Abstract
BackgroundNon-coding RNAs (ncRNAs) have been shown to regulate gene expression involved in tumor progression of multiple malignancies. Our previous studies indicated that large tumor suppressor kinase 1 (LATS1), a core part of Hippo signaling pathway, functions as a tumor suppressor in gastric cancer (GC). But, the underlying molecular mechanisms by which ncRNAs modulate LATS1 expression in GC remain undetermined.MethodsThe correlation of LATS1 and has-miR-424-5p (miR-424) expression with clinicopathological characteristics and prognosis of GC patients was analyzed by TCGA RNA-sequencing data. A novel circular RNA_LARP4 (circLARP4) was identified to sponge miR-424 by circRNA expression profile and bioinformatic analysis. The binding site between miR-424 and LATS1 or circLARP4 was verified using dual luciferase assay and RNA immunoprecipitation (RIP) assay. The expression and localization of circLARP4 in GC tissues were investigated by fluorescence in situ hybridization (FISH). MTT, colony formation, Transwell and EdU assays were performed to assess the effects of miR-424 or circLARP4 on cell proliferation and invasion.ResultsIncreased miR-424 expression or decreased LATS1 expression was associated with pathological stage and unfavorable prognosis of GC patients. Ectopic expression of miR-424 promoted proliferation and invasion of GC cells by targeting LATS1 gene. Furthermore, circLARP4 was mainly localized in the cytoplasm and inhibited biological behaviors of GC cells by sponging miR-424. The expression of circLARP4 was downregulated in GC tissues and represented an independent prognostic factor for overall survival of GC patients.ConclusioncircLARP4 may act as a novel tumor suppressive factor and a potential biomarker in GC.
Highlights
Non-coding RNAs have been shown to regulate gene expression involved in tumor progression of multiple malignancies
MiR-424-5p was negatively correlated with large tumor suppressor kinase 1 (LATS1) expression in gastric cancer (GC) Our previous studies showed that LATS1 is downregulated in GC compared with the pair-matched normal tissues [11]
We discovered little evidence regarding the dysregulation of LATS1 at the genetic (Additional file 2: Figure S1a and b) and methylation levels (Additional file 2: Figure S1c), suggesting that genetic alterations and methylation modification were not the main cause of the downregulation of LATS1 in GC
Summary
Non-coding RNAs (ncRNAs) have been shown to regulate gene expression involved in tumor progression of multiple malignancies. Our previous studies indicated that large tumor suppressor kinase 1 (LATS1), a core part of Hippo signaling pathway, functions as a tumor suppressor in gastric cancer (GC). Hippo signaling pathway was previously known to control organ size and growth, and accumulating evidence shows that this pathway acts a pivotal role in the regulation of cell proliferation, metastasis and oncogenesis [3,4,5,6]. Large tumor suppressor kinase 1 (LATS1) as a core member of this pathway dominates breast cell fate [7] and modulates liver progenitor cell proliferation and. Our previous study showed that loss of LATS1 is correlated with poor survival and recurrence and promotes growth and metastasis of GC cells [11]. LATS1/2 is proved to inhibit tumor immunity and provides a concept for targeting LATS1/2 in cancer immunotherapy [12]
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