Inhibited Gastric Cancer Cell Proliferation Research Articles

RFTN1 facilitates gastric cancer progression by modulating AKT/p38 signaling pathways

Gastric cancer (GC), a malignant tumor originating from the epithelium of the gastric mucosa, has been endangering human health for many years. The current standard surgical resection is not ideal for advanced gastric cancer. Therefore, it is urgent to find new prognostic indicators as well as drug targets. In our study, referring to clinicopathological characteristics of GC, we found that raftlin lipid raft linker 1 (RFTN1) had high expression in primary GC tissues. Subsequently, we showed that knockdown of RFTN1 inhibited GC cell proliferation and induced cell cycle arrest in G0/G1 phase, and promoted GC cell apoptosis. Conversely, overexpression of RFTN1 promoted GC cell proliferation and G0/G1 to S phase transition, and inhibited apoptosis. Furthermore, cell derived xenograft experiments showed that knockdown of RFTN1 inhibited GC cell growth in vivo. Notably, our experimental data demonstrated that knockdown of RFTN1 could inhibit the AKT signaling pathway and activate p38 signaling pathway, whereas overexpression of RFTN1 did the opposite. Moreover, the effects caused by knockdown of RFTN1 in GC cells could be rescued by using SC79 (an AKT activator). In conclusion, these results indicated that RFTN1 plays an oncogenic role in GC, and might act as a prospective prognostic indicator or therapeutic target for GC patients.

CircAKT3 promotes cell proliferation, survival and glutamine metabolism of gastric cancer by activating SLC1A5 expression via targeting miR-515-5p.

Gastric cancer (GC) is a common disorder in the population. Numerous studies have reported that the pathogenesis of GC is implicated in the dysregulation of circular RNAs (circRNAs). The aim of this study was to investigate the role and functional mechanism of circ_0000199 (circAKT3) in GC. The expression of circAKT3, miR-515-5p and solute carrier family 1 member 5 (SLC1A5) mRNA was measured by quantitative real-time PCR (qPCR). Cell proliferation was assessed by cell counting kit-8 (CCK-8) assay, colony formation assay and 5-ethynyl-2'-deoxyuridine (EdU) assay. Cell apoptosis was determined by flow cytometry assay and caspase 3/7 activity. The protein levels of glutaminase (GLS), proliferating cell nuclear antigen (PCNA) and cleaved-caspase3 were detected by western blot. The binding relationship between miR-515-5p and circAKT3 or SLC1A5 was verified by dual-luciferase reporter assay or RIP assay. The role of circAKT3 in vivo was investigated by establishing animal models. The abundance of Ki-67 and PCNA was detected by IHC assay. The expression of circAKT3 in GC tissues and cells was enhanced. The knockdown of circAKT3 inhibited GC cell proliferation, survival and glutamine metabolism, as well as tumor growth in animal models. MiR-515-5p was a target of circAKT3, and miR-515-5p suppressed the expression of SLC1A5 by binding to SLC1A5 3'UTR. CircAKT3 relieved the inhibition of miR-515-5p on SLC1A5 expression by targeting miR-515-5p. The effects of circAKT3 knockdown were reversed by miR-515-5p depletion, and the effects of miR-515-5p restoration were abolished by SLC1A5 overexpression. CircAKT3 promotes the malignant development of GC by activating SLC1A5 expression via targeting miR-515-5p.

