Treatment Of Gastric Carcinoma Research Articles

Gancao Xiexin Decoction inhibits gastric carcinoma proliferation and migration by regulating the JAK2/STAT3 signalling pathway

Ethnopharmacological relevanceThe incidence of gastric carcinoma (GC) is increasing rapidly. Traditional Chinese Medicine (TCM) plays a unique role in the treatment of GC. At present, Gancao Xiexin Decoction (GCXXD) has been proved to have a good therapeutic effect on diseases of the spleen and stomach system, but relevant molecular mechanisms remain incompletely explained. Aim of studyThe mechanism of GCXXD for GC was investigated by network pharmacology and verified by cell experiments. Materials and methodsFirstly, the public database was used to identify the core targets and key pathways of GCXXD in treating GC, followed by molecular docking and survival analysis. Subsequently, the effects of GCXXD on human gastric cancer AGS and HGC-27 cells were confirmed by a series of experiments, such as CCK-8, colony formation, apoptosis, cell cycle, wound scratch assay, transwell chamber assay, qRT-PCR and Western blot. ResultsThis study identified quercetin, wogonin, kaempferol, baicalein, sitosterol and beta-sitosterol as key ingredients, along with AKT1, TP53, JUN, STAT3, TNF, MAPK3, HSP90AA1 and EGFR as co targets, and the JAK/STAT signalling pathway as the key pathway. The experimental results showed that GCXXD inhibited the growth of GC cells, increased the apoptosis rate and the ratio of G0/G1 phase cells, and weakened the clone formation rate and inhibited cell migration and invasion. It also reduces the expression of core target genes and downregulates the expression of JAK2, p-JAK2, STAT3, and p-STAT3 proteins. ConclusionGCXXD inhibits GC cell growth, reduces clonogenic capacity, induces apoptosis, blocks the cell cycle, and decreases cell migration and invasion rates by inhibiting the JAK2/STAT3 signalling pathway.

CDK12 Promotes the Proliferation, Migration, and Angiogenesis of Gastric Carcinoma via Activating the PI3K/AKT/mTOR Signaling Pathway.

Cyclin-dependent kinase 12 (CDK12) has been found to regulate tumor progression. However, its function in gastric carcinoma (GC) remains controversial. This work aimed to explore the exact effect of CDK12 on GC progression. We detected the expression of CDK12 in GC cells and normal gastric mucosal epithelial cells. Then CDK12 function on GC cell proliferation, migration, and angiogenesis was researched by colony formation experiment, Transwell experiment, and angiogenesis assay. Moreover, CDK12 effect on the PI3K/AKT/mTOR pathway activity was explored by western blot. Further, we used LY294002 (10μM) to treat GC cells to verify whether CDK12 regulates GC progression by activating the PI3K/AKT/mTOR pathway. Additionally, CDK12 effect on the expression of prognostic factors of GC was detected by western blot, including alkaline phosphatase (ALP) and Ki67. Quantitative real-time polymerase chain reaction and western blot were utilized to evaluate the expression of mRNAs and proteins. As a result, CDK12 was upregulated in GC cells. CDK12 overexpression facilitated the proliferation, migration, and angiogenesis of GC cells. However, CDK12 silencing showed an opposite result. CDK12 overexpression activated the PI3K/AKT/mTOR pathway, but CDK12 silencing inactivated it in GC cells. The blockage of the PI3K/AKT/mTOR pathway induced by LY294002 treatment counteracted the promotion of CDK12 on the proliferation, migration, and angiogenesis of GC. Further, CDK12 silencing suppressed the expression of ALP and Ki67 proteins in GC cells. Taken together, CDK12 promotes the proliferation, migration, and angiogenesis of GC by activating the PI3K/AKT/mTOR pathway. It may be a novel target for GC treatment.

Vimentin binds to a novel tumor suppressor protein, GSPT1-238aa, encoded by circGSPT1 with a selective encoding priority to halt autophagy in gastric carcinoma

