Aggressiveness Of Gastric Cancer Research Articles

CircMTA2 Drives Gastric Cancer Progression through Suppressing MTA2 Degradation via Interacting with UCHL3.

Our previous study has reported that metastasis-associated protein 2 (MTA2) plays essential roles in tumorigenesis and aggressiveness of gastric cancer (GC). However, the underlying molecular mechanisms of MTA2-mediated GC and its upstream regulation mechanism remain elusive. In this study, we identified a novel circular RNA (circRNA) generated from the MTA2 gene (circMTA2) as a crucial regulator in GC progression. CircMTA2 was highly expressed in GC tissues and cell lines, and circMTA2 promoted the proliferation, invasion, and metastasis of GC cells both in vitro and in vivo. Mechanistically, circMTA2 interacted with ubiquitin carboxyl-terminal hydrolase L3 (UCHL3) to restrain MTA2 ubiquitination and stabilize MTA2 protein expression, thereby facilitating tumor progression. Moreover, circMTA2 was mainly encapsulated and transported by exosomes to promote GC cell progression. Taken together, these findings uncover that circMTA2 suppresses MTA2 degradation by interacting with UCHL3, thereby promoting GC progression. In conclusion, we identified a cancer-promoting axis (circMTA2/UCHL3/MTA2) in GC progression, which paves the way for us to design and synthesize targeted inhibitors as well as combination therapies.

Early-onset gasrtric cancer (review)

Objective. Early-onset gastric cancer (EOGC) constitutes a serious medical and social problem. Early-onset gastric cancer accounts for approximately 6% of all malignant epithelial neoplasms.Material and Methods. We reviewed retrospective and prospective randomized trials using Medline and Elibrary databases.Results. The applied significance of the molecular genetic classifications consist in the formation of groups for evaluating prognosis of the disease using multifactorial analysis. This classification indicates that EOGC diagnosed at a locally advanced stage and primary dissemination is most often caused by GS (TCGA) and MSS/EMT(ACRG) subtypes and is characterized by mutations in CDH1, RhoA, CLDN18-ARHGAP genes. These changes are accompanied by the prevalence of diffuse histological type of gastric cancer according to the Lauren classification and ulcerated or infiltrative type according to the Borrmann classification (type III and IV) with the presence of high-grade adenocarcinoma with a signet ring cell component.Conclusion. Considering the aggressiveness of gastric cancer in young patients, who more frequently present with locally advanced and metastatic disease at the time of diagnosis, there is a need for increased cancer alertness among physicians of other specialties, early endoscopic controls to detect cancer at early stages and benefit from both surgical and multimodal treatment.

Targeting TLK2 inhibits the progression of gastric cancer by reprogramming amino acid metabolism through the mTOR/ASNS axis.

Several recent studies have suggested that TLKs are related to tumor progression. However, the function and mechanism of action of TLK2 in gastric cancer (GC) remain elusive. In this study, TLK2 was found to be significantly upregulated in patients with GC and was identified as an independent prognostic factor for GC. Consistently, TLK2 knockdown markedly reduced the aggressiveness of GC, whereas its overexpression had the opposite effect. IP-MS revealed that the effects of TLK2 on GC were mainly associated with metabolism reprogramming. TLK2 knockdown suppressed amino acid synthesis by downregulating the mTORC1 pathway and ASNS expression in GC cells. Mechanistically, mTORC1 directly interacts with the ASNS protein and inhibits its degradation. Further experiments validated that the ASNS protein was degraded via ubiquitination instead of autophagy. Inhibiting and activating the mTORC1 pathway can upregulate and downregulate ASNS ubiquitination, respectively, and the mTORC1 pathway can reverse the regulatory effects of TLK2 on ASNS. Furthermore, TLK2 was found to regulate the mRNA expression of ASNS. TLK2 directly interacted with ATF4, a transcription factor of ASNS, and promoted its expression. The kinase inhibitor fostamatinib significantly inhibited the proliferative, invasive, and migratory capabilities of GC cells by inhibiting TLK2 activity. Altogether, this study reveals a novel functional relationship between TLK2 and the mTORC1/ASNS axis in GC. Therefore, TLK2 may serve as a potential therapeutic target for GC.