Downregulation of circular RNA circ-HN1 suppressed the progression of gastric cancer through the miR-485-5p/GSK3A pathway

ABSTRACT Gastric cancer (GC) is a malignancy with high incidence and mortality globally. Circular RNAs (circRNAs) are reported to regulate cellular processes in human diseases, including GC. Herein, the functions of circ-HN1 and its molecular mechanisms were investigated. circ-HN1, miR-485-5p, and GSK3A levels in GC were measured using Real time-quantitative polymerase chain reaction (RT-qPCR). Cell proliferation was analyzed using cell counting kit-8 (CCK-8) and colony formation assays. Meanwhile, the migration and invasion abilities were analyzed using the transwell assay. The targeted relationship was confirmed using a luciferase reporter assay and an RNA pull-down assay. In both GC tissues and cells, circ-HN1 expression was upregulated, and its silencing suppressed cellular processes. Moreover, circ-HN1 served as a sponge of miR-485-5p, which was reduced in patients with GC and negatively regulated by circ-HN1 in GC cells. Inhibition of miR-485-4p abolished the biological functions induced by the silencing of circ-HN1. Additionally, miR-485-5p targeted GSK3A in GC, whose expression was elevated in tumor tissues and was negatively correlated with miR-485-5p in tumor cells. GSK3A rescued the inhibition of miR-485-5p in the cellular processes. In conclusion, silencing of the circ-HN1–miR-485-5p–GSK3A regulatory network inhibited GC cell proliferation, migration, and invasion, suggesting that circ-HN1 is a potential target for GC therapy.

MiR-139-5p Inhibits the Development of Gastric Cancer through Targeting TPD52.

Background Many researchers have confirmed that miRNAs are involved in the pathogenesis of gastric cancer (GC). This study focused on investigating the specific functions of miR-139-5p in GC. Methods MiR-139-5p and TPD52 expressions were observed by qRT-PCR or western blot in GC. The functional mechanism of miR-139-5p was explored by the luciferase reporter assay, transwell assay, and MTT assay. Results MiR-139-5p downregulation and TPD52 upregulation were detected in GC. Adverse clinical features and prognosis in GC patients were related to low miR-139-5p expression. MiR-139-5p overexpression restrained GC cell proliferation and metastasis. Furthermore, miR-139-5p directly targeted TPD52. TPD52 silencing blocked GC progression. And TPD52 upregulation weakened the antitumor effect of miR-139-5p in GC. Conclusion MiR-139-5p inhibits GC cell proliferation and metastasis through downregulating TPD52.

Circ_0009910 Serves as miR-361-3p Sponge to Promote the Proliferation, Metastasis, and Glycolysis of Gastric Cancer via Regulating SNRPA.

Circular RNA (circRNA) has been proved to be a key regulator of gastric cancer (GC) progression. Circ_0009910 was found to be highly expressed in GC and related to GC progression, but its role and mechanism in GC progression need to be further improved. Our study aims to further reveal circ_0009910 roles in GC progression and elucidate its potential molecular mechanism. The expression of circ_0009910, microRNA (miR)-361-3p, and small nuclear ribonucleoprotein polypeptide A (SNRPA) mRNA was measured by quantitative real-time PCR. Protein expression was determined using western blot analysis. Cell proliferation, migration, invasion, and apoptosis were evaluated using EDU staining, transwell assay, and flow cytometry. Cell glycolysis were assessed by detecting glucose consumption, lactate production, and glycolysis-related markers protein expression. The relationship between miR-361-3p and circ_0009910 or SNRPA was confirmed by RNA pull-down assay and dual-luciferase reporter assay. In vivo experiments were performed to explore the effect of circ_0009910 silencing on GC tumorigenesis. Circ_0009910 and SNRPA were upregulated in GC tumor tissues and cells. Knockdown of circ_0009910 or SNRPA could inhibit GC cell proliferation, migration, invasion, glycolysis, and promote apoptosis. Circ_0009910 could sponge miR-361-3p, and miR-361-3p could target SNRPA. Further experiments confirmed that circ_0009910 positively regulated SNRPA by sponging miR-361-3p. Additionally, SNRPA overexpression abolished the negative regulation of circ_0009910 silencing on GC progression. Furthermore, silenced circ_0009910 also reduced GC tumorigenesis in vivo. Our data showed that circ_0009910 might be a target for GC treatment, which could promote GC proliferation, metastasis, and glycolysis by the miR-361-3p/SNRPA axis.