Circular RNAs (circRNAs) are covalently closed, endogenous molecules that are widespread in eukaryotes. Recent evidence indicates that circRNAs play important roles in carcinogenesis. Several circRNAs have been reported to comprise translatable RNA; however, whether circRNAs encode functional proteins remains unknown. In our study, circRNA sequencing was carried out using five pathologically diagnosed gastric carcinoma (GC) samples and their paired adjacent normal tissues, we characterized the circRNA GSPT1 (circGSPT1), which is expressed at low levels in GC. Antibody detections, and mass spectrometry were used to validate active circRNA translation. The spanning junction open reading frame in circGSPT1, driven by an internal ribosome entry site (IRES), encodes a functional peptide, termed GSPT1-238aa. Interestingly, GSPT1-238aa tends to select the start codon used to initiate translation. This is the first finding of selective translation driven by IRES. CircGSPT1 and GSPT1-238aa halted the proliferation, migration, and invasion in GC cells in vitro. We also confirmed that the vimentin/Beclin1/14-3-3 complex interacts with GSPT1-238aa and modulates autophagy via the PI3K/AKT/mTOR signaling pathway in GC cells. Our study reveals that GSPT1-238aa, a novel protein encoded by circGSPT1, halts GC tumorigenesis. We also provide insights into the function and underlying molecular mechanisms of GSPT1-238aa in GC and suggest that this protein represents a novel target for GC treatment.

Dynamic detection of HER2 of circulating tumor cells in patients with gastric carcinoma and its clinical application.

The aim of the present study was to construct and characterize human epidermal growth factor receptor2 (HER2) lipid magnetic ball (H‑LMB) for separating circulating tumor cells (CTCs) in patients with gastric carcinoma (GC) and to compare the result of separated CTC counts with that of next‑generation sequencing (NGS) for single‑gene analysis to verify the consistency for evaluating the association between the detection results and the progress of clinical treatment, so as to facilitate early diagnosis and dynamic monitoring of GC. A lipid magnetic ball (LMB), coated with Fe3O4 nanoparticles, was synthesized by microemulsion technique and an anti‑HER2 antibody was conjugated to the surface of LMB to form H‑LMB, followed by the characterization of the prepared H‑LMB. The detection of capture efficiency of LMBs in GC cells was tested by MTT and expression of HER2 mRNA was determined by reverse transcription‑quantitative PCR. The positive detection rate of HER2 was verified by HER2‑fluorescence insitu hybridization (FISH) test on the separated CTCs from GC. Further verification was performed based on the consistency between the result of separated CTCs and that of single‑gene NGS assay of HER2, associated with the determination of clinical consistency. The constructed H‑LMB exhibited good stability and specificity. The mutation rate of HER2 by the FISH test was 14% in the blood samples of 50patients with GC and was 14% by NGS assay. The mutation rate of HER2 was 12% in H‑LMB and the positive detection rate was 85.7% compared with the results of the FISH test, indicating consistency with the clinical diagnosis and pathological examination results. In conclusion, the anti‑HER2 antibody‑modified LMB can separate CTCs with HER2 abnormal expression, which exhibits an application potential in GC diagnosis and treatment and is of great clinical significance for the diagnosis and evaluation of its therapeutic effect on GC.

Mechanism of Herb Pairs Astragalus mongholicus and Curcuma phaeocaulis Valeton in Treating Gastric Carcinoma: A Network Pharmacology Combines with Differential Analysis and Molecular Docking.

Background Gastric carcinoma (GC) is a kind of digestive tract tumor that is highly malignant and has a very poor prognosis. Although both Astragalus mongholicus (AM, huáng qí) and Curcuma phaeocaulis Valeton (CPV, é zhú) can slow the onset and progression of GC, the mechanism by which AM-CPV works in the treatment of GC is uncertain. Materials and Methods The traditional Chinese medicine network databases TCMSP, TCMID, and ETCM were used to identify the key functional components and associated targets of AM and CPV. To establish a theoretical foundation, the development of gastric cancer (GC) was predicted utilizing a GEO gene chip and TCGA difference analysis mixed with network pharmacology. A herbal-ingredient-target network and a core target-signal pathway network were created using GO and KEGG enrichment analyses. The molecular docking method was used to evaluate seventeen main targets and their compounds. Results Cell activity, reactive oxygen species modification, metabolic regulation, and systemic immune activation may all be involved in the action mechanism of the AM-CPV drug-pair in the treatment of GC. It inhibits the calcium signaling route, the AGE-RAGE signaling system, the cAMP signaling pathway, the PI3K-Akt signaling network, and the MAPK signaling pathway, slowing the progression of GC. The number of inflammatory substances in the tumor microenvironment is reduced, GC cell proliferation is deprived, apoptosis is promoted, and GC progression is retarded through controlling the IL-17 signaling route, TNF signaling pathway, and other inflammation-related pathways. Conclusions The AM-CPV pharmaceutical combination regulates GC treatment via a multitarget, component, and signal pathway with a cooperative and bidirectional regulatory mechanism. Its active constituents may treat GC by regulating the expression of STAT1, MMP9, IL6, HSP90AA1, JUN, CCL2, IFNG, CXCL8, and other targets, as well as activating or inhibiting immune-inflammatory and cancer signaling pathways.