Micro RNA-365-3p as a Tumor Suppressor in Gastric Cancer: Inhibition of NUCKS1-Mediated PI3K/AKT Signaling and Anti-Tumor Effects

Increasing evidence supports that microRNAs (miRNAs) are essential regulators of tumor initiation and development in a wide range of human malignancies, including gastric cancer (GC). To date, it has been reported that miR-365-3p is abnormally expressed and influences tumor progression in multiple malignancies. However, the roles of miR-365-3p are yet to be known and are worth investigating in GC. Herein, we screened differentially expressed miRNAs in 3 pairs of matched gastric cancerous and adjacent normal specimens. A series of public datasets and collected clinical GC samples were employed to determine the expression profiles of miR-365-3p and its downstream target protein. Furthermore, the effects of miR-365-3p ectopic expression and depletion on GC cell proliferation, invasion and migration were explored in vitro via cell counting kit-8 (CCK-8), 5-Ethynyl-2′-deoxyuridine (EdU), clone formation and Transwell assays, and in vivo by applying the nude mice models. Dual-luciferase reporter, western blot and a series of rescue assays were carried out to investigate the potential interactions between miR-365-3p and NUCKS1 (Nuclear, casein kinase and cyclin-dependent kinase substrate 1) and downstream signaling pathways of the miR-365-3p/NUCKS1 axis. According to the analyses of the miRNA microarray and bioinformatics, we first identified miR-365-3p dysregulation in GC. Through miRNA qRT-PCR, we revealed that miR-365-3p was downregulated in GC samples and cell lines. Lower level of miR-365-3p was significantly associated with larger tumor size and advanced lymph node metastasis in GC patients. Downregulation of miR-365-3p accelerated, while ectopic miR-365-3p significantly suppressed GC cell proliferation, migration and invasion in vitro and in vivo. Results also showed that overexpression of miR-365-3p in gastric cancer cells significantly reduced the levels of pro-inflammatory cytokines, including interleukin-1β (IL-1β) and interleukin-6 (IL-6), while miR-365-3p knockdown increased their expression. Moreover, mechanistically, knockdown of miR-365-3p promoted tumor cell aggressiveness by enhancing the expression of NUCKS1 and subsequently resulted in the activation of PI3K/AKT signaling pathway in GC. In addition, either NUCKS1 silencing or the inhibition of PI3K/AKT signaling pathway, at least partially, reversed the promotive effects of miR-365-3p knockdown on GC aggressiveness. Altogether, these findings suggest that miR-365-3p inhibits tumor growth and metastasis by attenuating the expression of NUCKS1 and inactivation of its downstream PI3K/AKT signaling, thus, highlighting the potential of miR-365-3p as a therapeutic target in GC.

Fatty Acid Binding Protein 5 (FABP5) Promotes Aggressiveness of Gastric Cancer Through Modulation of Tumor Immunity.

Gastric cancer (GC) is the second most lethal cancer globally and is associated with poor prognosis. Fatty acid-binding proteins (FABPs) can regulate biological properties of carcinoma cells. FABP5 is overexpressed in many types of cancers; however, the role and mechanisms of action of FABP5 in GC remain unclear. In this study, we aimed to evaluate the clinical and biological functions of FABP5 in GC. We assessed FABP5 expression using immunohistochemical analysis in 79 patients with GC and evaluated its biological functions following in vitro and in vivo ectopic expression. FABP5 targets relevant to GC progression were determined using RNA sequencing (RNA-seq). Elevated FABP5 expression was closely associated with poor outcomes, and ectopic expression of FABP5 promoted proliferation, invasion, migration, and carcinogenicity of GC cells, thus suggesting its potential tumor-promoting role in GC. Additionally, RNA-seq analysis indicated that FABP5 activates immune-related pathways, including cytokine-cytokine receptor interaction pathways, interleukin-17 signaling, and tumor necrosis factor signaling, suggesting an important rationale for the possible development of therapies that combine FABP5-targeted drugs with immunotherapeutics. These findings highlight the biological mechanisms and clinical implications of FABP5 in GC and suggest its potential as an adverse prognostic factor and/or therapeutic target.

