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Exosomes are a type of cell-derived vesicles that range in size from 30 to 100 nm. They are widely present in various organisms and participate in diverse biological processes, playing crucial roles in tumorigenesis and progression. This study aimed to investigate whether LINC01480 in tumor-derived exosomes is involved in the molecular mechanism of gastric cancer by competitively upregulating the VCAM1 expression through binding miR-204-5p. The study analyzed transcriptome data related to gastric cancer from the cancer genome atlas database and constructed a risk-scoring model for epithelial-mesenchymal transition (EMT)-related lncRNAs to identify eight EMT-related lncRNAs associated with prognosis. EMT-related mRNAs positively correlated with LINC01480 were screened in the ExoRBase database. In vitro cell experiments showed that exosomal LINC01480 can promote the proliferation, migration, invasion, and EMT of gastric cancer cells by upregulating VCAM1 expression through competitive binding with miR-204-5p. In vivo experiments on nude mice showed that exosomal LINC01480 promotes the development of gastric cancer. These results suggest that exosomal LINC01480 could be a potential therapeutic target for gastric cancer.

Background: Helicobacter pylori ( H. pylori ) is recognized as a type I carcinogen in gastric cancer (GC). However, GC still occurs after H. pylori eradication, and its diagnosis is more complicated. This study aimed to summarize the characteristics of early GC (EGC) after H. pylori eradication to help accurately identify EGC and avoid missed diagnosis and misdiagnosis., Methods: A total of 81 patients of EGC after H. pylori eradication (Hp-eradicated group), resected by endoscopic submucosal dissection (ESD), and 105 cases of H. pylori infection-related EGC (control group) were assessed. After propensity-score matching, the clinical characteristics, endoscopic manifestations, and histopathological features of the 62 matched patients in each group were analyzed. We also conducted specific analyses in combination with endoscopic and histopathological images., Results: There were more patients in the Hp-eradicated group who received proton pump inhibitor (PPI) for >1 year compared to the control group ( p  < 0.001). More patients at OLGA stages I-II before the diagnosis of EGC were in the control group ( p  = 0.045), especially at stage II. The mucosa in the Hp-eradicated group showed more moderate-to-severe atrophy ( p  = 0.047), map-like redness ( p  < 0.001) and mild activity ( p  < 0.001). The predominant histopathological types differed between the two groups ( p  < 0.001), and the majority of cases in the Hp-eradicated group were high-grade intraepithelial neoplasia (HGIN). Ki-67 expression was lower in the Hp-eradicated group ( p  = 0.025). But different eradication intervals of H. pylori have little effect on the characteristics of EGC. Furthermore, PPI uses for >1 year ( p  = 0.005), mucosal map-like redness ( p  < 0.001), moderate mucosal atrophy ( p  = 0.017), and mild activity of gastric mucosa ( p  = 0.005) were independent characteristics of EGC after H. pylori eradication., Conclusion: Our multicenter study revealed that EGC after H. pylori eradication was characterized by long-term PPI use, moderate mucosal atrophy, mucosal map-like redness, the mild activity of gastric mucosa, a higher proportion of HGIN cases, and lower levels of Ki-67.

