Differentiation Of Gastric Cancer Research Articles

Putative Dual Roles of Bone Morphogenetic Protein 8B (BMP8B) in Disease Progression of Gastric Cancer.

Increased expression of bone morphogenetic protein 8B (BMP8B) in bone marrow and primary tumors of patients with gastric cancer (GC) is associated with disease progression and poor prognosis. However, a reduced expression has also been seen in GCs due to histone acetylation. This study aimed to evaluate BMP8B transcript levels in a large GC cohort and its impact on cellular functions. BMP8B transcripts were determined in 319 gastric tumors and compared with 182 adjacent normal tissues using real time PCR, with a further analysis conducted in the TCGA database. Kaplan-Meier plotter analysis was performed to evaluate the correlation between BMP8B and prognosis of the disease. BMP8B knockdown model was employed to determine the effect of BMP8B on the function of GC cells (HGC27). BMP8B mRNA levels were significantly up-regulated in the GC tissues compared with adjacent normal tissues in both TCGA database and our own database from Beijing Cancer Hospital, and high BMP8B expression was associated with poor prognosis. BMP8B is most likely to be involved in the differentiation of GC. Poorly differentiated GC samples presented a significantly reduced BMP8B expression in relation to well-differentiated and moderately differentiated GC. BMP8B knockdown inhibited proliferation of GC cells, while promoted invasion and migration of cancer cells. BMP8B was reduced in GCs, whereas higher BMP8B expression was associated with poor prognosis. BMP8B knockdown inhibited proliferation of GC cells, and promoted invasion and migration. Our results suggest that BMP8B plays dual roles in GC.

A retrospective study of adjuvant albumin-bound paclitaxel plus S-1 after D2 gastrectomy versus oxaliplatin plus S-1 in gastric cancer

Adjuvant oxaliplatin plus S-1 (SOX) chemotherapy for gastric cancer (GC) after D2 gastrectomy has been proven effective. There has yet to be a study that evaluates adjuvant nanoparticle albumin-bound paclitaxel (nab-paclitaxel) plus S-1. In this single-center, retrospective study, GC patients after D2 gastrectomy received either nab-paclitaxel plus S-1 (AS group) or SOX group were recruited between January 2018 and December 2020 in The First Affiliated Hospital of Zhejiang University. Intravenous nab-paclitaxel 120 mg/m2 or 260 mg/m2 and oxaliplatin 130 mg/m2 were administered as eight 3 week cycle, especially in the AS and SOX group. Patients received S-1 twice daily with a dose of 40 mg/m2 in the two groups on days 1–14 of each cycle. The end points were disease-free survival (DFS) rate at 3 years and adverse events (AEs). There were 56 eligible patients, 28 in the AS group and 35 in the SOX group. The 3 year DFS rate was 78.0% in AS group versus 70.7% in SOX group (p = 0.46). Subgroup analysis showed that the patients with signet-ring positive in the AS group had a prolonged DFS compared with the SOX group (40.0 vs. 13.8 m, p = 0.02). The diffuse-type GC or low differentiation in the AS group was associated with numerically prolonged DFS compared with the SOX group, but the association was not statistically significant (p = 0.27 and p = 0.15 especially). Leukopenia (14.3%) were the most prevalent AEs in the AS group, while thrombocytopenia (28.5%) in the SOX group. Neutropenia (7.1% in AS group) and thrombocytopenia (22.8% in SOX group) were the most common grade 3 or 4 AEs. In this study analyzing past data, a tendency towards a greater 3 year DFS was observed when using AS regimen in signet-ring positive patients. AS group had fewer thrombocytopenia compared to SOX group. More studies should be conducted with larger sample sizes.