MT1G inhibits the growth and epithelial-mesenchymal transition of gastric cancer cells by regulating the PI3K/AKT signaling pathway.

Gastric carcinoma (GC) is a malignant tumor that has high mortality and morbidity worldwide. Although many efforts have been focused on the development and progression of GC, the underlying functional regulatory mechanism of GC needs more clarification. Metallothionein 1G (MT1G) is a member of the metallothionein family (MTs), and hypermethylation of MT1G occurred in a variety of cancers, including gastric cancer. However, the functional mechanism of MT1G in GC remains unclear. Here, we demonstrated that MT1G was down-regulated in GC tissues and cells. Overexpression of MT1G inhibited cell proliferation, foci formation and cell invasion, while knockdown of MT1G increased cell proliferation, foci formation and cell invasion. In addition, MT1G overexpression inhibited cell cycle progression and MT1G deficiency exerted opposite phenotype. p-AKT was negatively regulated by MT1G. In summary, our study reveals that MT1G exerts crucial role in regulating of cell proliferation and migration of gastric cancer, providing new insights for MT1G-related pathogenesis and a basis for developing new strategies for treatment of GC.

Long noncoding RNA SGO1-AS1 inactivates TGF\u03b2 signaling by facilitating TGFB1/2 mRNA decay and inhibits gastric carcinoma metastasis

BackgroundAlthough thousands of long noncoding RNAs (lncRNAs) have been annotated, only a few lncRNAs have been characterized functionally. In this study, we aimed to identify novel lncRNAs involved in the progression of gastric carcinoma (GC) and explore their regulatory mechanisms and clinical significance in GC.MethodsA lncRNA expression microarray was used to identify differential lncRNA expression profiles between paired GCs and adjacent normal mucosal tissues. Using the above method, the lncRNA SGO1-AS1 was selected for further study. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and in situ hybridization (ISH) were performed to detect SGO1-AS1 expression in GC tissues. Gain-of-function and loss-of-function analyses were performed to investigate the functions of SGO1-AS1 and its upstream and downstream regulatory mechanisms in vitro and in vivo.ResultsSGO1-AS1 was downregulated in gastric carcinoma tissues compared to adjacent normal tissues, and its downregulation was positively correlated with advanced clinical stage, metastasis status and poor patient prognosis. The functional experiments revealed that SGO1-AS1 inhibited GC cell invasion and metastasis in vitro and in vivo. Mechanistically, SGO1-AS1 facilitated TGFB1/2 mRNA decay by competitively binding the PTBP1 protein, resulting in reduced TGFβ production and, thus, preventing the epithelial-to-mesenchymal transition (EMT) and metastasis. In addition, in turn, TGFβ inhibited SGO1-AS1 transcription by inducing ZEB1. Thus, SGO1-AS1 and TGFβ form a double-negative feedback loop via ZEB1 to regulate the EMT and metastasis.ConclusionsSGO1-AS1 functions as an endogenous inhibitor of the TGFβ pathway and suppresses gastric carcinoma metastasis, indicating a novel potential target for GC treatment.

An Advanced Systems Pharmacology Strategy Reveals AKR1B1, MMP2, PTGER3 as Key Genes in the Competing Endogenous RNA Network of Compound Kushen Injection Treating Gastric Carcinoma by Integrated Bioinformatics and Experimental Verification.

Gastric carcinoma (GC) is a severe tumor of the digestive tract with high morbidity and mortality and poor prognosis, for which novel treatment options are urgently needed. Compound Kushen injection (CKI), a classical injection of Chinese medicine, has been widely used to treat various tumors in clinical practice for decades. In recent years, a growing number of studies have confirmed that CKI has a beneficial therapeutic effect on GC, However, there are few reports on the potential molecular mechanism of action. Here, using systems pharmacology combined with proteomics analysis as a core concept, we identified the ceRNA network, key targets and signaling pathways regulated by CKI in the treatment of GC. To further explore the role of these key targets in the development of GC, we performed a meta-analysis to compare the expression differences between GC and normal gastric mucosa tissues. Functional enrichment analysis was further used to understand the biological pathways significantly regulated by the key genes. In addition, we determined the significance of the key genes in the prognosis of GC by survival analysis and immune infiltration analysis. Finally, molecular docking simulation was performed to verify the combination of CKI components and key targets. The anti-gastric cancer effect of CKI and its key targets was verified by in vivo and in vitro experiments. The analysis of ceRNA network of CKI on GC revealed that the potential molecular mechanism of CKI can regulate PI3K/AKT and Toll-like receptor signaling pathways by interfering with hub genes such as AKR1B1, MMP2 and PTGERR3. In conclusion, this study not only partially highlighted the molecular mechanism of CKI in GC therapy but also provided a novel and advanced systems pharmacology strategy to explore the mechanisms of traditional Chinese medicine formulations.

