STAT3-induced lncRNA HAGLROS overexpression contributes to the malignant progression of gastric cancer cells via mTOR signal-mediated inhibition of autophagy

Abstract

BackgroundLong noncoding RNAs (lncRNAs) are an important class of functional regulators involved in human cancers development, including gastric cancer (GC). Studying aberrantly expressed lncRNAs may provide us with new insights into the occurrence and development of gastric cancer by acting as oncogenes or tumor suppressors. In this study, we aim to examine the expression pattern of lncRNA HAGLROS in GC and its clinical significance as well as its biological role in tumor progression.MethodsBioinformatics analysis and qRT-PCR were performed to detect the relative expression of HAGLROS in GC tissues and cell lines. Gain or loss of function approaches were used to investigate the biological functions of HAGLROS. The effect of HAGLROS on proliferation was evaluated by MTT, colony formation assay and nude mouse xenograft model. Wound healing and Transwell assays were used to study the invasion and migration of GC cells. FISH, RIP, RNA-seq, Luciferase report assays, RNA pulldown and Western blot were fulfilled to measure molecular mechanisms. Results are shown as means ± S.D. and differences were tested for significance using Student’s t-test (two-tailed).ResultsWe screened out HAGLROS, whose expression was significantly increased and correlated with outcomes of GC patients by publicly available lncRNAs expression profiling and integrating analyses. Exogenous down-regulation of HAGLROS expression significantly suppressed the cell proliferation, invasion and migration. Mechanistic investigations showed that HAGLROS was a direct target of transcriptional factor STAT3. Moreover, HAGLROS knockdown decreased mTOR expression and increased autophagy-related genes ATG9A and ATG9B expression. Further investigation showed that HAGLROS regulated mTOR signals in two manners. In the one hand, HAGLROS competitively sponged miR-100-5p to increase mTOR expression by antagonizing miR-100-5p-mediated mTOR mRNA inhibition. On the other hand, HAGLROS interacted with mTORC1 components to activate mTORC1 signaling pathway which was known to be an important negative signal of autophagy. Here activation of mTORC1 signaling pathway by HAGLROS inhibited autophagy, thereby promoted excessive proliferation and maintained the malignant phenotype of GC cells.ConclusionThe present study demonstrates that HAGLROS overexpression contributes to GC development and poor prognosis and will be a target for GC therapy and further develop as a potential prognostic biomarker.Electronic supplementary materialThe online version of this article (10.1186/s12943-017-0756-y) contains supplementary material, which is available to authorized users.

Longevity‐related molecular pathways are subject to midlife “switch” in humans

“…In contrast, LINC00319 is down‐regulated with age and promotes tumor growth via transcriptional silencing (Zhang et al, ). Given the emerging evidence that lncRNAs help direct mTOR specificity in vitro (Chen et al, ; Li et al, ), this suggests that our age‐regulated lncRNAs can fine‐tune the regulation of longevity‐related proteins.…”

“…Furthermore, no study has utilized technology to both measure exon‐specific transcript signals and provide robust coverage of tissue long noncoding RNAs (lncRNAs, 50% of the human transcriptome; Timmons et al, ; Deveson, Hardwick, Mercer, & Mattick, ). Furthermore, emerging evidence demonstrates that lncRNAs can modulate mTOR activity (Chen et al, ; Li et al, ). These factors could combine to explain why existing models of human aging do not consistently identify a molecular program dominated by the canonical regulators of longevity in nonhuman systems.…”

Integrated Proteogenomic Deep Sequencing and Analytics Accurately Identify Non-Canonical Peptides in Tumor Immunopeptidomes

“…Two overlapping epitopes were identified in lncRNA HAGLROs, which were expressed and presented only in the lung tumor tissue. This lncRNA has been implicated in cancer progression 60,61 and should now be prioritized for downstream validation. Moreover, while Laumont et al 24 first proposed the existence of shared noncHLAIp, our work validates that noncHLAIp can be shared across multiple tumor samples and thus we anticipate greater efficiency in treatment with such shared noncHLAIp compared to private neoantigens 62,63 .…”

Microvesicles derived from human Wharton’s jelly mesenchymal stem cells enhance autophagy and ameliorate acute lung injury via delivery of miR-100

“…**p < 0.01, vs. control; ## p < 0.01, vs. ALI+vehicle; $ p < 0.05, $$ p < 0.01, vs. ALI+NCI-MVs 100 inhibition by miR-100 inhibitor aggravated the LPSinduced cell injury and inhibited LPS-induced autophagy in LPS-treated WI-38 human lung fibroblasts, a cell model of pulmonary injury [15]. The regulation of autophagy by miR-100 has been examined by several studies [26,27]. For example, Yu et al reported that in osteosarcoma, miR-100 upregulation enhanced cell autophagy and apoptosis induced by cisplatin via targeted inhibiting of mTOR, which was known to be an important negative signal of autophagy [28].…”