Analysis of endoscopic and pathological features of 6961 cases of gastric cancer

Gastric cancer (GC) stage and tissue differentiation affect treatment efficacy and prognosis, highlighting the importance of understanding the risk factors that affect these parameters. Therefore, this study analyzed risk factors affecting the GC stage and differentiation and the relationships between the cancer site and the sex and age of the patient. We collected clinical data from 6961 patients with GC, including sex, age, endoscopic lesion location, and pathological differentiation. Patients were grouped based on GC stage (early or advanced), differentiation (well or poorly differentiated), and lesion site (upper stomach [cardia and fundus], middle stomach [gastric body], and lower stomach [gastric antrum]). Differences in sex, age, location, stage, and degree of differentiation were assessed based on these groupings. Univariate analysis revealed that the disease location and differentiation significantly differed based on the GC stage (P < 0.05), whereas sex, age, site, and stage significantly differed based on GC differentiation (P < 0.05). A multivariate analysis confirmed these factors as independent risk factors affecting GC. Moreover, lesion sites significantly differed between sexes (P < 0.05) and among age groups (P < 0.05). Although the effects of family history, lifestyle, and Helicobacter pylori infection status of the patients were not considered, this single-center retrospective study established independent risk factors for GC.Trial registration ChiCTR2200061989.

Jianpi Yangzheng Xiaozheng decoction alleviates gastric cancer progression via suppressing exosomal PD-L1.

Jianpi Yangzheng Xiaozheng decoction (JPYZXZ) is an empirical traditional Chinese medicine formula that has been reported to significantly prolong the survival of patients with advanced gastric cancer (GC). However, its underlying mechanism have not been fully elucidated. The present work aims to explore the possible mechanism of JPYZXZ on regulating GC progression. We firstly confirmed the inhibitory effect of JPYZXZ in GC MKN74 cells and 615-strain mice, which was possibly mediated with IL-6/JAK2/STAT3 pathway dependent PD-L1 expression. Moreover, we showed that JPYZXZ diminished the expression levels of GC-derived exosomal PD-L1 in MFC murine cells and xenograft GC model, as well as stage IIA-IIIB GC patients. We further found that in different types of tumor-infiltrating immune cells, PD-L1 expression was most positively correlated with myeloid-derived suppressor cells (MDSCs) in GC in the TISIDB database. We isolated exosomes derived from supernatants of MFC cells and co-cultured with bone marrow cells derived from C57BL/6 mice, and further revealed that the expansion of MDSCs was mediated by GC-derived exosomal PD-L1. Meanwhile, our results indicated that JPYZXZ inhibited the delivery of exosomal PD-L1 from GC cells to bone marrow cells, thereby alleviating exosomal PD-L1-induced differentiation and expansion of MDSCs in the tumor microenvironment. This led to a decrease in the levels of several immunosuppressive factors, including iNOS, Arg-1, TGF-β, IL-10, and IL-6, in 615-strain mice. Moreover, clinical data also revealed a significant positive relationship between exosomal PD-L1 and polymorphonuclear MDSCs under the JPYZXZ treatment in stage IIA-IIIB GC patients. In conclusion, our study confirmed that exosomal PD-L1 could be a key factor in controlling MDSCs differentiation in GC. JPYZXZ alleviated GC progression via suppressing exosomal PD-L1 mediated expansion of MDSCs, thereby remodeling the immunosuppressive tumor microenvironment, which provided the experimental evidence for the clinical application of JPYZXZ in the treatment of GC via PD-L1.

Are radiomic spleen features useful for assessing the differentiation status of advanced gastric cancer?

