Abstract
BackgroundGastric cancer (GC) is among the most common and deadliest cancers globally. Many long non-coding RNAs (lncRNAs) are key regulators of GC pathogenesis. This study aimed to define the role of HOXA-AS3 in this oncogenic context.MethodsLevels of HOXA-AS3 expression in GC were quantified via qPCR. The effects of HOXA-AS3 knockdown on GC cells function were evaluated in vitro using colony formation assays, wound healing assays and transwell assays. Subcutaneous xenograft and tail vein injection tumor model systems were generated in nude mice to assess the effects of this lncRNA in vivo. The localization of HOXA-AS3 within cells was confirmed by subcellular fractionation, and predicted microRNA (miRNA) targets of this lncRNA and its ability to modulate downstream NF-κB signaling in GC cells were evaluated via luciferase-reporter assays, immunofluorescent staining, and western blotting.ResultsGC cells and tissues exhibited significant HOXA-AS3 upregulation (P < 0.05), and the levels of this lncRNA were found to be correlated with tumor size, lymph node status, invasion depth, and Helicobacter pylori infection status. Knocking down HOXA-AS3 disrupted GC cell proliferation, migration, and invasion in vitro and tumor metastasis in vivo. At a mechanistic level, we found that HOXA-AS3 was able to sequester miR-29a-3p, thereby regulating the expression of LTβR and modulating NF-κB signaling in GC.ConclusionHOXA-AS3/miR-29a-3p/LTβR/NF-κB regulatory axis contributes to the progression of GC, thereby offering novel target for the prognosis and treatment of GC.
Highlights
Gastric cancer (GC) was the 5th most prevalent form of cancer diagnosed in 2018 [1]
GC tumors exhibit the upregulation of HOXA‐AS3, which is correlated with poor patient prognosis We began by assessing HOXA-AS3 expression in human GC tissues based upon TCGA microarray data, revealing significant upregulation of this long noncoding RNAs (lncRNAs) in tumor tissues relative to healthy control tissue samples (P = 0.0119, Fig. 1a)
We identified one predicted miR-29a-3p binding site within LTβR (Fig. 5a), which has previously been shown to mediate alternative NF-κB signaling in the context of H. pylori-induced gastric inflammation [22]
Summary
Gastric cancer (GC) was the 5th most prevalent form of cancer diagnosed in 2018 [1]. While GC mortality rates have been declining over the past five decades, it is still the third leading cancer-associated cause of death [2]. Long non-coding RNAs (lncRNAs) lack the ability to encode protein, but are capable of regulating cellular physiology through complex epigenetic mechanism [3]. 7p15.2 in the HOX gene cluster, which encodes highly conserved and homologous transcription factors which play key roles in the process of embryo development [6], in addition to controlling hematopoietic cell differentiation [7]. HOXA-AS3 expression has previously been linked to poor prognosis in patients with hepatocellular carcinoma (HCC) and glioma [8, 9], and at a functional level, it has been shown to promote the proliferative and migratory activity of HCC, glioma, and lung adenocarcinoma cells [8,9,10]. There is evidence that HOXA-AS3 can mediate cisplatin resistance, making it a viable therapeutic target in non-small cell lung cancer (NSCLC) [11]. This study aimed to define the role of HOXA-AS3 in this oncogenic context
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