Novel Therapeutic Target For Gastric Cancer Research Articles

YTHDF1 Promotes Proliferation and Inhibits Apoptosis of Gastric Cancer Cells via Upregulating TCF7 mRNA Translation.

N6-methyladenosine (m6A) modification is one of the most common RNA modifications in mammals. m6A modification, and associated abnormal gene expression, occur during various biological processes, most notably tumorigenesis. YTH domain-containing family protein 1 (YTHDF1), a m6A reader, bind to messenger RNAs (mRNAs) containing a m6A modification and this enhances its interaction with the ribosome and promotes translation. The function of YTHDF1 in gastric cancer (GC) has been the subject of earlier studies; however, the precise mechanism underlying YTHDF1's role in GC has not been fully elucidated. The expression of YTHDF1 was evaluated using quantitative real time polymerase chain reaction (qRT-PCR), immunohistochemistry and western blotting. CCK-8, 5-Ethynyl-2'-deoxyuridine (EdU) and flow cytometry assays were utilized to explore the effect of YTHDF1 on GC cell viability and proliferation. Transcriptome sequencing and RNA immunoprecipitation assays were utilized to explore the underlying mechanisms mediated by YTHDF1. We observed that YTHDF1 is upregulated in GC cancer tissues. Knockdown of YTHDF1 in GC cells significantly inhibited proliferation and promoted apoptosis, suggesting that YTHDF1 increases proliferation and blocks apoptosis in GC cells. Mechanistically, data gathered suggest that YTHDF1 promotes the translation of the transcription factor TCF7 and this results in activation of the WNT signaling axis. We found that YTHDF1 was upregulated in GC and that YTHDF1 could promote GC progression through modulating the translational efficiency of TCF7. Taken together, these findings may provide a novel therapeutic target for GC.

STAT3–mediated up-regulation of DAB2 via SRC-YAP1 signaling axis promotes Helicobacter pylori-driven gastric tumorigenesis

BackgroundHelicobacter pylori (H pylori) infection is the primary cause of gastric cancer (GC). The role of Disabled-2 (DAB2) in GC remains largely unclear. This study aimed to investigate the role of DAB2 in H pylori-mediated gastric tumorigenesis.MethodsWe screened various datasets of GC to analyze DAB2 expression and cell signaling pathways. DAB2 expression was assessed in human GC tissue microarrays. H pylori infection in vivo and in vitro models were further explored. Immunostaining, immunofluorescence, chromatin immunoprecipitation, co-immunoprecipitation, Western blot, quantitative polymerase chain reaction, and luciferase reporter assays were performed in the current study.ResultsThe bioinformatic analysis verified that DAB2 was 1 of the 8 genes contributed to tumorigenesis and associated with poor prognosis in GC. The median overall survival and disease-free survival rates in DAB2high group were significantly less than those in DAB2low group. These findings demonstrated that H pylori transcriptionally activated DAB2 expression via signal transducer and activator of transcription 3 (STAT3)-dependent pathway. By bioinformatics analysis and knockdown or overexpression of DAB2, we found that DAB2 upregulated Yes-associated protein 1 (YAP1) transcriptional activity. Mechanistically, DAB2 served as a scaffold protein for integrin beta 3 (ITGB3) and SRC proto-oncogene non-receptor tyrosine kinase (SRC), facilitated the phosphorylation of SRC, promoted the small GTPase ras homolog family member A (RHOA) activation and phosphorylation of YAP1, and ultimately enhanced the YAP1 transcriptional activity.ConclusionsAltogether, these findings indicated that DAB2 is a key mediator in STAT3–regulated translation of YAP1 and plays crucial roles in H pylori-mediated GC development. DAB2 might serve as a novel therapeutic target for GC.