Hsa_circ_0000218/hsa-miR-139-3p/SOX4 regulatory feedback circuit influences the proliferation and apoptosis of gastric cancer cells.

Previous studies have reported that circular (circ)RNAs serve an important role in cancer progression, but the effects of hsa_circRNA_0000218 (circ_0000218) and its potential underlying mechanism in gastric cancer (GC) are not completely understood. In the present study, dual luciferase reporter and RNA pull down assays were performed to detect the relationship between microRNA (miR)-139-3p and circ_0000218, and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to detect circ_0000218, miR-139-3p and SRY-box transcription factor 4 (SOX4) mRNA expression levels in GC and GES-1 cells. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay and flow cytometry were used to detect cell proliferation and apoptosis, respectively. Western blotting was performed to assess cleaved-Caspase3 and Caspase3 expression levels in GC cells. circ_0000218 and SOX4 were highly expressed, whereas miR-139-3p was lowly expressed in GC cells. Moreover, circ_0000218 negatively regulated miR-139-3p in GC cells. circ_0000218 knockdown inhibited GC cell proliferation, promoted apoptosis and enhanced cleaved-Caspase3 expression in GC cells, whereas miR-139-3p knockdown reversed these effects. miR-139-3p overexpression inhibited proliferation and induced apoptosis in GC cells, but these effects were reversed by SOX4 overexpression. Collectively, the present study demonstrated that circ_0000218 upregulated SOX4 via downregulating miR-139-3p to promote GC progression.

Dysregulation of let-7c-5p/Tyrosyl-DNA phosphodiesterase 1 axis indicates an unfavorable outcome in gastric cancer

Introduction Tyrosyl-DNA phosphodiesterase 1 (TDP1) can repair oxidative damage-caused 3′-phosphoglycolates and promote cancer progression. However, the clinical significance of TDP1 and its correlation with microRNAs (miRNAs) in gastric cancer (GC) remains unknown. Methods The relationship of TDP1 or let-7c-5p with the clinical outcomes of GC was determined by a tissue microarray and TCGA dataset. Cell viability and invasion were assessed by MTT and Transwell assays. Pearson correlation analysis, luciferase gene report, qRT-PCR, and Western blot analyses were used to analyze the interaction between TDP1 and let-7c-5p in GC tissues and cells. Results We found that TDP1 expression was elevated in GC tissues and associated with the dysregulation of let-7c-5p. Knockdown of TDP1 inhibited GC cell proliferation and invasion. let-7c-5p could be found to bind with TDP1, reduce its expression levels, and represent a predictive marker in GC. Conclusion Our findings demonstrated that dysregulation of let-7c-5p/TDP1 axis could predict a poor prognosis in GC.

LHPP suppresses gastric cancer progression via the PI3K/AKT/mTOR signaling pathway.

Emerging evidence has revealed the anti-oncogenic role of LHPP in several malignancies. The current study aims to explore the underlying mechanism of LHPP in gastric cancer (GC). We used the TCGA and GEO databases to investigate the expression profile, prognostic value, and cellular function of LHPP in GC. LHPP expression pattern were further verified using clinical samples by immunohistochemistry and western blot analysis. Moreover, stable cancer cell lines with LHPP overexpression or knockdown were established. CCK-8 assay, colony formation assay, transwell assay, qRT-PCR, and western blot analysis were performed to uncover the underlying mechanism concerning LHPP during the progression of GC. The present study revealed that LHPP was down-regulated in GC cell lines and tissue samples at both mRNA and protein level. LHPP inhibited GC cells proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) in vitro. Mechanically, LHPP overexpression led to decreased level of PI3K/AKT/mTOR pathway phosphorylation, while LHPP depletion produced opposite results. Moreover, our data indicated that the enzymatic active site of LHPP is neither the cysteine residue at position 226 nor at position 53 in GC. Overall, our study demonstrated that LHPP function as a tumor suppressor gene in GC by regulating the PI3K/AKT/mTOR pathway.