Engineered exosome-mediated delivery of circDIDO1 inhibits gastric cancer progression via regulation of MiR-1307-3p/SOCS2 Axis

BackgroundOur previous study has identified a novel circRNA (circDIDO1) that is down-regulated in gastric cancer (GC) and significantly inhibits GC progression. The purpose of this study is to identify the molecular mechanism for circDIDO1 and to evaluate the therapeutic effect of circDIDO1 in GC.MethodsBy combining bioinformatic analysis with RNA sequencing data, we predicted the potential target of circDIDO1 and further validated the regulatory mechanisms for its tumor suppressor function in GC. RIP assay, luciferase reporter assay and in vitro cell function assays were performed to analyze circDIDO1-regulated downstream target genes. For the therapeutic study, circDIDO1-loaded, RGD-modified exosomes (RGD-Exo-circDIDO1) were constructed and its anti-tumor efficacy and biological safety were evaluated in vitro and in vivo.ResultsCircDIDO1 inhibited GC progression by regulating the expression of the signal transducer inhibitor SOSC2 through sponging miR-1307-3p. Overexpression of circDIDO1 or SOSC2 antagonized the oncogenic role of miR-1307-3p. RGD-Exo-circDIDO1 could efficiently deliver circDIDO1 to increase SOCS2 expression in GC cells. Compared with PBS and RGD-Exo-vector treatment, RGD-Exo-circDIDO1 treatment significantly inhibited the proliferation, migration and invasion of GC cells while promoted cell apoptosis. The therapeutic efficacy of RGD-Exo-circDIDO1 was further confirmed in a mouse xenograft tumor model. In addition, major tissues including the heart, liver, spleen, lungs and kidneys showed no obvious histopathological abnormalities or lesions in the RGD-Exo-circDIDO1 treated group.ConclusionOur findings revealed that circDIDO1 suppressed the progression of GC via modulating the miR-1307-3p/SOSC2 axis. Systemic administration of RGD modified, circDIDO1 loaded exosomes repressed the tumorigenicity and aggressiveness of GC both in vitro and in vivo, suggesting that RGD-Exo-circDIDO1 could be used as a feasible nanomedicine for GC therapy.

Cooperative Treatment of Gastric Cancer Using B7-H7 siRNA and Docetaxel; How Could They Modify Their Effectiveness?

Despite the high prevalence of gastric cancer (GC), drug resistance is a major problem for effective chemotherapy. B7-H7 is a novel member of the B7 superfamily and is expressed in most common cancers. However, the role of B7-H7 on the aggressiveness of GC and chemosensitivity has remained unknown. Therefore, this study was designed to assess the effect of B7-H7 suppression using small interference RNA (siRNA) in combination with docetaxel on GC cells. MTT test was applied to determine the IC50 of docetaxel and the combined effect of B7-H7 siRNA and docetaxel on the viability of the MKN-45 cells. To determine B7-H7, BCL-2, BAX, and caspase-3-8-9 genes expression, qRT-PCR was performed. Furthermore, flow cytometry was applied to evaluate apoptosis and the cell cycle status. Finally, to evaluate the effect of this combination therapy on migratory capacity and colony-forming ability, wound healing assay and colony formation test were employed, respectively. B7-H7 suppression increased the chemo-sensitivity of MKN-45 cells to docetaxel. The expression of B7-H7 mRNA was reduced after using B7-H7 siRNA and docetaxel in MKN-45 GC cells. Also, B7-H7 suppression alongside docetaxel reduced cell migration and colony formation rate, arrested the cell cycle at the G2-M phase, and induced apoptosis by modulating the expression of apoptotic target genes. B7-H7 plays a significant role in the chemo-sensitivity and pathogenesis of GC. Therefore, B7-H7 suppression, in combination with docetaxel, may be a promising therapeutic approach in treating GC.