H3K18 lactylation-mediated VCAM1 expression promotes gastric cancer progression and metastasis via AKT-mTOR-CXCL1 axis

The role of the Immunoglobulin Superfamily (IgSF) as adhesion molecules in orchestrating inflammation is pivotal, yet its specific involvement in gastric cancer (GC) remains unknown. We analyzed IgSF components and discerned conspicuously elevated VCAM1 expression in GC, correlating with a poor prognosis. Remarkably, VCAM1 enhances GC cell proliferation and migration by activating AKT-mTOR signaling. Moreover, lactate in the tumor microenvironment (TME) promotes dynamic lactylation of H3K18 (H3K18la), leading to transcriptional activation of VCAM1 in GC cells. Furthermore, VCAM1 actively mediates intercellular communication in the TME. AKT-mTOR-mediated CXCL1 expression is increased by VCAM1, facilitating the recruitment of human GC-derived mesenchymal stem cells (hGC-MSCs), thereby fostering immunesuppression and accelerating cancer progression. In summary, H3K18 lactylation upregulated VCAM1 transcription, which activated AKT-mTOR signaling, and promoted tumor cell proliferation, EMT Transition and tumor metastasis. VCAM1 upregulated CXCL1 expression by AKT-mTOR pathway, so as to facilitate hGC-MSCs and M2 macrophage recruitment and infiltration. These findings provide novel therapeutic targets for GC.

Identification of BANF1 as a novel prognostic biomarker in gastric cancer and validation via in-vitro and in-vivo experiments.

Gastric cancer (GC) is a widespread malignancy characterized by a notably high incidence rate and an unfavorable prognosis. We conducted a meticulous analysis of GC high-throughput sequencing data downloaded from the Gene Expression Omnibus (GEO) repository to pinpoint distinctive genes associated with GC. Our investigation successfully identified three signature genes implicated in GC, with a specific focus on the barrier to autointegration factor 1 (BANF1), which exhibits elevated expression across various cancer types, including GC. Bioinformatic analysis has highlighted BANF1 as a prognostic indicator for patients with GC, with direct implications for immune cell infiltration. To gain a more comprehensive understanding of the significance of BANF1 in GC, we performed a series of in vitro experiments to confirm its high expression in GC tissues and cellular components. Intriguingly, the induction of BANF1 knockdown resulted in a marked attenuation of proliferation, migratory capacity, and invasive potential in GC cells. Moreover, our in vivo experiments using nude mouse models revealed a notable impediment in tumor growth following BANF1 knockdown. These insights underscore the feasibility of BANF1 as a novel therapeutic target for GC.

GIPC1 promotes tumor growth and migration in gastric cancer via activating PDGFR/PI3K/AKT signaling.

The high mortality rate associated with gastric cancer (GC) has resulted in an urgent need to identify novel therapeutic targets for GC. This study aimed to investigate whether GAIP interacting protein, C terminus 1 (GIPC1) represents a therapeutic target and its regulating mechanism in GC. GIPC1 expression was elevated in GC tissues, liver metastasis tissues, and lymph node metastases. GIPC1 knockdown or GIPC1 blocking peptide blocked the platelet-derived growth factor receptor (PDGFR)/PI3K/AKT signaling pathway, and inhibited the proliferation and migration of GC cells. Conversely, GIPC1 overexpression markedly activated the PDGFR/PI3K/AKT signaling pathway, and promoted GC cell proliferation and migration. Furthermore, platelet-derived growth factor subunit BB (PDGF-BB) cytokines and the AKT inhibitor attenuated the effect of differential GIPC1 expression. Moreover, GIPC1 silencing decreased tumor growth and migration in BALB/c nude mice, while GIPC1 overexpression had contrasting effects. Taken together, our findings suggest that GIPC1 functions as an oncogene in GC and plays a central role in regulating cell proliferation and migration via the PDGFR/PI3K/AKT signaling pathway.

CircRPS19 affects HK2‑mediated aerobic glycolysis and cell viability via the miR‑125a‑5p/USP7 pathway in gastric cancer.

Despite advances in diagnosis and treatment, gastric cancer (GC) remains a refractory disease, which limits overall survival. Therefore, it is key to identify novel targets to develop more effective and precise treatment. Circular RNAs (circRNAs) serve essential roles in the process of various human cancers. Through analyzing GSE83521 dataset, the present study identified a novel circRNA derived from ribosomal protein S19 (circRPS19), which was considered a potential treatment target for GC. Results of RT‑qPCR indicated that circRPS19 was upregulated in GC compared with normal gastric epithelial cells. Loss‑of function assays revealed that silencing of circRPS19 suppressed proliferation and aerobic glycolysis but increased apoptosis of GC cells. circRPS19 upregulated ubiquitin‑specific processing protease 7 (USP7) expression by sponging microRNA (miR)‑125a‑5p. circRPS19 stabilized hexokinase 2 (HK2) protein by USP7‑mediated deubiquitination of HK2. Invivo experiments confirmed that circRPS19 promoted GC progression and aerobic glycolysis. Taken together, circRPS19 induced aerobic glycolysis of GC cells by stabilizing HK2 protein via the miR‑125a‑5p/USP7 axis and thus promoting the progression of GC. These findings suggested that circRPS19 served a critical role in the progression of GC and may be a novel therapeutic target for GC.