Long noncoding RNA HAGLR sponges miR-338-3p to promote 5-Fu resistance in gastric cancer through targeting the LDHA-glycolysis pathway.

Gastric cancer (GC) is one of the most common human malignancies due to its invasiveness and metastasis. 5‐Fu is a widely applied chemotherapeutic agent against GC. Although 5‐Fu therapy has achieved improvements in GC treatment, a large fraction of patients developed drug resistance which significantly limited its clinical applications. Recent studies revealed the pivotal roles of long noncoding RNAs (lncRNAs) in tumorigenesis and progressions of various tumors, including GC. However, the biological roles and molecular mechanisms of lncRNA HAGLR in GC remain unclear. Here, we report HAGLR was upregulated in both GC tissues and cell lines. In addition, HAGLR was associated with a poorly survival rate of GC patients. Blocking HAGLR inhibited GC cells proliferation and sensitized GC cells to 5‐Fu. Bioinformatical analysis and luciferase assay demonstrated that HAGLR sponged microRNA (miR)‐338‐3p, which functions as a tumor suppressor in GC to downregulate its expressions. Moreover, from the established 5‐Fu resistant GC cell line (HGC27 5‐Fu R), we detected significantly elevated HAGLR, downregulated miR‐338‐3p, and glucose metabolism compared with parental HGC27 cells. We identified lactate dehydrogenase‐A (LDHA), a glucose metabolism key enzyme, was the direct target of miR‐338‐3p in GC cells. Rescue experiments demonstrated that restoration of miR‐338‐3p in HAGLR‐overexpressing HGC27 5‐Fu R cells successfully overrode the HAGLR‐promoted 5‐Fu resistance through targeting LDHA. Taken together, this study revealed essential roles and molecular mechanisms for the HAGLR‐mediated 5‐Fu resistance in GC, contributing to the development of new noncoding RNA‐based therapeutic strategies against chemoresistant GC.

LncRNA FENDRR Inhibits Gastric Cancer Cell Proliferation and Invasion via the miR-421/SIRT3/Notch-1 Axis.

ObjectiveThis study aimed to investigate the regulatory effect of lncRNA fetal-lethal non-coding developmental regulatory RNA (FENDRR) on gastric cancer (GC) progression.MethodsThe expression levels of FENDRR in GC tissues and paracancerous tissues, as well as in gastric normal epithelial cell line and GC cell lines were detected. The Ad-FENDRR or si-FENDRR was transfected into AGS and SGC-7901 cells, and cell proliferation, invasion and apoptosis were determined. Online bioinformatics database predicted and screened miR-421 as a potential target of FENDRR, and SIRT3 was predicted as a target gene of miR-421. The pcDNA-SIRT3 or si-SIRT3 was transfected into AGS cells, and cell proliferation, invasion, apoptosis and Notch-1 protein expression were determined. Ad-FENDRR was transfected into AGS and SGC-7901 cells alone or together with miR-421 mimic to explore the effect of miR-421 on cells. The AGS cells transfected with Ad-FENDRR were injected into the armpits of nude mice to establish subcutaneous xenograft tumor model, and tumor growth was observed.ResultsFENDRR expression was downregulated in GC tissues and cell lines. Overexpression of FENDRR or SIRT3 inhibited tumor proliferation and invasion, and promoted apoptosis. The overexpression of Notch-1 reversed the inhibitory effect of SIRT3 on AGS cell. MiR-421 mimic reversed the inhibitory effect of FENDRR on the growth of AGS and SGC-7901 cells. Nude mice injected with FENDRR overexpressing AGS cells had smaller tumor volume and weight and weaker tumor cell proliferation ability.ConclusionFENDRR inhibits Notch-1 pathway to inhibit GC cell proliferation and invasion by upregulating SIRT3 expression via targeting miR-421.