Background and Purpose: Although endoscopic submucosal dissection (ESD) is considered standard treatment for early gastric cancer (EGC), patients with non-curative resection (NCR) of ESD may still require gastrectomy. The systemic immune-inflammation index (SII) showed great potential in predicting the prognosis of gastric cancer patients. This study aims to investigate the predictive validity of SII of NCR in EGC patients., Methods: We reviewed data from EGC patients who underwent ESD in the past. The relationship between SII and clinicopathologic features was investigated. We used Receiver operating characteristic curves to compare the predictive values of NCR between SII and other inflammation indices. Binary logistic analysis was used to identify independent risk factors for NCR. These factors were then used to construct a predictive nomogram., Results: SII was associated with larger tumor size, male gender, older age, submucosal invasion, and a greater risk of NCR. SII showed better predictivity of NCR than platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR). SII [odds ratio (OR) = 1.003, P = 0.001], NLR (OR = 1.520, P = 0.029), PLR (OR = 1.009, P = 0.010), upper stomach tumors (OR = 16.393, P < 0.001), poorly differentiated type (OR = 29.754, P < 0.001), ulceration (OR = 4.814, P = 0.001), and submucosal invasion (OR = 48.91, P < 0.001) were independent risk factors for NCR. The nomogram model based on these factors exhibited superior concordance and accuracy., Conclusion: SII could be considered a simple and effective predictor of NCR of ESD in EGC patients., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Gastric cancer (GC) as a serious global health problem is a threat to human longevity. Plasmacytoma variant translocation 1 (PVT1) participates in the formation and progression of various cancers, including GC. The aim of this study is to investigate the mechanism underlying the functions of PVT1 and explore a novel target for the diagnosis and treatment of GC. Analysis of the TCGA dataset using the R software identified that the lncRNA PVT1 was greatly upregulated in GC tissues. Twenty pairs of GC and adjacent normal tissues were acquired from patients with GC, and the expression of PVT1 was evaluated using RT-qPCR. Furthermore, PVT1 expression was knocked down in GC cells using siRNA, and the GC cells were divided into control, negative control (NC), and siRNA groups. Cell proliferation ability was analyzed using Cell Counting Kit-8 (CCK8) and colony formation assays, whereas cell migration and invasion ability were investigated through wound healing and Transwell assays. Moreover, Western blotting was used to analyze the expression of Yes-associated protein (YAP) and epithelial-to-mesenchymal transition (EMT) proteins. We also found that PVT1 and YAP expressions were upregulated in the GC tissues compared with those in the adjacent nontumor tissues. Knockdown of PVT1 was found to inhibit the proliferation, invasion, and migration and promote apoptosis of GC cells. Furthermore, knockdown of PVT1 downregulated YAP and promoted phosphorylation of YAP, suggesting that PVT1 exerts actions on GC cells by targeting YAP and inhibits cell apoptosis in vitro. The EMT process was also inhibited by the knockdown of PVT1. In summary, lncRNA PVT1 facilitated cell proliferation, invasion, and migration and suppressed cell apoptosis by targeting YAP. This study suggests that the expressions of PVT1 and YAP could be used for the early detection of GC and the occurrence and development of GC could be inhibited by interfering the interaction of PVT1 and YAP, which will provide new insights for the diagnosis, treatment, and prognosis of GC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest., (Copyright © 2022 Kaiyue Ji et al.)

ULK1 (Unc-51-like kinase 1) is an evolutionarily conserved serine/threonine kinase that plays a central role in the regulation of autophagy. ULK1 is associated with prognosis for metastasis and survival in several tumors. However, its relationship with Epstein-Barr virus (EBV) has not been studied. We found that the expression of ULK1 in EBV-associated gastric cancer cells was lower than that in EBV-negative gastric cancer cells. Further, a luciferase reporter gene assay showed that miR-BART2-3p directly targets ULK1. EBV-miR-BART2-3p attenuated endogenous protein expression levels of some autophagy-related genes. MiR-BART2-3p could thus be involved in the regulation of autophagy. Most important, our research indicates that miR-BART2-3p targets ULK1, resulting in downregulation of epithelial-mesenchymal transformation (EMT) -associated marker proteins and reducing EMT and cell migration. Our study shows that modulation of ULK1 is the likely mechanism by which miR-BART2-3p participates in the regulation of autophagy and cancer cell migration., (Copyright © 2021. Published by Elsevier B.V.)