LncRNA NORAD mediates KMT2D expression by targeting miR-204-5p and affects the growth of gastric cancer.

Long non-coding ribonucleic acids (lncRNAs) are a class of non-coding RNAs implicated in the development of many malignancies, including gastric cancer (GC). In this study, we investigated the functions and molecular mechanisms of non-coding RNA activated by deoxyribonucleic acid damage (NORAD) in GC. NORAD expression at the messenger RNA levels was determined by quantitative reverse transcriptase (RT)-polymerase chain reaction assays. Cell proliferation, migration, and invasion were detected by Cell Counting Kit-8 assays, in-vivo tumor formation assays, and Transwell assays. Cell-cycle distribution was detected by a flow cytometry analysis. NORAD location was detected by nucleocytoplasmic fractionation assays. The interaction between NORAD and the microRNA-204-5p (miR-204-5p)/Lysine Methyltransferase 2D (KMT2D) axis was verified by dual-luciferase reporter gene assays and RNA binding protein immunoprecipitation (RIP) assays. Western blot was used to study the phosphatase and tensin homolog (PTEN)/phosphoinositide 3-kinases (PI3K)/protein kinase B (AKT) signaling pathway. NORAD was upregulated in the GC tissues and cell lines. The silencing of NORAD repressed cell proliferation and the Growth 2 (G2)/Mitosis (M) cell-cycle transition in GC. NORAD also regulated KMT2D expression by targeting miR-204-5p and mediated PTEN/PI3K/AKT signaling in GC. We found that NORAD acts as an oncogene in GC. Our findings might provide a novel therapeutic target for GC.

The expression of long non-coding RNA LINC01389, LINC00365, RP11-138J23.1, and RP11-354K4.2 in gastric cancer and their impacts on EMT

BackgroundEpithelial cancers acquire the epithelial to mesenchymal transition (EMT), which leads tumor cells to invade and metastasize to adjacent and distant tissues. The mechanisms involved in EMT phenotype are controlled by numerous markers as well as signalling pathways. Recently, long non-coding RNAs (lncRNAs) were introduced that play the regulatory role in EMT via crosstalk with EMT-related transcription factors and signalling pathways. The present study aimed to investigate the expression of four lncRNAs in human GC and elucidate their probable role in EMT procedure and the pathogenesis of gastric cancer (GC). MethodsThe expression profile of lncRNAs (LINC01389, LINC00365, RP11-138J23.1, and RP11-354K4.2) and mRNAs (TWIST1, MMP13, MAML1, CD44s, and SALL4) between eighty-three GC and adjacent non-cancerous tissues were assessed by quantitative real-time PCR. ResultsThe significant downregulation of LINC00365 (66.3%) and RP11-354K4.2 (62.7%) were observed in GC samples; while the upregulation of LINC01389, RP11-138J23.1, TWIST1, MMP13, MAML1, CD44s, and SALL4 were found in 67.5%, 45.8%, 56.6%, 44.6%, 59%, 55.4%, and 62.7% tumors samples at the mRNA level, respectively. Dysregulation of these lncRNAs and EMT-related markers was significantly related to each other in a variety of clinicopathological features of patients (P < 0.05), indicating positive correlations between LINC01389, LINC00365, RP11-138J23.1, and RP11-354K4.2 with EMT status in GC. ConclusionThese EMT-regulating lncRNAs may play a key role in transforming gastric epithelial to mesenchymal phenotype and can be novel therapeutic targets for GC. Our results highlight the importance of discovering new lncRNAs involved in gastric carcinogenesis. Detailed molecular mechanisms of these noncoding-coding markers in GC are urgently required.

DSC2 Suppresses the Metastasis of Gastric Cancer through Inhibiting the BRD4/Snail Signaling Pathway and the Transcriptional Activity of β-Catenin.