Long non-coding RNA LINC00240 promotes gastric cancer progression via modulating miR-338-5p/METTL3 axis

ABSTRACT Gastric cancer (GC) is a common cancer with high incidence. Understanding the epidemiology and physiopathology of GC is crucial for formulating novel therapeutic strategies. Recent studies have implicated long non-coding RNA LINC00240, miR-338-5p and methyltransferase-like 3 (METTL3) in the progression of GC. In this study, we investigated the functional role of LINC00240/miR-338-5p/METTL3 axis in regulating the aggressiveness of GC cells. We first demonstrated that LINC00240 was upregulated in GC tissues and GC cell lines. High expression of LINC00240 was associated with advanced TNM stage, a higher extent of distant metastasis and lymph nodes metastasis, and the poor overall and disease-free survival of the patients. In GC cell lines, the knockdown of LINC00240 inhibited GC cell proliferation and migration, but induced cell apoptosis. We further identified and validated the functional interaction between LINC00240 and miR-338-5p. miR-338-5p seemed to function as a downstream target negatively regulated by LINC00240, and miR-338-5p could target METTL3 at 3ʹ UTR to downregulate its expression. In GC tissues, the expression of miR-338-5p was negatively correlated with LINC00240, and the expression of miR-338-5p was negatively correlated with METTL3. Importantly, miR-338-5p inhibitor or METTL3 overexpression could rescue the inhibitory effect of LINC00240 knockdown on cell proliferation and migration, and inhibit the apoptosis induction in GC cells. Taken together, our data imply that the upregulation of LINC00240 in GC cells promotes the malignant phenotype by modulating miR-338-5p/METTL3 axis, which could serve as potential therapeutic targets for GC treatment.

LncRNA NR038975, A Serum-Based Biomarker, Promotes Gastric Tumorigenesis by Interacting With NF90/NF45 Complex.

Gastric cancer (GC) is one of the deadliest cancers, and long noncoding RNAs (lncRNAs) have been reported to be the important regulators during the occurrence and development of GC. The present study identified a novel and functional lncRNA in GC, named NR038975, which was confirmed to be markedly upregulated in the Gene Expression Profiling Interactive Analysis (GEPIA) dataset and our independent cohort of GC tissues. We firstly characterized the full-length sequence and subcellular location of NR038975 in GC cells. Our data demonstrated that upregulated NR038975 expression was significantly related to lymph node metastasis and TNM stage. In addition, knockdown of NR038975 inhibited GC cell proliferation, migration, invasion, and clonogenicity and vice versa. Mechanistically, RNA pull-down and mass spectrometry assays identified the NR038975-binding proteins and NF90/NF45 complex, and the binding was also confirmed by RNA immunoprecipitation and confocal experiments. We further demonstrated that genetic deficiency of NR038975 abrogated the interaction between NF45 and NF90. Moreover, NF90 increased the stability of NR038975. Thus, NR038975-NF90/NF45 will be an important combinational target of GC. Finally, we detected NR038975 in serum exosomes and serum of GC patients. Our results indicated that NR038975 was a biomarker for gastric tumorigenesis. The current study demonstrated that NR038975 is a novel lncRNA that is clinically and functionally engaged in GC progression and might be a novel diagnostic marker and potential therapeutic target.

Regulatory Mechanism and Experimental Verification of Patchouli Alcohol on Gastric Cancer Cell Based on Network Pharmacology.