The differentiation status of gastric cancer is related to clinical stage, treatment and prognosis. It is expected to establish a radiomic model based on the combination of gastric cancer and spleen to predict the differentiation degree of gastric cancer. Thus, we aim to determine whether radiomic spleen features can be used to distinguish advanced gastric cancer with varying states of differentiation. January 2019 to January 2021, we retrospectively analyzed 147 patients with advanced gastric cancer confirmed by pathology. The clinical data were reviewed and analyzed. Three radiomics predictive models were built from radiomics features based on gastric cancer (GC), spleen (SP) and combination of two organ position (GC+SP) images. Then, three Radscores (GC, SP and GC+SP) were obtained. A nomogram was developed to predict differentiation statue by incorporating GC+SP Radscore and clinical risk factors. The area under the curve (AUC) of operating characteristics (ROC) and calibration curves were assessed to evaluate the differential performance of radiomic models based on gastric cancer and spleen for advanced gastric cancer with different states of differentiation (poorly differentiated group and non- poorly differentiated group). There were 147 patients evaluated (mean age, 60 years ± 11SD, 111 men). Univariate and multivariate logistic analysis identified three clinical features (age, cTNM stage and CT attenuation of spleen arterial phase) were independent risk factors for the degree of differentiation of GC (p =0.004,0.000,0.020, respectively). The clinical radiomics (namely, GC+SP+Clin) model showed powerful prognostic ability in the training and test cohorts with AUCs of 0.97 and 0.91, respectively. The established model has the best clinical benefit in diagnosing GC differentiation. By combining radiomic features (GC and spleen) with clinical risk factors, we develop a radiomic nomogram to predict differentiation status in patients with AGC, which can be used to guide treatment decisions.

The caspase-8 and procaspase-3 expression in gastric cancer and non-cancer mucosa in relation to clinico-morphological factors and some apoptosis-associated proteins

PurposeThe aim of the study was to assess the expression of caspase-8 and procaspase-3 proteins in gastric cancer (GC) cells and non-cancerous mucosa in relation to clinical and morphological characteristics of the tumor, postoperative survival as well as other apoptosis-related proteins. Materials and methodsThe study included 91 ​GC patients. Expression of the proteins was assessed using immunohistochemical method. ResultsPositive expression of procaspase-3 was found in all GC cells. A significant difference was found between high expression of this protein in cancer cells (70.3%) and non-cancerous mucosa (1.25%) (p ​≤ ​0.05). Caspase-8 expression was observed in 50.7% of GC cells and 46.7% of mucosa. Caspase-8 was more common in Lauren type II compared to Lauren type I cancer (p ​= ​0.009), while a statistically significant difference was reported between positive procaspase-3 expression and differentiation of GC (p ​= ​0.043) and Lauren's classification (p ​= ​0.028). We observed a significant positive correlation between the expression of caspase-8 and bcl-xl (p ​= ​0.030) as well as between the procaspase-3 and BID (p ​= ​0.026). Positive caspase-8 expression was associated with longer survival of GC patients (p ​≤ ​0.01). ConclusionsOur findings indicate the potential role of the analyzed proteins in GC pathogenesis. Positive expression of caspase-8 is associated with longer survival and better patient prognosis.

Plasma-Methylated SEPT9 for the Noninvasive Diagnosis of Gastric Cancer.

Gastric cancer (GC) is one of the most prevalent cancers globally. This study was designed to evaluate the potential performance of plasma SEPT9 methylation (mSEPT9) as a noninvasive biomarker for the diagnosis of GC. A total of 182 participants, i.e., 60 patients with GC, 39 with chronic superficial gastritis (CSG), 27 with chronic atrophic gastritis (CAG), 30 with gastric ulcer (GU), and 26 with gastric polys (GP), were recruited. The mSEPT9 level was measured using real-time polymerase chain reaction. As a diagnostic target, mSEPT9 (1/3 algorithm) had a sensitivity of 48.33 (95% confidence interval (CI): 35.40-61.48%) and a specificity of 86.89% (95% CI: 79.28-92.09%), and mSEPT9 (2/3 algorithm) had a sensitivity of 33.33 (95% CI: 22.02-46.79%) and a specificity of 98.36% (95% CI: 93.61-99.72%). The area under the receiver operating characteristic curve (ROC) curve of mSEPT9 was 0.698 (95% CI: 0.609-0.787) for the differentiation of GC from benign gastric diseases. The effectiveness of mSEPT9 (1/3 algorithm) was superior to that of CEA, CA19-9, and CA72-4. mSEPT9 was positively correlated with T, N, M, and the clinical stage of GC. Plasma mSEPT9 might serve as a useful and noninvasive biomarker for the diagnosis of GC.

