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Background: Helicobacter pylori (H. pylori) infection is the most common risk factor for gastric cancer (GC). The effect of the antioxidase manganese superoxide dismutase (SOD2 or MnSOD) in gastric tumorigenesis remains unclear. Methods: We explored the molecular and mechanical links between H. pylori, inflammation, and SOD2 in GC. RNA sequencing was conducted to identify the differentially expressed mRNAs between H. pylori-infected and uninfected cells. The putative role of SOD2 in gastric tumorigenesis in response to H. pylori infection was investigated in vitro and in vivo. Results: SOD2 is upregulated in GC. GC patients with high SOD2 expression clearly showed worse overall survival. H. pylori infection promoted SOD2 expression by activating the NF-κB signaling pathway. Knockdown of SOD2 led to increased levels of reactive oxygen species and oxidative stress in response to H. pylori infection. Meanwhile, the NF-κB binding site in the SOD2promoter region was evaluated through luciferase reporter and chromatin immunoprecipitation assays. SOD2 acted as an inhibitor of ferroptosis in GC cells, and SOD2 inhibition significantly sensitized GC cells to 5-fluorouracil treatment. Conclusions: Our results suggest that activation of the NF-κB pathway in GC cells infected with H. pylori leads to the upregulation of SOD2. Considering the prosurvival oncogenic features of SOD2 overexpression, our study further supports a novel relationship between infection, inflammation, and gastric carcinogenesis. Our results indicate that SOD2 may be a promising therapeutic candidate for GC.

Gastric cancer (GC) remains one of the most frequent cancers worldwide. Previous studies have shown that E3 ubiquitin ligase E3C (UBE3C) promotes the progression of multiple types of cancer. However, little is known about the expression and molecular mechanism of UBE3C in GC. In this study, UBE3C is upregulated in clinical GC samples and RNA-seq data from The Cancer Genome Atlas, and the UBE3C upregulation is correlated with poor clinical outcomes in patients with GC. In vitro, knockdown of UBE3C suppresses proliferation and enhances apoptosis in GC cells by inhibiting β-catenin signaling pathway. In contrast, in vitro overexpression of UBE3C promotes GC cell proliferation and inhibits apoptosis through the upregulation of β-catenin signaling by promoting ubiquitination of AXIN1. In vivo, knockdown of UBE3C inhibits tumor growth in a nude mouse model. Concurrently, the UBE3C knockdown resulted in an increase of AXIN1 and a reduction of β-catenin in the nucleus and cytoplasm in the xenograft tumor tissues. Our results demonstrate that UBE3C promotes GC progression through activating the β-catenin signaling via degradation of AXIN1. Our data suggest that UBE3C exerts oncogenic effects in GC and thus provides a promising prognostic biomarker and a potential therapeutic target for GC therapy.

Xin Zhang,1,* Hejing Huang,2,* Ziran Wei,1,* Zhenxin Zhu,1 Dejun Yang,1 Hongbing Fu,1 Jiapeng Xu,1 Zunqi Hu,1 Yu Zhang,1 Qing You,1 Xin Huang,1 Ronglin Yan,1 Weimin Wang,1 Qingping Cai1 1Department of Gastrointestinal Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, People’s Republic of China; 2Department of Ultrasound, Changzheng Hospital, Second Military Medical University, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qingping Cai; Ronglin Yan Tel +86-21-81885601; +86-21-81885603Fax +86-21-81886000Email caiqingping@smmu.edu.cn; yanronglin@smmu.edu.cnBackground: What is the optimal neoadjuvant chemotherapy (NAC) regimen for locally advanced gastric cancer (LAGC) remains debatable. The objective of this study was to compare the efficacy of docetaxel+oxaliplatin+S-1 (DOS) vs oxaliplatin+S-1 (SOX) as NAC for LAGC.Methods: Data of 248 LAGC patients who received either DOS or SOX as NAC in our hospital between January 2010 and January 2018 were reviewed retrospectively. Propensity score matched (PSM) analysis was applied to minimize the selection bias in both groups. Prognostic factors were screened by univariate and multivariate Cox regression analyses.Results: Of the 248 LAGC patients included, 180 patients were subjected to the PSM analysis. Patients in DOS group showed a better tumor response to NAC, higher radical resection rate and R0 resection rate than those in SOX group. The overall survival (OS) rate in DOS group was better than that in SOX group, although the overall incidence of Grade 3/4 NAC-related toxicity in DOS group was higher, as represented by leukopenia and neutropenia. Multivariate analysis revealed that the NAC regimen, cTNM stage and the R0 resection rate were independent prognostic factors. In addition, patients with TLND less than 16 population showed a worse OS rate. Subgroup analysis indicated that patients benefited from the addition of docetaxel regardless of the clinical T stage, but those with high clinical N stages (N2-3) did not.Conclusion: DOS is a safe and feasible NAC regimen for LAGC, which is worth popularizing in clinical practice.Keywords: locally advanced gastric cancer, neoadjuvant chemotherapy, radical gastrectomy, propensity score matched analysis, docetaxel