DEAD-Box Helicase 27 Triggers Epithelial to Mesenchymal Transition by Regulating Alternative Splicing of Lipoma-Preferred Partner in Gastric Cancer Metastasis

DEAD-box helicase 27 (DDX27) was previously identified as an important mediator during carcinogenesis, while its role in gastric cancer (GC) is not yet fully elucidated. Here, we aimed to investigate the mechanism and clinical significance of DDX27 in GC. Public datasets were analyzed to determine DDX27 expression profiling. The qRT-PCR, Western blot, and immunohistochemistry analyses were employed to investigate the DDX27 expression in GC cell lines and clinical samples. The role of DDX27 in GC metastasis was explored in vitro and in vivo. Mass spectrometry, RNA-seq, and alternative splicing analysis were conducted to demonstrate the DDX27-mediated molecular mechanisms in GC. We discovered that DDX27 was highly expressed in GCs, and a high level of DDX27 indicated poor prognosis. An increased DDX27 expression could promote GC metastasis, while DDX27 knockdown impaired GC aggressiveness. Mechanically, the LLP expression was significantly altered after DDX27 downregulation, and further results indicated that LPP may be regulated by DDX27 via alternative splicing. In summary, our study indicated that DDX27 contributed to GC malignant progression via a prometastatic DDX27/LPP/EMT regulatory axis.

Olea europaea leaf extract suppress stemness-Characteristics of gastric cancer via long non-coding RNAs

5-Fluorouracil (5-FU) and Cisplatin (Cis) are insufficient to fight against stem-like cancer cell (CSC)-phenotype Gastric cancer (GC). Therefore, new therapeutic approaches are required to treat CSC-GC patients. Although the anticancer effect of Olea europaea leaf extract (OLE) has been described for multiple types of cancer, including GC, the potential of OLE to be used as a complementary to 5-FU and Cis to treat CSC-GC remains largely unknown. This study uniquely investigated the potential of OLE to be used as complementary to 5-FU-Cis therapy to alleviate the CSC-mediated aggressiveness of GC. The AGS cells, A GC cell line was treated with OLE-only and its combinations with 5-FU-Cis. Tumor aggressiveness, colony formation, and vascularization were analyzed using tumorsphere and clonogenic assays and ex-vivo analyses. In addition, their effect on the expression of CSC markers, including CD133, OCT4, NANOG, and SOX2 and LncRNA, PVT1, MALAT1, H19, and SNHG16, was investigated using RT-qPCR. OLE-only and involvement of OLE to 5-FU+Cis treatment reduced the size of tumor-spheres ( p < 0.0001), number of colonies ( p < 0.0001), and vascularization. In addition, the OLE-5-FU-Cis combination decreased mRNA expression levels CSC markers and LncRNA, PVT1, H19, and SNHG16 expression levels compared to 5-FU+Cis ( p < 0.05). OLE reduced the survival capacity of CSC phenotype cells by decreasing LncRNA PVT1, MALAT1, and H19 and facilitates the aggressive features of GC cells. Further analysis and validations are required; current findings suggest that OLE could be complementarily used to improve the effect of 5-FU+Cis therapy for GC.

Prognostic Value of TRPM7 Expression and Factor XIIIa-Expressing Tumor-Associated Macrophages in Gastric Cancer.

Purpose TRPM7 is known to play a key role in tumor progression by regulating cellular proliferation, migration, and invasion in various cancer cell lines. However, there are no comprehensive clinical studies about the effect of TRPM7 expression on gastric cancer (GC) prognosis. In this study, it was aimed at investigating the effect of TRPM7 expression on prognosis in GC patients. Additionally, for the first time, it was investigated whether the density of Factor XIIIa-expressing tumor-associated macrophages (TAMs) in GC has an effect on the biological behaviour of the tumor. Methods TRPM7 expression and Factor XIIIa-expressing TAM density were immunohistochemically evaluated in paraffin-embedded tumor tissues of 204 GC patients undergoing surgery at a single institution. Results Tumor size was clearly higher in cases with high TRPM7 expression than those with low expression (p < 0.001, Mann-Whitney U). TRPM7 overexpression was closely related to high depth of tumor invasion (p < 0.001, ANOVA), increased lymph node metastasis (p < 0.001, ANOVA), and high distant metastasis rate (p < 0.001, Mann-Whitney U). These findings exposed that high TRPM7 expression is effective in the progression and aggressiveness of GC. In addition, while high CD8+ TIL density affects the prognosis positively, it was determined that high Factor XIIIa+ TAM density negatively affects the prognosis of patients with GC. Furthermore, multivariate analyses revealed TRPM7 overexpression was independently related with short overall (HR 9.64, 95% CI 5.74–16.19, p < 0.001) and disease-free survival (HR 5.67, 95% CI 3.61-8.92, p < 0.001) in GC patients. Conclusions Our data suggest that high TRPM7 expression is closely related to progressive tumor behaviour in GC and independently negatively affects survival in patients. In addition, it was determined that a high density of Factor XIIIa+ TAMs negatively affects the prognosis of patients with GC.