Apatinib combined with Keytruda treatment induces apoptosis of gastric carcinoma cells through CES4/miR-616-5p/DUSP2 axis.

Gastric carcinoma (GC) is a highly malignant and heterogeneous tumour. Long non-coding RNA CES4 is down-regulated in GC. However, whether CES4 can participate in GC remains unclear; we have carried out research on this topic. GC cells (HGC-27 and MKN-7) were treated with anti-tumour drugs: apatinib combined with Keytruda. Cell viability and apoptosis were detected by CCK-8 assay and flow cytometry. Gene and protein expression were examined by quantitative real-time PCR and western blot. Luciferase reporter assay was performed to verify the relationship among CES4, miR-616-5p and dual-specificity phosphatase-2 (DUSP2). CES4 was highly expressed in the apatinib combined with Keytruda-treated HGC-27 and MKN-7 cells. Apatinib combined with Keytruda treatment repressed cell viability and promoted apoptosis of HGC-27 and MKN-7 cells, which was abrogated by CES4 knockdown. Furthermore, CES4 promoted DUSP2 expression by sponging miR-616-5p in HGC-27 and MKN-7 cells. CES4 knockdown promoted cell viability and inhibited apoptosis of drug-treated HGC-27 and MKN-7 cells by regulating miR-616-5p/DUSP2 axis. In conclusion, these data demonstrate that apatinib combined with Keytruda treatment induces apoptosis of GC cells through CES4/miR-616-5p/DUSP2 axis. Thus, this work provides the experimental basis for the combination of apatinib and Keytruda as a treatment for GC.

Comparison of Clinical Efficacy Between Laparoscopic and Open Distal Gastrectomy in the Treatment of Gastric Carcinoma: A Meta-Analysis

Objectives: The purpose of this article was to systematically evaluate the clinical efficacy of laparoscopy-assisted distal gastrectomy (LDG) and open distal gastrectomy (ODG) in the treatment of gastric carcinoma (GC). Methods: PubMed, Web of Science, Embase, CNKI, and Wanfang databases were systematically searched for relevant articles on surgical treatment of GC published from 2010 to 2020. GC patients in the treatment group received LDG, whereas those in the control group received ODG. The evaluation criteria of these two surgical methods included operation time, intraoperative blood loss, postoperative first exhaust time, number of dissected lymph nodes, postoperative hospital stay, and incidence of complications. Results: A total of 18 studies, with 2102 patients, which met the criteria were included in this meta-analysis. The analysis results showed that in comparison with the control group, both the incidence rate of complications (odds ratio = 0.31, 95% confidence interval, CI [0.23 to 0.41]) and intraoperative blood loss (standardized mean difference, SMD = -2.72, 95% CI [-3.43 to -2.00]) were lower in the treatment group. In addition, in comparison with the control group, LDG led to an increase in the number of dissected lymph nodes (SMD = 0.08, 95% CI [-1.10 to 0.25], P = .403) and associated with shorter hospital stay (SMD = -1.42, 95% CI [-1.90 to -0.94]) and earlier postoperative first exhaust time (SMD = -2.12, 95% CI [-2.86 to -1.38]). Conclusion: LDG can significantly reduce the incidence of complications of GC, intraoperative blood loss, postoperative exhaust time, and hospital stay, whereas increase the number of lymph node dissection. Therefore, LDG is worthy of clinical application.

CCL21 activation of the MALAT1/SRSF1/mTOR axis underpins the development of gastric carcinoma