Plasma Methylated RNF180 for Noninvasive Diagnosis of Gastric Cancer.

Background RNF180 is a tumor suppressor gene involved in cell development, proliferation, and apoptosis. Methylation of RNF180 (mRNF180) leads to low expression of RNF180, which is closely related to the occurrence and development of gastric cancer (GC). This study was designed to evaluate the potential performance of plasma mRNF180 as noninvasive biomarker for the diagnosis of GC. Methods A total of 156 participants, including 60 patients with GC, 39 with chronic superficial gastritis (CSG), 27 with chronic atrophic gastritis (CAG), and 30 with gastric ulcer (GU) were recruited for this study. Plasma mRNF180 level was measured using real-time polymerase chain reaction. Results As a diagnostic target, mRNF180 had a sensitivity of 71.67% (95% CI: 58.36%–82.18%) and specificity of 59.38% (95% CI: 48.85%–69.14%). The area under the ROC curve value of mRNF180 was 0.731 (95% CI: 0.648%–0.813%) for differentiation of GC from benign gastric diseases (BGD). The effectiveness of mRNF180 was superior to that of CEA, CA199, and CA724. mRNF180 was positively correlated with age, tumor size, T stage, N stage, M stage, and clinical stage of patients with GC. Conclusions Plasma mRNF180 might serve as a useful and noninvasive biomarker for the diagnosis of GC and can be used to evaluate its prognosis.

The origin of gastric cancer stem cells and their effects on gastric cancer: Novel therapeutic targets for gastric cancer.

Gastric cancer (GC) is one of the most prevalent malignancies and the most common causes of cancer-related mortality worldwide. Furthermore, the prognosis of advanced GC remains poor even after surgery combined with chemoradiotherapy. As a small group of cells with unlimited differentiation and self-renewal ability in GC, accumulating evidence shows that GC stem cells (GCSCs) are closely associated with the refractory characteristics of GC, such as drug resistance, recurrence, and metastasis. With the extensive development of research on GCSCs, GCSCs seem to be promising therapeutic targets for GC. However, the relationship between GCSCs and GC is profound and intricate, and its mechanism of action is still under exploration. In this review, we elaborate on the source and key concepts of GCSCs, systematically summarize the role of GCSCs in GC and their underlying mechanisms. Finally, we review the latest information available on the treatment of GC by targeting GCSCs. Thus, this article may provide a theoretical basis for the future development of the novel targets based on GCSCs for the treatment of GC.

Clinicopathological and Prognostic Value of USP22 Expression in Gastric Cancer: A Systematic Review and Meta-Analysis and Database Validation.