Helicobacter pylori and Epstein-Barr Virus Coinfection Stimulates Aggressiveness in Gastric Cancer through the Regulation of Gankyrin.

ABSTRACTPersistent coinfection with Helicobacter pylori and Epstein-Barr virus (EBV) promotes aggressive gastric carcinoma (GC). The molecular mechanisms underlying the aggressiveness in H. pylori and EBV-mediated GC are not well characterized. We investigated the molecular mechanism involved in H. pylori- and EBV-driven proliferation of gastric epithelial cells. Results showed that the coinfection is significantly more advantageous to the pathogens as coinfection creates a microenvironment favorable to higher pathogen-associated gene expression. The EBV latent genes ebna1 and ebna3c are highly expressed in the coinfection compared to lone EBV infection at 12 and 24 h. The H. pylori-associated genes 16S rRNA, cagA, and babA were also highly expressed during coinfection compared to H. pylori alone. In addition, upregulation of gankyrin, which is a small oncoprotein, modulates various cell signaling pathways, leading to oncogenesis. Notably, the knockdown of gankyrin decreased the cancer properties of gastric epithelial cells. Gankyrin showed a similar expression pattern as that of ebna3c at both transcript and protein levels, suggesting a possible correlation. Further, EBV and H. pylori created a microenvironment that induced cell transformation and oncogenesis through dysregulation of the cell cycle regulatory (ccnd1, dapk3, pcna, and akt), GC marker (abl1, tff-2, and cdx2), cell migration (mmp3 and mmp7), DNA response (pRB, pten, and p53), and antiapoptotic (bcl2) genes in infected gastric epithelial cells through gankyrin. Our study provides a new insight into the interplay of two oncogenic agents (H. pylori and EBV) that leads to an enhanced carcinogenic activity in gastric epithelial cells through overexpression of gankyrin.IMPORTANCE In the present study, we evaluated the synergistic effects of EBV and H. pylori infection on gastric epithelial cells in various coinfection models. These coinfection models were among the first to depict the exposures of gastric epithelial cells to EBV followed by H. pylori; however, coinfection models exist that narrated the scenario upon exposure to H. pylori followed by that to EBV. We determined that a coinfection by EBV and H. pylori enhanced the expression of oncogenic protein gankyrin. The interplay between EBV and H. pylori promoted the oncogenic properties of AGS cells like elevated focus formation, cell migration, and cell proliferation through gankyrin. EBV and H. pylori mediated an enhanced expression of gankyrin, which further dysregulated cancer-associated genes such as cell migratory, tumor suppressor, DNA damage response, and proapoptotic genes.

Long Noncoding RNA SNHG16 Silencing Inhibits the Aggressiveness of Gastric Cancer via Upregulation of microRNA-628-3p and Consequent Decrease of NRP1 [Retraction

[This retracts the article DOI: 10.2147/CMAR.S211856.].

Abstract 2655: Abundance of intra-tumoral angiogenesis is associated with attenuated tumor aggressive biology, tumor microenvironment, as well as worse survival in gastric cancer patients