BackgroundAs a significant cause of malignancy mortality, gastric carcinoma (GC) has been well documented to be an often-fatal diagnosis. Despite the limitations of effective therapy, immunotherapy has emerged as a promising therapeutic approach capable of killing cancer cells via the immune system. The current study was conducted to investigate the effect of cytokine C–C motif chemokine ligand 21 (CCL21) on GC progression through the metastasis-associated lung adenocarcinoma transcript 1/serine arginine-rich splicing factor 1/mammalian target of rapamycin (MALAT1/SRSF1/mTOR) axis.MethodsBioinformatics analysis was conducted to identify the key genes associated with GC and to subsequently predict their downstream genes. The effect of CCL21, MALAT1, and SRSF1 on the malignant phenotypes and epithelial-mesenchymal transition (EMT) of SGC-7901 and MGC-803 cells in-vitro and the tumorigenesis of SGC-7901 and MGC-803 cells in-vivo were assessed by expression determination and plasmid transfection. Additionally, RNA pull-down and RNA binding protein immunoprecipitation experiments were performed to determine the MALAT1-microRNA-202-3p (miR-203-3p) interaction and miR-202-3p-SRSF1 interaction followed by the analysis of their effect on the mTOR pathway.ResultsCCL21 was identified as a key GC immune gene. Overexpressed CCL21, MALAT1, and SRSF1 along with poorly expressed miR-202-3p were identified in the GC cells. CCL21 induced the MALAT1 expression in a time- and dose-dependent manner. Functionally, MALAT1 targeted miR-202-3p but upregulated SRSF1 and activated mTOR. Crucially, evidence was obtained indicating that CCL21 promoted both the malignant phenotypes and EMT of SGC-7901 and MGC-803 cells in-vitro and the tumorigenesis of SGC-7901 and MGC-803 cells in-vivo by increasing the MALAT1-induced upregulation of SRSF1.ConclusionsTaken together, the key observations of our study provide evidence that CCL21 enhances the progression of GC via the MALAT1/SRSF1/mTOR axis, providing a novel therapeutic target for the treatment of GC.

Metabolomic Study on the Therapeutic Effect of the Jianpi Yangzheng Xiaozheng Decoction on Gastric Cancer Treated with Chemotherapy Based on GC-TOFMS Analysis.

Objective This study aimed to find new biomarkers of prognosis and metabolomic therapy for gastric carcinoma (GC) treated with chemotherapy and investigate the metabolic mechanism of the Jianpi Yangzheng Xiaozheng (JPYZXZ) decoction in the treatment of GC. Methods First, 36 patients with GC were randomly assigned to the treatment (chemotherapy plus JPYZXZ) and control (chemotherapy alone) groups. The clinical efficacy, side effects, and quality of life of patients in the two groups were evaluated after treatment. Then, the serum samples taken from 16 randomly selected patients (eight treatment cases and eight control cases with no evident pattern characters) and eight healthy volunteers were tested to identify the differential metabolite under the gas chromatography-time-of-fight mass spectrometry platform. The relevant metabolic pathways of differential substances were analyzed using multidimensional statistical analysis. Results JPYZXZ combined with chemotherapy resulted in a lower risk of leucopenia, thrombocytopenia, and gastrointestinal reaction (P < 0.05). Additionally, patients in the treatment group showed a higher Karnofsky (KPS) scale (P < 0.05). Compared with healthy persons, patients with GC were found to have 26 significant differential metabolites after chemotherapy; these metabolites are mainly involved in 12 metabolic pathways, such as valine, leucine, and isoleucine biosynthesis. JPYZXZ primarily influences the pentose phosphate pathway; glutathione metabolism; glyoxylate and dicarboxylate metabolism; porphyrin and chlorophyll metabolism; and glycine, serine, and threonine metabolism of patients with GC treated with chemotherapy. Conclusions The metabolic characteristics of patients with GC after chemotherapy are mainly various amino acid metabolic defects, especially L-glutamine, L-leucine, L-alloisoleucine, and L-valine. These defects lead to a series of problems, such as decreased tolerance and effectiveness of chemotherapy, increased side effects, decreased immunity, and shortened survival time. In addition, the remarkable upregulation of the gluconolactone level in patients with GC suggests the high proliferative activity of GC cells. Thus, gluconolactone may be used as a potential prognostic and diagnostic evaluation index. Moreover, JPYZXZ can reduce the incidence of ADRs and improve the life quality of patients by the correction of L-glutamine, L-leucine, L-alloisoleucine, and L-valine metabolism deficiency. In addition, gluconolactone metabolism is inhibited by JPYZXZ. Such inhibition may be one of the antitumor mechanisms of JPYZXZ.

Identification of anti-Epstein-Barr virus (EBV) antibody signature in EBV-associated gastric carcinoma.