BackgroundPogostemon cablin is a traditional Chinese medicine (TCM) that is frequently used to treat various gastrointestinal diseases. Patchouli alcohol (PA), a compound extracted from the Pogostemon cablin, has been shown to have anti-tumor efficacy in human colorectal cancer. However, the mechanism of PA’s anticancer effect on gastric cancer (GC) remains unknown.MethodsWe used the public database to obtain the potential targets of PA and genes related to GC. Bioinformatic analyses, such as the Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), and protein-protein interactions (PPI), were used for analyzing the potential signal pathways and targets. Cell experiments were also conducted to further explain the impact and molecular mechanism of PA on GC, as well as to confirm the findings of network pharmacology.ResultsUsing network pharmacological analysis, 161 possible targets were identified for the treatment of GC. Network analysis and functional enrichment analysis show that PA produced a marked effect in the treatment of GC through multi-targets and multi-pathways, especially the MAPK and PI3K/AKT signal pathways. In addition, PA showed the inhibition of GC cell proliferation, migration and invasion in cell experiments. According to our findings, PA could also cause G0/G1 phase arrest and apoptosis in GC cells.ConclusionUsing network pharmacology, we aim to uncover the possible molecular mechanism of PA on GC treatment in this research. Cell experiments were also conducted to confirm the therapeutic effect of PA on GC.

Podofilox suppresses gastric cancer cell proliferation by regulating cell cycle arrest and the c-Myc/ATG10 axis.

Gastric cancer (GC) is a malignancy for which effective therapeutic drugs are limited. Podofilox exhibits antitumor effects in various types of cancer; however, whether it may inhibit GC growth remains unknown. The aim of the present study was to investigate the role of podofilox in GC. Cell Counting Kit-8, colony formation and cell cycle assays were used to detect the role of podofilox on cellular proliferation and the cell cycle, respectively. A microarray was used to detect the transcriptional changes induced by podofilox in GC cells. The results of the present study demonstrated that podofilox inhibited GC cell proliferation and colony formation. The half maximal inhibitory concentration of podofilox in AGS and HGC-27 cells was 2.327 and 1.981 nM, respectively. In addition, treatment with podofilox induced G0/G1 cell cycle arrest. Molecular analysis based on microarray data demonstrated that podofilox altered the expression levels of genes involved in the cell cycle, c-Myc and p53 signaling. Autophagy-related 10 (ATG10), which was highly expressed in GC tissues, was also downregulated by podofilox, as demonstrated by the results of the microarray analysis and immunoblotting. To determine the involvement of ATG10 in GC, ATG10 was knocked down in GC cells by small interfering RNA, which suppressed the proliferation and colony formation of GC cells compared with those observed in the control-transfected cells. Taken together, the results of the present study suggested that podofilox may inhibit GC cell proliferation by preventing the cell cycle progression and regulating the c-Myc/ATG10 signaling pathway.

The effects of T-DXd on the expression of HLA class I and chemokines CXCL9/10/11 in HER2-overexpressing gastric cancer cells

Trastuzumab deruxtecan (T-DXd), a HER2-targeting antibody–drug conjugate with a topoisomerase I inhibitor deruxtecan (DXd), exhibits an excellent anti-tumor effect in previously treated HER2-positive tumors. A recent study demonstrated that T-DXd not only suppressed tumor growth but also enhanced anti-tumor immunity through increasing the number of tumor-infiltrating CD8+ T cells and enhancement of major-histocompatibility-complex class I expression on tumor cells in a mouse model. However, the effect of T-DXd on anti-tumor immune responses in human cancers is largely unknown. We investigated the effect of T-DXd on the expression of HLA class I and CXCL9/10/11, T-cell chemoattractants, in HER2-positive human gastric cancer (GC) cells. We found that T-DXd significantly inhibited GC cell proliferation in a HER2-dependent manner, while it slightly increased the expression of HLA class I in HER2-positive GC cells. Moreover, we revealed that T-DXd significantly induced mRNA expression of CXCL9/10/11 in HER2-positive GC cells. T-DXd-triggered up-regulation of these chemokines was mediated through the activation of DNA damage signaling pathways. These results suggest that T-DXd triggers anti-tumor immune responses at least in part through induction of the expression of HLA class I and CXCL9/10/11 on HER2-positive GC cells, resulting in the enhancement of anti-tumor immunity in human GC.