Downregulated DSC2 involved in the metastasis of cancers. Unfortunately, its role on the development of gastric cancer (GC) and the potential mechanisms remain unclear. Bioinformatics analysis, Western blot, qRT-PCR, and immunohistochemistry were performed to detect the DSC2 levels of human GC and normal stomach tissues. The role of DSC2 and the downstream signaling in gastric carcinogenesis were explored by using GC specimens, GC cells with different DSC2 expression, inhibitors, and mouse metastasis models. We found that the level of DSC2 decreased significantly in GC tissues and cells. Recovered DSC2 inhibited the invasion and migration of GC cells both in culture and in xenografts. Mechanistically, DSC2 could not only decrease Snail level and nuclear BRD4 level by forming DSC2/BRD4, but also inhibit nuclear translocation of β-catenin. We concluded that DSC2 inhibited the metastasis of GC, and the underlying mechanisms were closely related to the regulation on nuclear translocation of BRD4 and β-catenin. Our results suggest that DSC2 may serve as a novel therapeutic target for GC.

LncRNA LINC00342 promotes gastric cancer progression by targeting the miR-545-5p/CNPY2 axis

BackgroundThis study aimed to explore the role and underlying molecular mechanisms of long non-coding RNA (lncRNA) LINC00342 in gastric cancer (GC).MethodsThe expression of LINC00342 in GC tissues was evaluated by Quantitative reverse transcription polymerase chain reaction (qRT-PCR). Silencing of LINC00342 was conducted to investigate the effect of LINC00342 in vitro and in vivo. The underlying molecular mechanisms of LINC00342 were determined by dual luciferase reporter assay, Western blotting analysis and rescue experiments. Biological functions of LINC00342 were evaluated by cell counting kit-8 (CCK-8) assay, colony formation assay, wound healing assay and Transwell assays. In addition, a tumor model was used to verify the effect of LINC00342 in tumorigenesis in vivo.ResultsLINC00342 was significantly upregulated in GC tissues and cell lines. Silencing of LINC00342 efficiently inhibited proliferation, migration and invasion of AGS cells in vitro, and also suppressed the tumorigenesis of GC in vivo. Functional experiments showed that LINC00342 regulated the expression of canopy fibroblast growth factor signaling regulator 2 (CNPY2) by competitively sponging miR-545-5p. Rescue experiments showed that inhibition of miR-545-5p and overexpression of CNPY2 significantly reversed cell phenotypes caused by silencing of LINC00342.ConclusionLINC00342 plays a potential oncogenic role in GC by targeting the miR545-5p/CNPY2 axis, and might act as a novel therapeutic target for GC.

FOXC2-AS1 stabilizes FOXC2 mRNA via association with NSUN2 in gastric cancer cells.

Long noncoding RNA (lncRNA) FOXC2-AS1 has been reported to act as an oncogene in multiple human cancers. However, the clinical significance, functional role and underlying mechanism of FOXC2-AS1 in gastric cancer (GC) remains largely unknown. Here, we found that FOXC2-AS1 expression was significantly elevated in GC tissues and cells, and overexpression of FOXC2-AS1 indicated advanced TNM stage and shorter overall survival in GC patients. Functionally, knockdown of FOXC2-AS1 attenuated the proliferation, migration and invasion of GC cells, whereas overexpression of FOXC2-AS1 showed the opposite effects. Further investigation revealed that FOXC2-AS1 interacted with FOXC2 mRNA and repressed its degradation. FOXC2-AS1 recruited RNA methyltransferase NSUN2 to FOXC2 mRNA, increasing its m5C level and association with YBX1. Taken together, our findings suggested that FOXC2-AS1 acted as an oncogenic lncRNA by stabilizing FOXC2 mRNA in an m5C-dependent manner, which may provide a novel therapeutic target for GC.

Circ_0027599 elevates RUNX1 expression via sponging miR-21-5p on gastric cancer progression.