Around 10% of gastric carcinomas (GC) contain Epstein-Barr virus (EBV) DNA. We characterized the GC-specific antibody response to this common infection, which may provide a noninvasive method to detect EBV-positive GC and elucidate its contribution to carcinogenesis. Plasma samples from EBV-positive (n = 28) and EBV-negative (n = 34) Latvian GC patients were immune-profiled against 85 EBV proteins on a multi-microbial Nucleic Acid Programmable Protein Array (EBV-NAPPA). Antibody responses were normalized for each sample as ratios to the median signal intensity (MNI) across all antigens, with seropositivity defined as MNI ≥ 2. Antibodies with ≥ 20% sensitivity at 95% specificity for tumor EBV status were verified by enzyme-linked immunosorbent assay (ELISA) and validated in independent samples from Korea and Poland (n = 24 EBV-positive, n = 65 EBV-negative). Forty anti-EBV IgG and eight IgA antibodies were detected by EBV-NAPPA in ≥ 10% of EBV-positive or EBV-negative GC patients, of which nine IgG antibodies were discriminative for tumor EBV status. Eight of these nine were verified and seven were validated by ELISA: anti-LF2 (odds ratio = 110.0), anti-BORF2 (54.2), anti-BALF2 (44.1), anti-BaRF1 (26.7), anti-BXLF1 (12.8), anti-BRLF1 (8.3), and anti-BLLF3 (5.4). The top three had areas under receiver operating characteristics curves of 0.81-0.85 for distinguishing tumor EBV status. The EBV-associated GC-specific humoral response was exclusively directed against lytic cycle immediate-early and early antigens, unlike other EBV-associated malignancies such as nasopharyngeal carcinoma and lymphoma where humoral response is primarily directed against late lytic antigens. Specific anti-EBV antibodies could have utility for clinical diagnosis, epidemiologic studies, and immune-based precision treatment of EBV-positive GC.

Identification of a nine-gene prognostic signature for gastric carcinoma using integrated bioinformatics analyses.

BACKGROUNDGastric carcinoma (GC) is one of the most aggressive primary digestive cancers. It has unsatisfactory therapeutic outcomes and is difficult to diagnose early.AIMTo identify prognostic biomarkers for GC patients using comprehensive bioinformatics analyses.METHODSDifferentially expressed genes (DEGs) were screened using gene expression data from The Cancer Genome Atlas and Gene Expression Omnibus databases for GC. Overlapping DEGs were analyzed using univariate and multivariate Cox regression analyses. A risk score model was then constructed and its prognostic value was validated utilizing an independent Gene Expression Omnibus dataset (GSE15459). Multiple databases were used to analyze each gene in the risk score model. High-risk score-associated pathways and therapeutic small molecule drugs were analyzed and predicted, respectively.RESULTSA total of 95 overlapping DEGs were found and a nine-gene signature (COL8A1, CTHRC1, COL5A2, AADAC, MAMDC2, SERPINE1, MAOA, COL1A2, and FNDC1) was constructed for the GC prognosis prediction. Receiver operating characteristic curve performance in the training dataset (The Cancer Genome Atlas-stomach adenocarcinoma) and validation dataset (GSE15459) demonstrated a robust prognostic value of the risk score model. Multiple database analyses for each gene provided evidence to further understand the nine-gene signature. Gene set enrichment analysis showed that the high-risk group was enriched in multiple cancer-related pathways. Moreover, several new small molecule drugs for potential treatment of GC were identified.CONCLUSIONThe nine-gene signature-derived risk score allows to predict GC prognosis and might prove useful for guiding therapeutic strategies for GC patients.

Inhibiting the GAS6/AXL axis suppresses tumor progression by blocking the interaction between cancer-associated fibroblasts and cancer cells in gastric carcinoma.

The effects of cancer-associated fibroblasts (CAF) on the progression of gastric carcinoma (GC) has recently been demonstrated. However, agents targeting the interaction between CAF and GC cells have not been applied in a clinical setting. Here, we examined if inhibition for Axl receptor tyrosine kinase (AXL) can suppress CAF-induced aggressive phenotype in GC. We investigated the function of CAF-derived growth arrest-specific 6 (GAS6), a major ligand of AXL, on the migration and proliferation of GC cells. The effect of the AXL inhibitor, BGB324, on the CAF-induced aggressive phenotype of GC cells was also investigated. In addition, we performed immunohistochemistry to examine the expression of phosphorylated AXL protein in 175 GC tissues and evaluated its correlation with the prognosis. The qPCR and western blot analysis showed that GAS6 expression was higher in CAF relative to other cells. We found that co-culture with CAF increased the phosphorylation of AXL (P-AXL), differentiation into a mesenchymal-like phenotype, and cell survival in GC cell lines. When the expression of AXL was genetically inhibited in GC cells, the effect of CAF was reduced. BGB324, a small molecule inhibitor of AXL, suppressed the effects of CAF on GC cell lines. In GC tissues, high levels of P-AXL were significantly associated with poor overall survival (P = 0.022). We concluded that CAF are a major source of GAS6 and that GAS6 promotes an aggressiveness through AXL activation in GC. We suggested that an AXL inhibitor may be a novel agent for GC treatment.

Identification of lapatinib sensitivity-related genes by integrative functional module analysis.