Background: When the risk of lymph node metastasis (LNM) is considered minimal in patients with early gastric cancer (EGC), endoscopic submucosal dissection (ESD) is an effective alternative to radical resection. This study aims to estimate the feasibility of ESD for EGC with ulceration., Patients and Methods: We retrospectively reviewed data from 691 patients who underwent gastrectomy for EGC with ulceration. Subsequently, a stratification system for lesions was created based on the expanded ESD criteria, and the associations between the subgroups and the rate of LNM were analyzed., Results: LNM was confirmed in 16.5% (114/691) of patients. Univariate analysis demonstrated that age, sex, tumor size, macroscopic features, depth of invasion, tumor differentiation, Lauren type, lymphovascular invasion (LVI), and perineural invasion were associated with LNM. Multivariate analysis showed that LVI [odds ratio (OR) = 16.761, P < 0.001], SM1 invasion (OR = 2.159, P = 0.028), and SM2 invasion (OR = 3.230, P < 0.001) were independent risk factors for LNM. LNM occurred in undifferentiated mucosal tumors, with ulceration being 1.7% (2/116) when the lesion was smaller than 20 mm. Further stratification revealed that among lesions < 30 mm in size, undifferentiated tumors with SM1 invasion had a higher rate of LNM and a lower disease-free survival rate than differentiated tumors with SM1 invasion and tumors limited to the mucosal layer., Conclusions: Depth of invasion and LVI were strongly associated with LNM in ulcerative EGC. Endoscopic resection may be applicable for undifferentiated mucosal ulcerative EGC < 30 mm in size, and additional investigation is needed to evaluate its safety.

The aim of this study was to investigate predictors of lymph node metastasis (LNM) in early gastric signet-ring cell carcinoma (SRCC) and determine clinicopathologic and prognostic differences of different histologic subtypes. We retrospectively analyzed 13,661 gastric cancer patients; 231 were eligible for inclusion. Data for clinical, endoscopic, and histopathologic characteristics and prognoses were collected. Patients were followed up regarding postresection survival; overall and disease-specific survival rates were estimated by the Kaplan-Meier method with a log-rank test, and prognostic factors were evaluated by Cox regression. LNM incidence in early SRCC was 16.0% (37/231) overall: 6.9% (8/116) and 25.2% (29/115) in patients with pure and mixed SRCC, respectively. Univariate and multivariate analyses revealed SM2 invasion (odds ratio [OR]=5.070, P=0.003), lymphovascular invasion (LVI) (OR=14.876, P<0.001), pathologic pattern of mixed SRCC (OR=3.226, P=0.026), ulcer presence (OR=3.340, P=0.019) and lesion size over 20 mm (OR=2.823, P=0.015) as independent risk factors for LNM. Compared with pure SRCC, the mixed subtype was associated with older age, larger lesion size, higher LVI frequency, more frequent perineural invasion, and most importantly, higher LNM incidence. Patients with pure SRCC showed significantly longer overall survival (P=0.004) and disease-specific survival (P=0.002) than mixed SRCC patients. Pathologic subtype (hazard ratio [HR]=3.682; P=0.047), age (HR=5.246; P=0.001), SM1 invasion (HR=6.192; P=0.023), SM2 invasion (HR=7.529; P=0.021) and LNM (HR=5.352; P<0.001) were independent prognostic factors. Independent risk factors for LNM in early gastric SRCC were SM2 invasion, LVI, pathologic pattern, ulcer presence and lesion size over 20 mm. Early SRCC should be further classified by the purity of the SRC component.

Recently, microRNA-498 (miR-498) plays important effect in human cancers. Nonetheless, the role of miR-498 is still unclear in gastric cancer (GC). Therefore, this study was designed to investigate the function of miR-498 in GC tissues and cell lines (SGC-7901, BGC-823, MGC-803). The expressions of miR-498 and BMI-1 were examined in GC tissues via the RT-qPCR assay. The function of miR-498 was investigated through MTT and transwell assays. The relationship between miR-498 and BMI-1 was testified by dual luciferase assay. The protein expression of EMT markers, AKT pathway markers and BMI-1 was measured through western blot. The expression of miR-498 was decreased in GC tissues which predicted poor prognosis of GC patients. Moreover, functional analyses show that the overexpression of miR-498 inhibited the progression of GC. Furthermore, BMI-1 was a direct target of miR-498 which was upregulated in GC. Especially, the upregulation of BMI-1 recovered the suppressive effect of miR-498 in GC. In addition, miR-498 inhibited the metastasis and proliferation of GC cells through blocking EMT and AKT pathway. MiR-498, by targeting BMI-1, presents a plethora of tumor suppressor activities in GC cells.