Increasing evidence has shown that circular RNAs (circRNAs) serve as vital regulators in tumour progression. In this study, we focused on the functions of circ_0027599 in gastric cancer (GC) progression. The levels of circ_0027599, runt-related transcription factor 1 (RUNX1) mRNA and microRNA-21-5p (miR-21-5p) were detected by quantitative real-time polymerase chain reaction (qRT-PCR) assay. The protein levels of RUNX1, E-Cadherin, vimentin and N-Cadherin were measured by Western blot assay. Cell viability, colony formation, metastasis and cell cycle process were evaluated by Cell Counting Kit-8 (CCK-8) assay, colony formation assay, transwell assay and flow cytometry analysis, respectively. The interaction between circ_0027599 and miR-21-5p and the interaction between miR-21-5p and RUNX1 were verified by dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay. The role of circ_0027599 in tumour growth in vivo was investigated by murine xenograft model assay. Circ_0027599 and RUNX1 were downregulated in GC tissues and cells. Circ_0027599 level was associated with the overall survival of GC patients. Circ_0027599 or RUNX1 overexpression inhibited GC cell viability, colony formation, migration, invasion and cell cycle process in vitro. For mechanism analysis, circ_0027599 positively regulated RUNX1 expression via functioning as the sponge for miR-21-5p. RUNX1 inhibition reversed circ_0027599 overexpression mediated malignant behaviours of GC cells. Moreover, circ_0027599 overexpression repressed tumour growth in vivo. Circ_0027599 overexpression repressed GC progression via modulation of miR-21-5p/RUNX1 axis, which might illumine a novel therapeutic target for GC.

High expression of COL5A2, a member of COL5 family, indicates the poor survival and facilitates cell migration in gastric cancer.

Background: Gastric cancer (GC) metastasis determines the prognosis of patients, and exploring the molecular mechanism of GC metastasis is expected to provide a theoretical basis for clinical treatment. Recent studies have shown that extracellular matrix protein is closely related to GC metastasis. The present study aimed to explore the expression profile and role of COL5A2, as an extracellular matrix protein, in GC.Methods: The expression, overall survival, and progression-free survival data of COL5 family members were extracted from The Cancer Genome Atlas (TCGA) database, respectively. Weighted gene co-expression network analysis of the GSE62229 database was performed out to identify modules and associated genes.Results: COL5A2 was selected as our research target in the TCGA database, and was also verified in the GSE62229 and GSE15459 datasets. COL5A2 was up-regulated in GC tissues by paraffin immunohistochemistry and RT-qPCR. The prognosis of patients with low COL5A2 expression was better than that of patients with high COL5A2 expression. Scratch and migration experiments showed that knockdown of COL5A2 decreased the migration ability of gastric cancer cells compared with the control group. In vivo, mice with tail vein injection COL5A2 knockdown had fewer and smaller metastatic nodules in liver. GSEA results showed that the TCGA and GSE62229 samples were significantly enriched in several well-known cancer-related pathways, such as the TGF-β, MAPK, and JAK2 signaling pathways.Conclusion: COL5A2 was most closely related to advanced GC among COL5 family members. High COL5A2 expression is associated with a poor prognosis, and may be a novel therapeutic target for GC.

Screening of Potential Biomarkers for Gastric Cancer with Diagnostic Value Using Label-free Global Proteome Analysis

Gastric cancer (GC) is known as a top malignant type of tumors worldwide. Despite the recent decrease in mortality rates, the prognosis remains poor. Therefore, it is necessary to find novel biomarkers with early diagnostic value for GC. In this study, we present a large-scale proteomic analysis of 30 GC tissues and 30 matched healthy tissues using label-free global proteome profiling. Our results identified 537 differentially expressed proteins, including 280 upregulated and 257 downregulated proteins. The ingenuity pathway analysis (IPA) results indicated that the sirtuin signaling pathway was the most activated pathway in GC tissues whereas oxidative phosphorylation was the most inhibited. Moreover, the most activated molecular function was cellular movement, including tissue invasion by tumor cell lines. Based on IPA results, 15 hub proteins were screened. Using the receiver operating characteristic curve, most of hub proteins showed a high diagnostic power in distinguishing between tumors and healthy controls. A four-protein (ATP5B-ATP5O-NDUFB4-NDUFB8) diagnostic signature was built using a random forest model. The area under the curve (AUC) values of this model were 0.996 and 0.886 for the training and testing sets, respectively, suggesting that the four-protein signature has a high diagnostic power. This signature was further tested with independent datasets using plasma enzyme-linked immune sorbent assays, resulting in an AUC value of 0.778 for distinguishing GC tissues from healthy controls, and using immunohistochemical tissue microarray analysis, resulting in an AUC value of 0.805. In conclusion, this study identifies potential biomarkers and improves our understanding of the pathogenesis, providing novel therapeutic targets for GC.