BackgroundGlobally, gastric carcinoma (GC) is one of the most commonly encountered malignancies and is the second highest contributor to cancer mortality. Lapatinib is a potent, orally-bioavailable small-molecule inhibitor of both epidermal growth factor receptor and human epidermal growth factor receptor-2 tyrosine kinases, and is administered to treat GC. However, a large proportion of patients either develop resistance to or do not respond to lapatinib, often because the treatment activates alternative signaling pathways. It is, therefore, vital to identify the key pathways which mediate resistance to lapatinib treatment.MethodsThe lapatinib sensitivity-related genes were extracted from the CellMiner database (version 2.2) using “NCI-60 Analysis Tools”. The differentially expressed genes (DEGs) in gastric cancer were derived from The Cancer Genome Atlas (TCGA) database, the protein-protein interaction (PPI) network was derived from the Human Protein Reference Database (HPRD), and the Database for Annotation, Visualization and Integrated Discovery (DAVID) facilitated the functional analysis. The cell function was tested by CCK-8 cell viability assay, colony formation assay, acridine orange/ethidium bromide (AO/EB) staining, and Transwell assay.ResultsThe functional linkage networks of lapatinib sensitivity were constructed. Two modules were identified, and pathway analysis indicated that these modules were involved in several pathways, including the neuroactive ligand-receptor interaction network and the Rap1 signaling pathway. Finally, the breast cancer anti-estrogen resistance 1 (BCAR1) gene was selected for further study with lapatinib-resistant SUN216 cells (SUN216/LR). We found the expression of BCAR1 was upregulated in SUN216/LR cells compared to SUN216 cells. The IC50 of lapatinib in SUN216/LR cells was reduced upon BCAR1 knockdown, as measured by a CCK-8 assay. A clonogenic assay showed fewer SUN216/LR colonies with BCAR1 knockdown and lapatinib treatment.ConclusionsIn brief, we efficiently identified those crucial modules highly related to lapatinib sensitivity in GC by using a topological network method. BCAR1 was identified as a potentially critical gene that plays a role in lapatinib sensitivity, and experiments confirmed that BCAR1 might contribute to lapatinib resistance in GC. These results provide further insight into the molecular basis of lapatinib sensitivity and may offer novel strategies for the future treatment of GC.

A multicenter phase II trial of tumor treating fields plus chemotherapy for first-line treatment of gastric adenocarcinoma.

TPS474 Background: Gastric carcinoma (GC) is the third-leading cause of death in China (291,000 deaths in 2015). Current therapies include surgery, chemotherapy, radiotherapy and targeted therapy, which prolong PFS and OS to 6 months and 8-14 months, respectively. Tumor Treating Fields (TTFields) are a non-invasive, regional antimitotic treatment modality approved by the FDA for glioblastoma and malignant pleural mesothelioma. TTFields at specific frequency (100- 500 kHz) are delivered via transducer arrays placed on the skin of the upper abdomen, back, right and left hypochondriac regions where the primary tumor lesion is located. TTFields were effective in preclinical models of gastric cancer and there are several ongoing Phase 3 trials of TTFields in multiple solid tumors. In this phase 2, single arm, open-label, multi-center study, we will investigate for the first time the efficacy and safety of TTFields concomitant with XELOX (oxaliplatin/capecitabine) as the first-line treatment of GC. Methods: Patients (N = 50) with histologically confirmed unresectable, locally advanced or metastatic Gastroesophageal Junction (GEJ) or Gastric Adenocarcinoma (GC), aged ≥ 18 years, ECOG PS 0-1, who had no previous systemic treatment for the recurrent or metastatic disease will be enrolled. Patients will receive TTFields (150 kHz via the NovoTTF-100L (P) medical device for average monthly use of 18 hrs/day) plus XELOX chemotherapy (Oxaliplatin: 130 mg/m2 on day 1 every 3 weeks; Capecitabine: 1000 mg/m2, PO, BID on day 1-14 every 3 weeks). For HER-2 positive patients, trastuzumab is allowed. The primary endpoint is investigator-assessed Objective Response Rate (ORR) per RECIST 1.1. Secondary endpoints are time to tumor progression (TTP), progression-free survival (PFS), overall survival (OS), and 12-month OS rate. Adverse events (AEs) will be graded for severity according to CTCAE 5.0. Based on the historical ORR data in first-line chemotherapy in GC, we assumed that ORR will be higher than 45% with TTFields concomitant with chemotherapy. At least 45 patients need to be enrolled to ensure the lower boundary is 30% of the 95% CI. Estimating a patient drop-out rate of 10%, 50 patients will be actually enrolled.