Salidroside is an active ingredient extracted from Rhodiola rosea that has anti-tumor activities. The current paper attempted to assess the impact of Salidroside on gastric cancer (GC) and explore the potential mechanism. GC cell lines (SNU-216 and MGC803) and gastric epithelial cell line GES-1 were treated with Salidroside. CCK-8 assay, colony formation assay, flow cytometry and Transwell assay were respectively performed to evaluate GC cells phenotype. qRT-PCR and western blot were conducted to reveal the downstream genes and signaling of Salidroside. We found that 800 μM Salidroside was capable of reducing GC cells viability, while has no such impacts on GES-1 cells. Salidroside inhibited GC cells proliferation, migration, invasion and promoted apoptosis, which coupled with the down-regulation of p21, Bcl-2, MMP2, RhoA, p-ROCK1, Vimentin and the up-regulations of CyclinD1, Bax, cleaved caspases. miR-99a was found to be highly expressed in response to Salidroside treatment. Besides, the inhibition of MAPK/ERK and PI3K/AKT signaling induced by Salidroside was attenuated by miR-99a silence and in this process, IGF1R worked as a target of miR-99a. The anti-GC effect of Salidroside was also confirmed in a mouse model of GC. The promoting effect of Salidroside on miR-99a expression was also verified in vivo . Furthermore, Salidroside promoted the cisplatin-sensitivity of SGC7901/DDP cells. In conclusion, this study demonstrated that Salidroside possessed anti-GC effects through regulating miR-99a/IGF1R axis and inhibiting MAPK/ERK and PI3K/AKT pathways.

Background: Endoscopic submucosal dissection (ESD) has been routinely performed in applicable early gastric cancer (EGC) patients as an alternative to conventional surgical operations that involve lymph node dissection. The indications for ESD have been recently expanded to include larger, ulcerated, and undifferentiated mucosal lesions, and differentiated lesions with slight submucosal invasion. The risk of lymph node metastasis (LNM) is the most important consideration when deciding on a treatment strategy for EGC. Despite the advantages over surgical procedures, lymph nodes cannot be removed by ESD. In addition, whether patients who meet the expanded indications for ESD can be managed safely remains controversial., Aim: To determine whether the ESD indications are applicable to Chinese patients and to investigate the predictors of LNM in EGC., Methods: We retrospectively analyzed 12552 patients who underwent surgery for gastric cancer between June 2007 and December 2018 at the Affiliated Hospital of Qingdao University. A total of 1262 (10.1%) EGC patients were eligible for inclusion in this study. Data on the patients' clinical, endoscopic, and histopathological characteristics were collected. The absolute and expanded indications for ESD were validated by regrouping the enrolled patients and determining the positive LNM results in each subgroup. Predictors of LNM in patients were evaluated by univariate and multivariate analyses., Results: LNM was observed in 182 (14.4%) patients. No LNM was detected in the patients who met the absolute indications (0/90). LNM occurred in 4/311 (1.3%) patients who met the expanded indications. According to univariate analysis, LNM was significantly associated with positive tumor marker status, medium (20-30 mm) and large (>30 mm) lesion sizes, excavated macroscopic-type tumors, ulcer presence, submucosal invasion (SM1 and SM2), poor differentiation, lymphovascular invasion (LVI), perineural invasion, and diffuse and mixed Lauren's types. Multivariate analysis demonstrated SM1 invasion (odds ration [OR] = 2.285, P = 0.03), SM2 invasion (OR = 3.230, P < 0.001), LVI (OR = 15.702, P < 0.001), mucinous adenocarcinoma (OR = 2.823, P = 0.015), and large lesion size (OR = 1.900, P = 0.006) to be independent risk factors., Conclusion: The absolute indications for ESD are reasonable, and the feasibility of expanding the indications for ESD requires further investigation. The predictors of LNM include invasion depth, LVI, mucinous adenocarcinoma, and lesion size., Competing Interests: Conflict-of-interest statement: All authors declare no conflicts of interest related to this article.