BackgroundIt has been reported that there is a correlation between the level of ubiquitin-specific protease 22 (USP22) and the clinicopathological parameters and prognosis of gastric cancer (GC) patients, but the conclusions are inconsistent. Hence, a meta-analysis must be conducted to clarify the relationship between USP22 expression and clinicopathological and prognostic value of GC patients to provide more accurate evidence.MethodsAccording to the predetermined selection criteria, systematic file retrieval was performed. The hazard ratio (HR) or odds ratio (OR) and its 95% confidence interval (CI) were used to evaluate the relationship between USP22 expression and clinicopathological and prognostic value of GC patients.ResultsIn a total of 802 patients, those with GC were finally included in 6 studies. The pooled results demonstrated that the expression of USP22 was significantly increased in GC tissues compared with control tissues (OR = 9.947, 95% CI, 6.074–16.291, P = 0.000), and USP22 expression was related to lymph node metastasis (OR = 2.415, 95% CI, 1.082, P = 0.031), distant metastasis (OR = 3.956, 95% CI, 1.365–11.464, P = 0.011) and TNM stage (OR = 2.973, 95% CI, 1.153–7.666, P = 0.024). Nevertheless, the expression of USP22 was not correlated with gender (OR = 1.202, 95% CI, 0.877–1.648, P = 0.253), age (OR = 1.090, 95% CI, 0.811–1.466, P = 0.568), tumor size (OR = 0.693,95% CI, 0.348–1.380, P = 0.297), tumor differentiation (OR = 1.830, 95%CI, 0.948–3.531, P = 0.072) and depth of invasion (OR = 2.320, 95% CI, 0.684–7.871, P = 0.177). Moreover, a high expression of USP22 predicted a poor overall survival (OS) in GC patients (HR = 2.012, 95% CI, 1.522–2.658, P = 0.000). The database of Kaplan–Meier plotter confirmed that a high expression of USP22 was correlated with poor prognostics in GC patients (HR = 1.41, 95% CI, 1.18–1.68, P < 0.01).ConclusionUSP22 overexpression in GC tissues is positively related to lymph node metastasis, distant metastasis and TNM stage and indicates a poor clinical outcome of GC patients, but it is not associated with age, gender, depth of invasion, tumor differentiation and tumor size of GC patients.Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier: 338361.

The clinical features, management, and survival of elderly patients with gastric cancer.

It is anticipated that the number of elderly patients with gastric cancer (GC) will increase with population aging; however, most studies on GC set the upper age limit at 80 years old, studies on the prognosis of elderly patients with GC over 80 years old is very limited. In this study, we conducted a retrospective analysis of this sub-cohort. This retrospective cohort study aimed to analyze the clinical data of patients aged >80 who died of GC in People's Liberation Army General Hospital between 1985 and 2020. We collected clinical informations about pathological GC types, differentiation degrees, clinical stages, anatomic sites and Bormann types of the selected case. Characteristics of participants, such as smoking, drinking, and tumor history, age, gender, and complications, were also recorded. The Kaplan-Meier method, a multivariate Cox multivariate proportional hazard model, and logistic regression were used to analyze the patient overall survival (OS) rates and treatment outcomes. The study included 92 patients (83.7% men) with a median OS of 45 months. The most common site for GC was the gastric antrum (GA), the most common site of metastatic spread was the liver, and the most common pathological GC type was tubular adenocarcinoma/papillary adenocarcinoma (TAC/PAC). Furthermore, the prevalent complications were hypertension, coronary heart disease, and diabetes. Diabetes was a risk factor affecting the total survival time [hazard ratio (HR) =2.326, P=0.029]. The most often-used GC treatment was curative surgery. The survival time was significantly longer in the curative surgery group and curative surgery + adjuvant chemotherapy group compared with the support care group (HR =0.119, P=0.001; HR =0.110, P=0.001). There was no significant difference in survival time among the palliative chemotherapy group, palliative surgery group, and support care group. Tumor staging was significantly correlated with OS rate, the median survival time of patients at stage III and stage IV GC were significantly lower than the median survival time of patients at stage I GC (HR =6.235, P=0.001; HR =30.955, P=0.001). For patients over 80 years old with good physical conditions in the early stage of GC, more active treatment can still bring better prognosis.