Abstract Background: Across the world, gastric cancer is the third leading cause of cancer deaths. There is an urgent need to develop a predictive biomarker that help guide treatment decision-making to precisely address gastric cancer progression and metastasis. Angiogenesis is the creation of de novo blood vessels from existing ones, and it is a cornerstone of cancer as it paves the way for cancer progression and metastasis. Angiogenic factors such as vascular endothelial growth factor (VEGF) and endothelial cell growth factor (EGF) are produced by cancer and stromal cells in many types of cancers including gastric cancer. We hypothesized that intra-tumoral angiogenesis plays a role in gastric cancer aggressiveness. Methods: The angiogenesis level of tumors from 1,348 gastric cancer patients in multiple cohorts was measured using the Gene Set Variation Analysis (GSVA) method to score tumor transcriptomes with the Hallmark angiogenesis gene set. Results: Gastric cancers with high angiogenesis score were significantly associated with high expression of multiple angiogenesis-related genes including VEGF-related, endothelial cell marker-related, and vascular stability-related genes in the TCGA and GSE84437 cohorts. Furthermore, in both cohorts, the angiogenesis score was moderately correlated with not only vessel-related stromal cells (endothelial cells [spearman r = 0.557, 0.473], lymphatic [r = 0.520, 0.597] and microvascular endothelial cells [r = 0.470, 0.460], and pericytes [r = 0.555, 0.301]), but also fibroblasts (r = 0.485, 0.467) and chondrocytes (r = 0.565, 0.601) in the tumor microenvironment. Tumors with high angiogenesis score were associated with a lower fraction of Th1, Th2, and dendritic cells, and a higher fraction of M1 macrophages compared with low angiogenesis score tumors. Gastric cancer with a high angiogenesis score was enriched with coagulation, epithelial mesenchymal transition, hypoxia, and TGF-β signaling gene sets in the TCGA, GSE84437, and GSE26253 cohorts. Interestingly, a high angiogenesis score was significantly associated with greater AJCC stage and T-category, but not N-category. Finally, patients with a high score had significantly shorter survival in three cohorts (overall survival: p = 0.002 in the TCGA, p &amp;lt; 0.001 in the GSE84437, and disease-free survival: p = 0.011 in GSE26253). Conclusion: The angiogenesis score can be a useful tool to assess intra-tumoral angiogenesis, which is associated with clinical outcomes in gastric cancer patients. Citation Format: Masanori Oshi, Tae Hee Kim, Vikas Satyananda, Fernando A. Angarita, Yoshihisa Tokumaru, Li Yan, Ryusei Matsuyama, Itaru Endo, Kazuaki Takabe. Abundance of intra-tumoral angiogenesis is associated with attenuated tumor aggressive biology, tumor microenvironment, as well as worse survival in gastric cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2655.

Long Noncoding RNA RGMB-AS1 Acts as a microRNA-574 Sponge Thereby Enhancing the Aggressiveness of Gastric Cancer via HDAC4 Upregulation [Retraction

[This retracts the article DOI: 10.2147/OTT.S234144.].

Long non-coding RNA NEAT1 increases the aggressiveness of gastric cancer by regulating the microRNA-142-5p/JAG1 axis.

Gastric cancer has been indicated to have a high recurrence rate in China. Previous studies have revealed that long non-coding RNA nuclear-enriched abundant transcript 1 (NEAT1) exerted critical roles in cancers. Therefore, the present study aimed to determine the function of NEAT1 and explore the unknown molecular mechanisms of gastric cancer pathogenesis. Reverse transcription-quantitative PCR assay was used to examine the expression of NEAT1, microRNA (miR)-142-5p and jagged1 (JAG1) in gastric cancer. Cell Counting Kit-8 and Transwell assays were conducted to examine cell proliferation, migration and invasion. The protein expression levels of N-cadherin, Vimentin, E-cadherin and JAG1 were quantified by western blot assay. The associations among NEAT1, miR-142-5p and JAG1 were confirmed by dual-luciferase reporter assay and RNA immunoprecipitation. The effects of NEAT1 silencing on tumor growth were evaluated by tumor xenografts. The results indicated that NEAT1 was highly expressed in tumor tissues and cells compared with that in paracancerous tissues and the normal gastric epithelial cell line GES-1 and significantly associated with poor prognosis in gastric cancer. Functional analyses further demonstrated that NEAT1 knockdown suppressed proliferation, motility and tumor growth in vitro and in vivo. Mechanistically, NEAT1 sponged miR-142-5p to regulate JAG1 expression. In addition, the effects of NEAT1 knockdown on the proliferation, migration and invasion of gastric cancer cells could be rescued by miR-142-5p inhibitor, and JAG1 overexpression reversed the miR-142-5p-mediated effects on gastric cancer cells. These findings demonstrated that long non-coding RNA NEAT1 regulated gastric cancer progression by targeting the miR-142-5p/JAG1 axis.