Celastrol could inhibit cancer cell growth in vitro. However, effect(s) of celastrol on gastric cancer is not well studied. Therefore, we investigated the effects of celastrol on human gastric cancer cell line MKN45 and the underlying mechanisms. We found that celastrol inhibited cell proliferation, migration, and invasion and induced cell apoptosis and G2/M cell cycle arrest (p < .05, p < .01, or p < .001). Under celastrol treatment, overexpression of microRNA-21 (miR-21) increased cell viability, migration, and invasion and inhibited cell apoptosis compared with negative control (p < .05, p < .01, or p < .001). In addition, the phosphorylation of PTEN was significantly up-regulated, whereas PI3K, AKT, p65, and IκBα phosphorylation was statistically decreased by celastrol (p < .05 or p < .01) and then further reversed by miR-21 overexpression (p < .05 or p < .01). On the other side, miR-21 silence showed contrary results (p < .05) as relative to miR-21 overexpression. In conclusion, celastrol inhibits proliferation, migration, and invasion and inactivates PTEN/PI3K/AKT and nuclear factor κB signaling pathways in MKN45 cells by down-regulating miR-21., (© 2019 John Wiley & Sons, Ltd.)

Aim: To gain insight into the histopathological responses and molecular targets in the inhibition of growth of human gastric cancer treated with celecoxib (a cyclooxygenase [COX]-2 inhibitor) combined with octreotide., Methods: Seventy five patients with gastric cancer undergoing curative gastrectomy or extended resection were randomly divided into 3 groups. The apoptosis of tumor cells was measured by terminal deoxynucleotide transferase-mediated dUTP nick endlabeling (TUNEL) assay. Gastric cancer microvessel density (MVD) and the expression of COX-2 were evaluated by immunohistochemical staining. The expression of somatostatin receptor (SSTR)-2 was detected with the biomolecular interaction analysis system. The transcription of non-steroidal anti-inflammatory drug-activated gene (NAG)-1 was measured by RT-PCR., Results: Compared with the control and celecoxib groups, more necrosis in the combination group was observed. The apoptotic rate in the combination group (7.06%+/-0.67%) was significantly higher than that in the control group (6.23%+/-1.29%, P<0.05). The MVD decreased considerably in the combination group. The upregulation of NAG-1 was displayed both in the celecoxib and combination groups. The positive rate of SSTR-2 in gastric cancers treated with celecoxib (48%) was significantly higher than that of control group (12%) after surgery (P<0.05)., Conclusion: Celecoxib combined with octreotide significantly promoted necrosis in gastric adenocarcinoma through the induction of apoptosis and the reduction of MVD. NAG-1 and SSTR-2 might be the molecular targets for celecoxib or octreotide.

Objective: To investigated if cyclooxygenase-2 (COX-2) inhibitor celecoxib in combination with somatostatin (SST) analog octreotide is able to inhibit the metastasis of human gastric cancer (GC) in vivo., Methods: Seventy five patients with GC were randomly divided into 3 equal groups: control group, taking no anti-tumor medicine before GC resection; celecoxib group, receiving celecoxib orally 200 mg/d for 7 days before surgery; and combination group, receiving celecoxib orally 200 mg/d and octreotide 100 microg injected subcutaneously for 7 days before operation. The resected specimens were studied for the expression of epithelial cadherin (E-Cad) and matrix metalloproteinase (MMP) by using immunohistochemical staining. MMP-2 and MMP-9 were also quantified with Western blotting. The GC cells from the resected gastric cancer specimens were isolated by immunomagnetic separation. Modified Boyden chamber membrane invasion culture system coated with Matrigel was used to observe the migration and invasion of the GC cells., Results: The abnormal staining rates of E-Cad of GC tissue in the combination group and the celecoxib group were 28.0% and 44.0%, significantly lower than that in the control group (56.0%, both P < 0.05). The grey level of MMP-2 and MMP-9 in the combination and celecoxib groups were (99 +/- 20, 89 +/- 13) and (260 +/- 15, 180 +/- 13) respectively, both significantly lower than that of the control group [(314 +/- 11, 241 +/- 12), P < 0.05]. The number of GC cells that penetrated the membrane was (2.75 +/- 0.58)/10(3) cells in the combination group, (2.29 +/- 0.58)/10(3) cells, the migration rate of the combination group was lower by 38% compared with that of the control group (F = 6.44, P < 0.05)., Conclusion: The metastasis of human gastric carcinoma cells may be inhibited by the combinative treatment of celecoxib and octreotide.