MicroRNA-200b-3p restrains gastric cancer cell proliferation, migration, and invasion via C-X-C motif chemokine ligand 12/CXC chemokine receptor 7 axis

ABSTRACT This study was conducted to investigate the impact of microRNA (miR)-200b-3p on viability, migration, and invasion of gastric cancer (GC) cells and its mechanism. Quantitative real-time PCR (qRT-PCR) was conducted to measure miR-200b-3p expression in GC tissues and cells; besides, the relationship between miR-200b-3p expression and overall survival time (OS) was analyzed with OncomiR database; cell counting kit-8 (CCK-8), colony formation assay, flow cytometry, scratch healing assay, and Transwell assay were performed to detect the proliferation, cell cycle progression, migration, and invasion of GC cells; a lung metastasis model in nude mice was used to examine the effect of miR-200b-3p on the metastasis of GC cells in vivo; the interplay between miR-200b-3p and C-X-C motif chemokine ligand 12 (CXCL12) mRNA 3’ UTR was predicted by bioinformatics and verified with a dual-luciferase reporter gene assay; besides, the expression of CXCL12 and CXC chemokine receptor 7 (CXCR7) was probed by Western blot. It was found that miR-200b-3p expression was down-regulated in GC tissues, which was remarkably associated with the lymph node metastasis and decrease of differentiation of GC; transfection with miR-200b-3p mimics restrained the growth, migration, and invasion of GC cells in vitro, induced cell cycle arrest, and inhibited CXCL12 and CXCR7 expression levels; transfection of miR-200b-3p inhibitors worked oppositely in vitro and promoted lung metastasis in vivo. CXCL12 was confirmed as the downstream target of miR-200b-3p and was negatively modulated by miR-200b-3p. In conclusion, miR-200b-3p inhibited GC progression via regulating CXCL12/CXCR7 axis.

Circular RNA circ-TNPO3 suppresses metastasis of GC by acting as a protein decoy for IGF2BP3 to regulate the expression of MYC and SNAIL

Gastric cancer (GC) continues to be the most common gastrointestinal malignancy in China, and tumor metastases are a major reason for poor prognosis. Circular RNAs (circRNAs) are an intriguing type of noncoding RNAs with important regulatory roles. However, the roles of circRNAs in GC metastasis have not been fully elucidated. Here, we reported that circ-transportin 3 (TNPO3) was significantly downregulated in 103 pairs of GC tissues compared with matched noncancerous tissues. The level of circ-TNPO3 expression correlated with differentiation of GC, and plasma circ-TNPO3 could serve as a potential diagnostic biomarker. Functionally, circ-TNPO3 inhibited proliferation and migration of GC in vitro and in vivo. We further verified that circ-TNPO3 competitively interacted with insulin-like growth factor 2 binding protein 3 (IGF2BP3) protein; thus, the role of IGF2BP3 in stabilizing MYC mRNA was weakened, which inhibited the expression of MYC and its target SNAIL. Taken together, circ-TNPO3 acts as a protein decoy for IGF2BP3 to regulate the MYC-SNAIL axis, thereby suppressing the proliferation and metastasis of GC. Therefore, circ-TNPO3 has the potential to serve as a therapeutic target for GC.

15-PGDH Expression in Gastric Cancer: A Potential Role in Anti-Tumor Immunity.

IntroductionHost immunity plays a vital role in tumorigenesis, including in tumor invasion and metastasis. However, the precise underlying mechanism remains to be explored. The enzyme 15-PGDH, which plays a key role in prostaglandin degradation, is a critical inflammatory mediator in gastric cancer (GC) tumorigenesis.Materials and MethodsImmunohistochemistry was performed to determine 15-PGDH expression in GC and the corresponding adjacent non-neoplastic tissues (n=92).ResultsThe expression of 15-PGDH in GC tissues was significantly lower than that in paracancerous tissues (P<0.001) and found to correspond inversely with GC differentiation (P=0.043) and lymph node metastasis (P=0.046). In contrast, FOXP3 expression was increased in poorly differentiated GC tissues (P=0.001). Kaplan–Meier analysis revealed that GC patients with low expression of 15-PGDH (Log rank test, P=0.007) and high expression of FOXP3 (Log rank test, P=0.009) had shorter overall survival (OS) than those with high 15-PGDH and low FOXP3 expression. OS was also correlated with pathological tumor-node-metastasis stage (Log rank test, P=0.014). Furthermore, using Cox proportional hazard regression, 15-PGDH expression [hazard ratio (HR): 0.605 (0.440–0.833); P=0.002] was identified as an independent factor for OS.ConclusionOur data suggest that 15-PGDH may contribute to anti-tumor immunity by regulating FOXP3+ Treg cells. The findings are useful for the identification of therapeutic targets for the management of GC.