Reevaluation of lymphovascular invasion in gastric cancer using endothelial markers D2-40 and EVG: Enhanced detection, better predictor of lymph node metastasis and biological aggressiveness.

The diagnosis of lymphovascular invasion (LVI) is often inaccurate with routine histology. This study aimed to evaluate the use of immunohistochemistry (IHC) in detecting LVI and reevaluate the clinical implications of LVI in gastric cancer. This prospective unrandomized cohort study analyzed the rates of LVI positivity and its relevance with other clinicopathologic features. Between November 2017 and April 2018, 558 patients undergoing curative gastrectomy were enrolled and assigned to the IHC group (n = 285) and hematoxylin-eosin group (n = 273). The use of IHC increased the rates of LVI positivity (60.8% vs. 43.3%, p < .001) and decreased the rates of undetermined LVI subtype (7.7% vs. 27.1%, p < .001). The LVI-negative patients identified by IHC had fewer lymph node metastases (16.8% vs. 34.6%, p = .002) and earlier pathological stage (p = .004) than those identified by routine histology. The LVI-positive patients identified by IHC had a higher percentage of perineural invasion (p = .019). The use of endothelial markers significantly enhanced the detection of LVI. The LVI detected by IHC could be a better predictor of lymph node metastasis and biological aggressiveness in gastric cancer.

The Extracellular Small Leucine-Rich Proteoglycan Biglycan Is a Key Player in Gastric Cancer Aggressiveness.

Simple SummaryApproximately 80% of gastric cancer patients are diagnosed at advanced stages with an average five-year survival rate of less than 30%. Alterations of the extracellular matrix proteins have been largely demonstrated in all steps of the disease. Thus, studies for the identification of novel prognostic biomarkers and efficient therapeutic strategies are urgently needed. In this study, we report the oncogenic role of biglycan, an extracellular proteoglycan, in gastric carcinogenesis. Biglycan was able to modulate gastric cancer aggressive features as cell survival, migration, and angiogenesis. Additionally, high levels of biglycan expression correlates with tumorigenic gene signatures and they are associated with poor patient prognosis in advanced stages of the disease. These results point biglycan as a key player in gastric cancer aggressiveness and further studies should be done to investigate the therapeutic potential of biglycan to tackle gastric cancer progression.Biglycan (BGN gene), an extracellular proteoglycan, has been described to be associated with cancer aggressiveness. The purpose of this study was to clarify the clinical value of biglycan as a biomarker in multiple independent GC cohorts and determine the in vitro and in vivo role of biglycan in GC malignant features. We found that BGN is commonly over-expressed in all analyzed cohorts, being associated with disease relapse and poor prognosis in patients with advanced stages of disease. In vitro and in vivo experiments demonstrated that biglycan knock-out GC cells display major phenotypic changes with a lower cell survival, migration, and angiogenic potential when compared with biglycan expressing cells. Biglycan KO GC cells present increased levels of PARP1 and caspase-3 cleavage and a decreased expression of mesenchymal markers. Importantly, biglycan deficient GC cells that were supplemented with exogenous biglycan were able to restore biological features, such as survival, clonogenic and migratory capacities. Our in vitro and in vivo findings were validated in human GC samples, where BGN expression was associated with several oncogenic gene signatures that were associated with apoptosis, cell migration, invasion, and angiogenesis. This study provided new insights on biglycan role in GC that should be taken in consideration as a key cellular regulator with major impact in tumor progression and patients’ clinical outcome.

MiR-301a-5p/SCIN promotes gastric cancer progression via regulating STAT3 and NF-κB signaling.