CircEVI5 acts as a miR-4793-3p sponge to suppress the proliferation of gastric cancer

Circular RNAs (circRNAs) are a novel class of endogenous noncoding RNAs (ncRNAs) with a covalently closed loop structure. Accumulating evidence shows that circRNAs play vital roles in the growth, metastasis, treatment and prognosis of various cancers. However, the detailed functions and underlying mechanisms of circEVI5 (hsa_circ_0013162) in gastric cancer (GC) remain undocumented. In this study, the expression levels and prognostic value of circEVI5 were validated in GC tissue samples by using qRT-PCR. circEVI5 was significantly downregulated in GC tissues and cells, and low circEVI5 expression was correlated with poor prognosis. Next, in vitro CCK-8 assay, EdU incorporation assay, PI staining cell cycle assay, and in vivo xenograft mouse models were conducted to assess the functions of circEVI5. Gain of function experiments indicated that circEVI5 could inhibit GC cell proliferation and retard the cell cycle. Moreover, bioinformatics prediction showed that circEVI5 binds to miR-4793-3p, while FOXO1 may be a target of miR-4793-3p. Pull-down assays, RNA immunoprecipitation (RIP) assays, luciferase assays, and western blot were used to confirm the interactions between circEVI5, miR-4793-3p, and FOXO1. Functional assays demonstrated that circEVI5 suppressed the proliferation of GC by sponging miR-4793-3p and increasing FOXO1 expression levels. In conclusion, our study demonstrated that circEVI5 can bind miR-4793-3p as a ceRNA to eliminate the negative regulation of FOXO1, therefore suppressing GC proliferation.

ELTD1 Promotes Gastric Cancer Cell Proliferation, Invasion and Epithelial-Mesenchymal Transition Through MAPK/ERK Signaling by Regulating CSK.

PurposePatients with gastric cancer (GC) often die from metastasis. However, the exact molecular mechanism underlying GC metastasis is complicated and still remains elusive. Epidermal growth factor, latrophilin and seven-transmembrane domain-containing 1 (ELTD1), has been reported to be involved in cancer metastasis, but its role in GC is still missing.Patients and MethodsWe first analyzed the expression of ELTD1 in GC using public databases (TCGA, Oncomine, and GEO) and our clinical samples. The functions of ELTD1 in GC proliferation, invasion and metastasis were determined by in vitro and in vivo experiments. The functional mechanism of ETLD1 in GC was also investigated. Finally, the association between ELTD1 expression and the overall survival of GC patients was analyzed using public databases.ResultsELTD1 is significantly upregulated in GC tissues. Knockdown of ELTD1 inhibits GC cell proliferation, migration and invasion in vitro as well as tumor growth and metastasis in vivo, while ELTD1 overexpression obtains opposite results. Moreover, ELTD1 could promote epithelial to mesenchymal transition (EMT) in GC. Mechanistically, ELTD1 exerts its tumor-promoting effect by activating MAPK/ERK signaling. Subsequent studies demonstrated that ELTD1 could interact with C-terminal Src kinase (CSK) and inhibit its expression, which finally lead to MAPK/ERK activation. Data from TGCA and GEO both revealed that GC patients with high ELTD1 expression had poorer prognosis and the combination of ELTD1 with CSK showed better predictive performance.ConclusionELTD1 plays an oncogene role in GC through MAPK/ERK signaling via inhibiting CSK, which may be a useful prognostic predictor and potential therapeutic target for GC.

CircTMC5 promotes gastric cancer progression and metastasis by targeting miR-361-3p/RABL6.

