Abstract
ObjectiveRecently, long noncoding RNA SLCO4A1 antisense RNA 1 (SLCO4A1-AS1) has been shown to act as an oncogene in several cancer types; however, its role in gastric cancer (GC) and its underlying molecular mechanisms are yet to be elucidated.MethodsUsing the ENCORI database, we identified SLCO4A1-AS1, miR-149-5p (miR-149), and the X-linked inhibitor of apoptosis (XIAP) whose expressions were obviously changed in GC samples, and analyzed the correlation between their expressions in GC samples. Moreover, we explored the expression of SLCO4A1-AS1, miR-149, and XIAP in clinical samples and GC cell lines using RT-qPCR and western blotting assay; the correlation between them was analyzed using RNA immunoprecipitation and dual-luciferase reporter. CCK-8, colony formation, and Transwell assays were conducted to determine the effects of SLCO4A1-AS1, miR-149, and XIAP expression on cell proliferation, migration, and invasion, respectively. A nude mouse xenograft model was used to explore their function in xenograft growth.ResultsSLCO4A1-AS1 was significantly upregulated in the GC samples and cell lines, and a high level of SLCO4A1-AS1 was associated with an advanced tumor stage and shortened patient survival. Mechanistically, SLCO4A1-AS1 post-transcriptionally regulated XIAP by functioning as competing endogenous RNA in GC to sponge miR-149. Further functional assays revealed that the overexpression of miR-149 and knockdown of XIAP considerably inhibited GC cell viability and its migratory and invasive characteristics in vitro. SLCO4A1-AS1 knockdown also determined the function of GC cells but was diminished by the miR-149 inhibitor in vitro. Finally, we demonstrated that the deletion of SLCO4A1-AS1 suppressed tumor growth and metastasis in vivo.ConclusionsAltogether, these findings suggest that SLCO4A1-AS1 functions as a crucial oncogenic lncRNA in GC and it can facilitate GC tumor growth and metastasis by interacting with miR-149 and enhancing XIAP expression. Therefore, SLCO4A1-AS1 is a potential novel therapeutic target in GC treatment.
Highlights
Gastric cancer (GC) is the fourth most frequently diagnosed malignancy that as a high mortality due to its high recurrence rate and distant metastasis [1, 2]
These findings showed that SLCO4A1-AS1 expression was enhanced in GC and may act as an oncogenic gene in GC progression
We further investigated the biological function of the SLCO4A1AS1/miR-149/XIAP axis in GC cells. shXIAP, miR-149, shSLCO4A1-AS1 along with the miR-149 inhibitor were transfected into MKN45 and AGS cells via lentivirus transduction, and western blotting assay was conducted to determine XIAP expression (Figure 4A)
Summary
Gastric cancer (GC) is the fourth most frequently diagnosed malignancy that as a high mortality due to its high recurrence rate and distant metastasis [1, 2]. Significant progress has been made in the diagnosis and treatment strategies for GC, the prognosis for patients in the advanced stage remains poor [4]. Long noncoding RNAs (lncRNAs) are noncoding RNAs (>200 nt) that are dysregulated in several types of cancer and involved in the regulation of various cellular processes, such as cell proliferation, apoptosis, and invasion [5, 6]. LINC00682 suppresses GC progression through the modulation of the microRNA-9-LMX1A axis [7]; UCA1 facilitates GC cell proliferation and migration by suppressing p21 and SPRY1 levels [8]; and KRT19P3 represses GC metastasis through the regulation of COPS7A-mediated NF-kB signaling [9]. It has been reported that lncRNA SLCO4A1-AS1 functions as an oncogenic gene in colorectal and bladder cancer [10, 11]. The biological functions and underlying mechanisms of SLCO4A1-AS1 in GC are yet to be determined
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