Objective: Gastric cancer (GC) is a type of highly malignant cancer. Although the diagnostic and therapeutic methods are innovating, the outcome of GC patients is still poor. Therefore, our research was carried out to explore potential molecular mechanism in the diagnosis of GC.Materials and methods: Bioinformatics analyses were used to obtain microRNA and target mRNA of interest. The expression level of miR-301a-5p and Scinderin (SCIN) mRNA were detected by quantitative real-time PCR (qRT-PCR). Western blot assay was used to investigate SCIN protein level. Cell Counting Kit-8 assay (CCK-8) and colony formation assay were used to investigate cell proliferation ability. Transwell assay was employed to examine cell motility. The interaction between miR-301a-5p and SCIN mRNA was verified by dual-luciferase reporter assay.Results: The qRT-PCR analysis revealed that the expression of miR-301a-5p was higher in gastric cancer tissues than para-cancer tissues (P<0.05). Cox regression analysis showed upregulated miR-301a-5p was associated with larger tumor size (P=0.036) and more advanced TNM stage (P=0.048). The Kaplan-Meier analysis showed a correlation between increased miR-301a-5p expression and shorter overall survival (OS)(P=0.018). By using bioinformatic analysis, SCIN was predicted as one of the targets of miR-301a-5p. Overexpressing miR-301a-5p promoted proliferation and motility of GC cells while knockdown of SCIN exhibited the same performance. Further, we verified the alteration of miR-301a-5p and SCIN expression level could affect the epithelial-mesenchymal transition (EMT) progression on GC cells via STAT3 and NF-κB signaling.Conclusion: Highly expressed miR-301a-5p was associated with aggressiveness of GC. Upregulation of miR-301a-5p promoted malignant phenotype of GC by targeting SCIN. The present results indicated miR-301a-5p might be a promising molecule in the prognosis of GC.

Inhibition or Reversal of the Epithelial-Mesenchymal Transition in Gastric Cancer: Pharmacological Approaches.

Epithelial-mesenchymal transition (EMT) constitutes one of the hallmarks of carcinogenesis consisting in the re-differentiation of the epithelial cells into mesenchymal ones changing the cellular phenotype into a malignant one. EMT has been shown to play a role in the malignant transformation and while occurring in the tumor microenvironment, it significantly affects the aggressiveness of gastric cancer, among others. Importantly, after EMT occurs, gastric cancer patients are more susceptible to the induction of resistance to various therapeutic agents, worsening the clinical outcome of patients. Therefore, there is an urgent need to search for the newest pharmacological agents targeting EMT to prevent further progression of gastric carcinogenesis and potential metastases. Therapies targeted at EMT might be combined with other currently available treatment modalities, which seems to be an effective strategy to treat gastric cancer patients. In this review, we have summarized recent advances in gastric cancer treatment in terms of targeting EMT specifically, such as the administration of polyphenols, resveratrol, tangeretin, luteolin, genistein, proton pump inhibitors, terpenes, other plant extracts, or inorganic compounds.

Mir-20a-5p induced WTX deficiency promotes gastric cancer progressions through regulating PI3K/AKT signaling pathway

BackgroundThe X-linked gene WTX (also called AMER1) has been reported to function as a tumour suppressor gene in Wilms’ tumour. In our previous study, WTX expression was shown to be significantly reduced in gastric cancer (GC), but the function and mechanism associated with WTX loss had yet to be fully elucidated.MethodsWTX expression and clinical significance were father analyzed in GC and control normal gastric tissues, and validated in public databases. The candidate pathway which was regulated by WTX during GC progression was searched by KEGG pathway analysis. The miRNA which monitored WTX expression was screened by miRNA microarray. After verified the pathway and miRNA both in vitro and in vivo, the relationship of miRNA, WTX and the downstream pathway were analyzed by Western blot, immunohistochemistry, RT-PCR, Co-immunoprecipitation (Co-IP), and luciferase analyses.ResultsThe results showed that WTX serves as a tumour suppressor gene in GC. The loss of WTX which is associated with the aggressiveness of GC by promoting GC cell proliferation in vitro and high metastasis in vivo. Furthermore, WTX expression was positively correlated with the overall survival of GC patients. Microarray assays, bioinformatics analysis, and verification experiments showed that WTX loss activates the PI3K/AKT/mTOR pathway and promotes GC cell proliferation and invasion. And the aberrant miR-20a-5p upregulation contributes to WTX loss in GC, which stimulates PI3K phosphorylation to activate PI3K/AKT/mTOR signaling pathway and promoted GC progression.ConclusionsThe results of the present study elucidated the mechanism of GC progression, which is at least partially caused by aberrant miR-20a-5p upregulation leading to the inhibition of WTX expression and PI3K/AKT/mTOR signaling pathway activation. These findings provide a comprehensive understanding of the action of the miR-20a-5p/WTX/PI3K/AKT/mTOR signaling pathway in the progression and metastasis of GC.