Upregulation of Cullin 4B Promotes Gastric Cancer and Predicts Poor Prognosis.

AimCullin 4B (CUL4B) is a member of the cullin ubiquitin-ligase family, which participates in proteolysis. Aberrant CUL4B expression has been shown in many malignancies. This study aimed to elucidate oncogenic role of CUL4B in gastric cancer (GC).MethodsCUL4B expression in GC tissues was examined by RT-PCR and immunohistochemistry. The proliferation, invasion and tumorigenicity of GC cells with CUL4B overexpression or knockdown were evaluated.ResultsCUL4B expression significantly increased in GC tissues, and was correlated to UICC stage and differentiation of GC, as well as poor overall survival and disease-free survival. Both univariate and multivariate analysis identified CUL4B as an independent predictor for GC patient prognosis. In addition, CUL4B promoted GC cell proliferation and invasion in vitro and tumor formation in vivo.ConclusionCUL4B is overexpressed to promote GC development and progression. CUL4B is a promising prognostic marker and therapeutic target for GC.

Expression of programmed death ligand 1 (PD-L1) is associated with metastasis and differentiation in gastric cancer

AimsProgrammed death ligand 1 (PD-L1, CD274) has been reported to be expressed abnormally in many cancers, nevertheless, effect of PD-L1 on tumor cells remains unclear, especially in gastric cancer (GC). This study aimed to investigate the role of PD-L1 in metastasis and differentiation in GC. Main methodsImmunohistochemistry was performed on 237 paired GC tissues. shPD-L1 cells were generated by lentivirus shRNA solution and PD-L1-overexpressing cells were constructed by pcDNA3.1. Expression of PD-L1 and E-cadherin in GC cells were detected by western blot. Key findingsPD-L1 expression was significantly lower in GC than that in adjacent normal tissues, especially in poorly differentiated and metastatic GC, but was positively correlated to survival time of patients. Moreover, PD-L1 ablation could decrease E-cadherin expression, promote cell migration and wound repair ability. In turn, overexpression of PD-L1 increased E-cadherin expression and inhibited wound repair ability. At the same time, All-trans retinoic acid (ATRA), which has the properties of pro-differentiation and inhibition of invasion and metastasis, upregulated the expression of PD-L1 and E-cadherin. SignificanceThese findings not only identify PD-L1 may have a positive role for the treatment of GC, but also implicate that ATRA combined PD-L1 antibody drugs may enhance anti-tumor Immunity in GC.

HEF1 regulates differentiation through the Wnt5a/β-catenin signaling pathway in human gastric cancer

The human enhancer of filamentation 1 (HEF1) is a multi-domain docking protein of the p130 Cas family. Research reports on the mechanism of HEF1 in gastric cancer (GC) differentiation are limited. In this study, we reveal that HEF1 plays an essential role in regulating of differentiation in human GC. HEF1 was found to be highly expressed in GC tissues. Besides, In GC tissues or cells, cellular level of HEF1 negatively correlated with tumor differentiation. In addition, we showed that upregulation of HEF1 increased Wnt5a expression and the nuclear translocation of β-catenin, thereby resulting in poor differentiation in GC. Notably, GC patients with a higher expression of HEF1 showed significantly poorer disease-free and overall survival. Thus, our findings suggest that HEF1 reduces differentiation through the Wnt5a/β-catenin signaling pathway and that HEF1 is an independent unfavorable prognostic death factor in GC.