Nicotinamide N-Methyltransferase Is a Prognostic Biomarker and Correlated With Immune Infiltrates in Gastric Cancer

Gastric cancer (GC) is the third most common cause of cancer-related death in the word. Immunotherapy is a promising treatment of cancer. However, it is unclear which GC subpopulation would benefit most from immunotherapy and it is necessary to develop effective biomarkers for predicting immunotherapy response. Nicotinamide N-methyltransferase (NNMT) is a metabolic regulator of cancer-associated fibroblast (CAF) differentiation and cancer progression. In this study, we explored the correlations of NNMT to tumor-infiltrating immune cells (TIICs) and immune marker sets in The Cancer Genome Atlas Stomach Adenocarcinoma STAD (TCGA-STAD). Subsequently, we screened the NNMT correlated genes and performed the enrichment analysis of these genes. We eventually predicted the 19 most potential small-molecule drugs using the connectivity map (CMap) and Comparative Toxicogenomics Database (CTD). Also, nadolol, tranexamic acid, felbinac and dapsone were considered the four most promising drugs for GC. In summary, NNMT can be used as a prognostic biomarker that reflect immune infiltration level and a novel therapeutic target in GC.

Silencing of LncRNA C1RL-AS1 Suppresses the Malignant Phenotype in Gastric Cancer Cells via the AKT/β-Catenin/c-Myc Pathway.

Purpose: Numerous studies have shown that lncRNAs play vital roles in the development and progression of cancer. However, investigations of lncRNAs in gastric cancer are limited and need to be further pursued.Materials and Methods: According to RNA-seq results of gastric cancer (GC) tissues, we identified a novel lncRNA, C1RL-AS1. qRT-PCR was used to detect the expression level of C1RL-AS1 in paired GC and normal tissues. Nuclear/cytoplasmic fractionation was applied to evaluate the distribution of C1RL-AS1 in GC cells. For functional evaluation, CCK-8, colony formation, transwell, and apoptosis assays were used to determine the oncogenic role of C1RL-AS1.Results: C1RL-AS1 was upregulated in GC tissues, and high expression levels of C1RL-AS1 were associated with poor prognosis. Further in vitro functional assays revealed that silencing C1RL-AS1 attenuated the proliferation rate and migration ability and enhanced the apoptotic rate and the senescence of GC cells. The subsequent underlying mechanistic investigation revealed that Wnt/β-catenin was involved in C1RL-AS1-mediated signaling. Rescue experiments suggested that C1RL-AS1 probably promoted the malignant phenotype via the AKT/β-catenin pathway by downregulating c-Myc.Conclusions: C1RL-AS1 probably exerts its biological function by mediating the AKT/β-catenin/c-Myc pathway, indicating a novel therapeutic target in GC.

MiR-874 inhibits gastric cancer cell proliferation by targeting SPAG9

BackgroundmicroRNAs (miRNAs) play essential roles in the development and progression of gastric cancer (GC). Although aberrant miR-874 expression has been reported in various human cancers, its role in GC remains obscure.MethodsmiR-874 expression was assessed by real-time quantitative polymerase chain reaction (RT-qPCR) in 62 matched GC and adjacent normal tissues, as well as in GC cell lines and immortalized human gastric epithelial cells. CCK8 assay, colony formation assay, and flow cytometry were used to assess the role of miR-874 in GC cell proliferation and apoptosis in vitro. Additionally, to determine the effects of miR-874 on GC cell proliferation and apoptosis in vivo, BALB/c nude mice were injected with GC cells transfected with a miR-874 mimic. The role of miR-874 in SPAG9 expression was assessed by luciferase assay, Western blotting, and RT-qPCR.ResultsmiR-874 was downregulated in GC cell lines and tissues. miR-874 overexpression in GC cells led to inhibition of cell proliferation and induction of apoptosis. Moreover, SPAG9 was identified as a direct miR-874 target, the expression of which was suppressed by miR-874. SPAG9 overexpression markedly promoted GC cell proliferation.ConclusionsmiR-874 inhibited cell proliferation and induced apoptosis in GC cells. SPAG9 downregulation was crucial for the tumor-suppressive effects of miR-874. Hence, the miR-874/SPAG9 axis could serve as a novel therapeutic target in GC.

TYRO3 facilitates cell growth and metastasis via activation of the Wnt/β-catenin signaling pathway in human gastric cancer cells.