Prognostic Value of ANXA8 in Gastric Carcinoma.

Gastric carcinoma (GC) remains one of the most common and deadly cancers worldwide. In China, the incidence and mortality rates related to GC were quite high. Annexin A8 (ANXA8) is a member of the annexins family of calcium-dependent membrane phospholipid binding proteins. According to recent research, the up-regulation of ANXA8 is closely associated with various types of tumors. However, the specific role of ANXA8 in GC remains unclear. In our study, we explored the prognostic value of ANXA8 in GC. Here, with the data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets (GSE19826 and GSE13861) analyzed, we further performed quantitative real-time polymerase chain reaction (qRT-PCR) using 58 pairs of fresh-frozen tissues. We also subjected 152 pairs of formalin-fixed, paraffin-embedded GC tumor tissues from patients, and the adjacent normal gastric tissues (ANGTs) to immunohistochemical (IHC) analysis. Hence, we found an elevated expression of ANXA8 in tumor tissues with bioinformatics analyses, qRT-PCR, western blot and IHC. Over-expression of ANXA8 was strongly correlated with TNM stages and differentiation grades. Kaplan-Meier and cox proportional-hazard analyses showed that the increased expression of ANXA8 was strongly associated with overall survival (OS) and disease-free survival (DFS) in GC patients. Moreover, we found that ANXA8 is an independent prognostic factor of GC patients' OS and DFS. In brief, those results suggest that ANXA8 can act as an oncogene of GC development and can serve as a potential prognostic biomarker for GC treatment.

Dihydroartemisinin inhibits the growth and invasion of gastric cancer cells by regulating cyclin D1-CDK4-Rb signaling

BackgroundDihydroartemisinin (DHA), a semisynthetic derivative of artemisinin, has a broad range of biological properties, including antitumor activity. However, the mechanisms by which DHA affects the tumorigenesis of gastric carcinoma (GC) are poorly understood. Material and methodsThe targets of DHA were identified by network pharmacology, and the association of CDK4 with clinicopathological characteristics and prognosis in patients with GC was analyzed by using TCGA data. CCK8, Transwell and flow cytometric analyses, as well as a tumor xenograft model, were used to assess the effects of DHA on the growth and migration of GC cells. qRT-PCR and Western blot analyses were used to determine the effects of DHA on the cyclin D1-CDK4-Rb signaling pathway. ResultsWe identified 13 DHA targets and measured their expression of whichCDK4 expression levels were substantially higher in GC tissues than those in adjacent normal tissues, and high CDK4 expression acted as an independent prognostic factor of poor survival in patients with GC. DHA suppressed cell proliferation, migration and invasion in vitro and in vivo and induced G1 phase cell cycle arrest in a dose-dependent manner by regulating cyclin D1-CDK4-Rb signaling. ConclusionsDHA inhibits the tumorigenesis and invasion of GC by regulating cyclin D1-CDK4-Rb signaling and may provide therapeutic strategies for the treatment of GC.

Identification of GOLM1 as a positively regulator of tumor metastasis by regulating MMP13 in gastric carcinoma.

Metastatic gastric carcinoma (GC) is a typically incurable disease. The progression of anti-metastatic treatment is hampered because the underlying mechanisms regulating the metastasis of GC cell are not well illuminated. Therefore, further elucidation of the molecular mechanism behind the metastatic traits of GC cells is needed for optimizing GC treatment. The levels of GOLM1 and MMP13 in GC cells and tissues were measured by using qPCR assay. The growth of GC cells in vitro was detected using MTS and colony formation assays. The migration and invasion of GC cells was analyzed using wound healing test and Transwell invasion assay. The level of MMP13 in GC cell was measured using immunoblotting and the level of GOLM1 was measured using immunofluorescence staining. The role of GOLM1 on the distant metastasis of GC SGC7910 cell was analyzed using experimental metastasis assay. Transplanted tumor model was constructed to analyze the influence of GOLM1 on GC cell growth in vivo. Here, we report that GOLM1 is over-expressed in GC and knockdown GOLM1 impairs the aggressive phenotypes of GC cell in vitro. Furthermore, downregulation of GOLM1 restrains the tumor growth of GC cell in nude mice. Nevertheless, upregulation of GOLM1 distinctly elevated the growth, migration ability and invasiveness of GC SGC7910 cell. Finally, GOLM1 increases the metastatic phenotypes of GC cell in a MMP13-dependent manner. Altogether, this investigation demonstrates the crucial function of GOLM1 in the progression of GC, which indicating GOLM1 as a potential target for GC treatment.