Gastric cancer (GC) is common in East Asia, yet its molecular and pathogenic mechanisms remain unclear. Circular RNAs (circRNAs) are differentially expressed in GC and may be promising biomarkers. Here, we investigated the role and regulatory mechanism of circTMC5 in GC. CircTMC5 expression was detected in human GC and adjacent tissues using microarray assays and qRT-PCR, while the clinicopathological characteristics of patients with GC were used to assess its diagnostic and prognostic value. The circTMC5/miR-361-3p/RABL6 axis was examined in vitro and vivo, and the immune roles of RABL6 were evaluated using bioinformatics analyses and immunohistochemistry (IHC). CircTMC5 was highly expressed in GC tissues, plasma, and cell lines, and was closely related to histological grade, pathological stage, and T classification in patients with GC. CircTMC5 expression was also an independent prognostic factor for GC and its combined detection with carcinoembryonic antigen may improve GC diagnosis. Low circTMC5 expression correlated with good prognosis, inhibited GC cell proliferation, and promoted apoptosis. Mechanistically, circTMC5 overexpression promoted GC cell proliferation, invasion, and metastasis but inhibited apoptosis by sponging miR-361-3p and up-regulating RABL6 in vitro and vivo, whereas miR-361-3p up-regulation had the opposite effects. RABL6 was highly expressed in GC and was involved in immune regulation and infiltration in GC. CircTMC5 promotes GC and sponges miR-361-3p to up-regulate RABL6 expression, thus may have diagnostic and prognostic value in GC. RABL6 also displays therapeutic promise due to its role in the immune regulation of GC.

Long Noncoding RNA HCG11 Acts as a Tumor Suppressor in Gastric Cancer by Regulating miR-942-5p/BRMS1 Axis.

The functions of long noncoding RNAs (lncRNAs) have been widely investigated in human cancers, including gastric cancer (GC). The purpose of this study was to elucidate the role of lncRNA HCG11 in GC. In this study, mRNA and protein expressions were detected by quantitative real-time polymerase chain reaction assays (RT-qPCR) and Western blot analysis. The proliferation ability of GC cells was examined by (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyl Tetrazolium Bromide) MTT assays. The invasion and migration abilities of GC cells were evaluated by Transwell assays. The binding sites between miR-942-5p and HCG11/BRMS1 were confirmed by dual-luciferase reporter assays. Results showed that LncRNA HCG11 was downregulated in GC cells. Functionally, overexpression of HCG11 inhibited GC cell proliferation, migration, and invasion. In addition, lncRNA HCG11 was found to act as a molecular sponge of miR-942-5p. Furthermore, miR-942-5p promoted GC progression by suppressing lncRNA HCG11 expression. Besides that, BRMS1 was confirmed as a direct target of miR-942-5p. More importantly, breast cancer metastasis suppressor 1 (BRMS1) inhibited GC progression by upregulating lncRNA HCG11 and downregulating miR-942-5p. In conclusion, LncRNA HCG11 inhibited cell proliferation, migration, and invasion in GC by sponging miR-942-5p and upregulating BRMS1.

TYMSOS drives the proliferation, migration, and invasion of gastric cancer cells by regulating ZNF703 via sponging miR-4739.

Gastric cancer (GC) is a kind of malignancy originating from the epithelium of gastric mucosa. Long noncoding RNAs (lncRNAs) are tightly related to the GC progression. Herein, our research was meant to investigate a novel lncRNA thymidylate synthetase opposite strand (TYMSOS) in GC. Quantitative real-time polymerase chain reaction was used to analyze TYMSOS expression in GC cells. 5-Ethynyl-2'-deoxyuridine, flow cytometry analysis, and transwell assay detected the influence of TYMSOS on GC cell proliferation, apoptosis, migration, and invasion. Subcellular fractionation and fluorescent in situ hybridization assays determined the cellular localization of TYMSOS in GC cells. Bioinformatics programs, RNA-binding protein immunoprecipitation, RNA pull-down, and luciferase reporter assays measured the molecular interplays of TYMSOS in GC cells. In brief, TYMSOS was highly expressed in GC cells, and TYMSOS silence inhibited GC cell proliferation, migration, and invasion while elevating cell apoptosis. Functionally, TYMSOS functioned as a competing endogenous RNA to posttranscriptionally modulate GC progression. TYMSOS interacted with miR-4739 to regulate its target gene zinc finger protein 703. Collectively, our study proved the tumor-promoting role of TYMSOS in GC cells, which might offer the utility value for GC treatment.