It has become increasingly important to identify valuable therapeutic targets to improve the prognosis of cancer patients. Although emerging evidence has suggested TYRO3 as a potential therapeutic target in various types of cancers, less is known about its role in gastric cancer (GC) development. Herein, we investigated the functional and molecular mechanisms by which TYRO3 influenced GC. TYRO3 mRNA and protein were evaluated by quantitative real-time PCR (qRT-PCR), western blotting, and immunohistochemistry. Other methods including stable transfection of TYRO3 into GC cells, wound healing, Transwell assays, CCK-8 assays, colony formation assays, immunocytochemistry in vitro, and tumorigenesis in vivo were also conducted. Our results indicated that high levels of TYRO3 significantly correlated with clinical metastasis and poor prognoses in patients with GC. In addition, TYRO3 silencing distinctively suppressed GC cell growth, invasion, and metastasis both in vitro and in vivo. Conversely, TYRO3 overexpression led to the opposite effects. Mechanistic analyses revealed that the Wnt/β-catenin signaling pathway might be involved in TYRO3-facilitated GC cell behavior. Collectively, we demonstrated that elevated TYRO3 expression contributed to GC cell growth and metastasis via the Wnt/β-catenin pathway, suggesting a novel therapeutic target for GC.

Long Non-Coding RNA TMPO-AS1 Promotes Cell Migration and Invasion by Sponging miR-140-5p and Inducing SOX4-Mediated EMT in Gastric Cancer.

BackgroundMounting evidence show that long non-coding RNAs (lncRNAs) play critical roles in the progression of various human cancers, including gastric cancer (GC), a common gastrointestinal tumor. In this study, the biological functions of lncRNA TMPO-AS1 in GC were studied.MethodsTMPO-AS1 and miR-140-5p expression levels were detected in GC tissues and cell lines by RT-qPCR analysis. Knockdown or overexpression of TMPO-AS1 was conducted to evaluate the effects of TMPO-AS1 on the malignant behaviors of GC cells. Bioinformatic prediction and dual-luciferase reporter assay were performed to investigate the direct interaction between TMPO-AS1 and miR-140-5p in GC.ResultsWe observed that TMPO-AS1 was up-regulated in GC tissues, and high TMPO-AS1 expression in GC patients was closely correlated with aggressive clinicopathologic characteristics and poor overall survival. Functionally, gain- and loss-of-function studies showed that TMPO-AS1 overexpression enhanced the proliferation, migration, invasion and EMT of GC cells in vitro, whereas knockdown of TMPO-AS1 inhibited these malignant traits. Importantly, we demonstrated that TMPO-AS1 could function as a competing endogenous RNA (ceRNA) by sponging miR-140-5p in GC cells, thereby diminishing the inhibition on SOX4, an EMT regulator.ConclusionOur findings indicated that TMPO-AS1 promotes GC progression partly by regulating miR-140-5p/SOX4 axis, and may serve as a novel therapeutic target for GC.

CircDUSP16 promotes the tumorigenesis and invasion of gastric cancer by sponging miR-145-5p

BackgroundCircular RNAs (circRNAs) as a novel subgroup of non-coding RNAs act a critical role in the pathogenesis of gastric cancer (GC). However, the underlying mechanisms by which hsa_circ_0003855 (circDUSP16) contributes to GC are still undocumented.MaterialsThe differentially expressed circRNAs were identified by GEO database. The association of circDUSP16 or miR-145-5p expression with clinicopathological features and prognosis in GC patients was analyzed by FISH and TCGA-seq data set. Loss- and gain-of-function experiments as well as a xenograft tumor model were performed to assess the role of circDUSP16 in GC cells. circDUSP16-specific binding with miR-145-5p was confirmed by bioinformatic analysis, luciferase reporter, and RNA immunoprecipitation assays.ResultsThe expression levels of circDUSP16 were markedly increased in GC tissue samples and acted as an independent prognostic factor of poor survival in patients with GC. Knockdown of circDUSP16 repressed the cell viability, colony formation, and invasive potential in vitro and in vivo, but ectopic expression of circDUSP16 reversed these effects. Moreover, circDUSP16 possessed a co-localization with miR-145-5p in the cytoplasm, and acted as a sponge of miR-145-5p, which attenuated circDUSP16-induced tumor-promoting effects and IVNS1ABP expression in GC cells. MiR-145-5p had a negative correlation with circDUSP16 expression and its low expression was associated with poor survival in GC patients.ConclusionsCircDUSP16 facilitates the tumorigenesis and invasion of GC cells by sponging miR-145-5p, and may provide a novel therapeutic target for GC.