated that the malignant phenotypes in GC cells, including cell proliferation, invasion, epithelial-mesenchymal transition (EMT) and tumorigenesis, were negatively regulated by LncRNA MIR503HG. Mechanistically, LncRNA MIR503HG upregulated TUSC3 in GC cells through sponging miR-224-5p, resulting in the repression of GC progression. Finally, we validated that knock-down of ATF6, but not other two branches of UPR (PERK1 and IRE1), partially rescued cell proliferation and EMT in the GC cells with LncRNA MIR503HG overexpression.ConclusionsTargeting the LncRNA MIR503HG/miR-224-5p/TUSC3 signaling cascade suppressed ATF6-mediated UPR, resulting in the blockage of GC development.
Highlights
Unfolded protein response (UPR)-mediated tumor-promoting functions have been identified in multiple cancers, and this study focused on investigating the role and molecular mechanisms of UPR in modulating gastric cancer (GC) pathogenesis
We investigated the expression status of long noncoding RNAs (LncRNAs) MIR503HG, miR-224-5p and tumor suppressor candidate 3 (TUSC3) in GC tissues and cells, and the Real-Time qPCR results showed that LncRNA MIR503HG (Figure 1A) and TUSC3 mRNA (Figure 1C) were downregulated, while miR-224-5p (Figure 1B) was significantly upregulated in the cancerous tissues, in contrast with the corresponding adjacent normal tissues collected from GC patients (N = 42)
The above results were supported by the following Pan-cancer analysis, which indicated that miR-224-5p tended to be enriched, while TUSC3 was downregulated in the cancer tissues (N = 375), compared to the normal samples (N = 32), collected from patients with stomach adenocarcinoma (STAD) (Figures 1D, E)
Summary
Unfolded protein response (UPR)-mediated tumor-promoting functions have been identified in multiple cancers, and this study focused on investigating the role and molecular mechanisms of UPR in modulating gastric cancer (GC) pathogenesis. Identification of cancer associated biomarkers has been proved as a reasonable strategy to provide novel targets for gastric cancer (GC) diagnosis, prognosis and therapy [1, 2], and the long noncoding RNAs (LncRNAs) are closely associated with GC pathogenesis. Those LncRNAs, including LncRNA MEG3 [3], LncRNA PVT1 [4], LncRNA AK023391 [5], and LncRNA HOXA11-AS [6], play important roles in GC. Yuasa et al try to investigate the association of TUSC3 methylation with GC [20], the detailed mechanistic information are still not fully delineated
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