Overview of MDM2 and B-RAF Expression in Gastric Lesions

BACKGROUND:Globally, gastric cancer (GC) it is the fourth most common cancer and the third cause of cancer-related deaths. Overexpression of MDM2 and B-RAF appeared to be increased in malignancy and associated with poor prognosis in several human tumours, but their role in gastric cancer remains controversial.AIM:We had investigated the immunohistochemical expression of MDM2 and B-RAF in 136 gastric lesions with/without H. pylori association.MATERIAL AND METHODS:Studied specimens include chronic gastritis (32), intestinal type GC (70), diffuse GC (22) and gastrointestinal stromal tumours (GIST) (12).RESULTS:MDM2 expression increased significantly in intestinal GC compared to other groups (p < 0.001), while B-RAF expression increased significantly in GIST compared to other groups (p < 0.001). H. pylori increased expression of MDM2 in intestinal GC cases but did not affect B-RAF expression. MDM2 expression correlated with high grade of tumor differentiation (p < 0.001), deep invasion (p < 0.05), nodal metastases (p < 0.05) and distant metastases (p < 0.1) in intestinal GC, while B-RAF expression did not correlate with TNM stage (p < 0.1).CONCLUSION:MDM2 up-regulation was more frequent in intestinal GC, while B-RAF up-regulation was more frequent in GIST compared to other groups; MDM2 expression in intestinal GC was correlated with H. pylori association, high grade of differentiation, deep invasion, nodal and distant metastases, meanwhile, B-RAF expression was correlated with high-grade intestinal GC but did not correlate with H. pylori or TNM stage. The possible role of both MDM2 and B-RAF in predicting progression of gastric tumours and prognosis deserves further investigations.

The function of Notch1 intracellular domain in the differentiation of gastric cancer.

Due to the complex function of the Notch signal pathway in gastric cancer (GC), the association between Notch homolog 1 (Notch1) intracellular domain (NICD) and differentiation of GC remains unknown. The present study aimed to investigate the potential association between NICD and GC differentiation, and demonstrated that poorly differentiated GC expressed increased NICD levels compared with well differentiated GC. A γ-secretase inhibitor inhibited the growth of AGS cells through downregulating NICD level. Additional data suggested that a COX-2 inhibitor caused a marked reduction of NICD level in comparison with a control group treated with dimethyl sulfoxide. Combined administration of γ-secretase and COX-2 inhibitor produced a marked inhibition of growth in AGS cells, which suggests that patients with poorly differentiated GC may benefit from the blockage of NICD, which potentially serves a role in GC differentiation.

Functional role of miR-27b in the development of gastric cancer.

Previous studies have demonstrated that microRNAs (miRNAs/miRs) act as tumor suppressors or oncogenes during multiple processes in cancer. It has been observed that miR-27b may act as a tumor-suppressor and was significantly downregulated in a number of types of cancer. However, the functions of miR-27b in gastric cancer (GC) remain unclear. The present study aimed to investigate the functional role of miR-27b in the progression of GC. The downregulation of miR-27b in human GC plasma was confirmed using miRNA microarray and reverse transcription-quantitative polymerase chain reaction analyses. The association between circulating miR-27b expression and clinicopathological features of GC was analyzed and the results demonstrated that the level of circulating miR-27b was significantly correlated with GC differentiation. Receiver operating characteristic curve analysis identified that the plasma level of miR-27b may be a potential biomarker for differentiating patients with GC from healthy controls. In order to investigate the effect of miR-27b on GC cell behavior, miR-27b was overexpressed using miR-27b mimics, and it was observed that miR-27b was able to inhibit cell proliferation and induce apoptosis in SGC7901 cells. Previous studies have demonstrated that vascular endothelial growth factor C (VEGFC) is a target of miR-27b, and the results of the present study were consistent with these reports. Taken together, the results of the present study indicated that miR-27b may act as a potential biomarker for differentiating patients with GC from healthy controls, and serve as a tumor suppressor in GC by targeting VEGFC.