Altered expression of family with sequence similarity 84, member B (FAM84B) has been found in various human cancers. However, the expression and function of FAM84B in pancreatic ductal adenocarcinoma (PDAC) has not been studied. Here, by analyzing The Cancer Genome Atlas cohort, we found that FAM84B amplification was observed in 11% of 141 PDAC patients, and FAM84B amplification was correlated with higher mRNA expression of FAM84B. FAM84B amplification and overexpression was significantly correlated with poor overall survival. Moreover, knockdown of FAM84B in PDAC cell lines suppressed cell proliferation and induced apoptosis. FAM84B knockdown also suppressed mitochondrial function and glycolysis of PDAC cells. Interestingly, knockdown of FAM84B decreased the nuclear accumulation of β-catenin, and the expression of c-Myc and lactate dehydrogenase A, but enhanced the expression of Survivin. On the contrary, FAM84B overexpression displayed reversed effects in cell proliferation, apoptosis, mitochondrial function, and glycolysis, which was blocked by the Wnt/β-catenin pathway inhibitor (XAV939). In addition, PDAC cells with lower expression of FAM84B were more sensitive to gemcitabine-induced cell proliferation inhibition both in vitro and in vivo. In conclusion, FAM84B plays an important role in aerobic glycolysis and tumorigenesis in PDAC and Wnt/β-catenin may be involved in this process.

Xin Zhang,1,* Ronglin Yan,1,* Ziran Wei,1,* Dejun Yang,1 Zunqi Hu,1 Yu Zhang,1 Xin Huang,1 Hejing Huang,2 Weijun Wang1 1Department of Gastrointestinal Surgery, Second Affiliated Hospital of Naval Medical University, Shanghai, 200003, People’s Republic of China; 2Department of Ultrasound, Second Affiliated Hospital of Naval Medical University, Shanghai, 200003, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hejing Huang, Tel +86-21-81886051, Email huanghejinga@163.com; Weijun Wang, Tel +86-21-81885602, Email wangweijun@smmu.edu.cnIntroduction: Gastric cancer remains a major clinical issue and little progress has been made in the treatment of gastric cancer patients during recent decades. Nanoparticles provide a versatile platform for the diagnosis and treatment of gastric cancer.Methods: We prepared 7-ethyl-10-hydroxycamptothecin (SN-38) 125I-radiolabelled biodegradable nanoparticles with folate surface modification (125I-SN-38-FA-NPs) as a novel nanoplatform for targeted gastric carcinoma theranostics. We characterized this system in terms of particle size, morphology, radiostability, and release properties and examined the in vitro cytotoxicity and cellular uptake properties of 125I-SN-38-FA-NPs in MNK 7 and NCI-N7 cells. The pharmacokinetics and biodistribution of 125I-SN-38-FA-NPs were imaged by single photon emission computer tomography (SPECT). An MNK7 tumor-bearing model were established and the in vivo antitumor activity of 125I-SN-38-FA-NPs was evaluated.Results: SN-38 was readily radiolabeled with 125I and exhibited high radiostability. Poly-lactic-co-glycolic acid (PLGA) nanoparticles (NPs) were formed by solvent exchange, and displayed spherical morphology of 100 nm in diameter as characterized by dynamic light scattering (DLS) and transmission electron microscopy (TEM). A 2.5-fold greater uptake of 125I-radiolabelled SN-38-loaded folate-decorated PLGA nanoparticles (125I-SN-38-FA-NPs) than 125I-radiolabelled SN-38-loaded PLGA nanoparticles (125I-SN-38-NPs) were record in MKN7 tumor cells. NPs and folate-decorated PLGA nanoparticles (FA-NPs) also had good biocompatibility in methyl thiazolyl tetrazolium (MTT) assays. Pharmacokinetic, biodistribution and SPECT imaging studies showed that 125I-SN-38-FA-NPs had prolonged circulation, were distributed in the reticuloendothelial system, and had high uptake in tumors with a higher tumor accumulation of 125I-SN-38-FA-NPs than 125I-SN-38-NPs recorded at 24 h postinjection. In vivo SN-38-FA-NPs significantly inhibited tumor growth without causing obvious side effects.Conclusion: Folate receptor alpha (FOLR1) targeted drug-loaded nanoparticles enable SPECT imaging and chemotherapy, and provide a novel nanoplatform for gastric carcinoma active targeting theranostics.Keywords: folate, biodegradable nanoparticles, active targeting, SN-38, SPECT

Background: The optimal treatment for gastric cancer with peritoneal metastasis (GCPM) remains debatable. This study aimed to compare the efficacy and safety of neoadjuvant intraperitoneal and systemic chemotherapy (NIPS) versus neoadjuvant systemic chemotherapy (NSC) for GCPM. Methods: Patients of GCPM received neoadjuvant chemotherapy with docetaxel, oxaliplatin and S-1 between January 2011 and June 2019 were retrospectively evaluated. Propensity score matched (PSM) analysis was carried out to reduce the selection bias. Multivariate Cox regression model was applied to screen the prognostic factors. Results: After PSM processing, 71 patients in each group were matched among the 186 GCPM patients included. NIPS yielded a better ascites and cytology response to chemotherapy, higher conversion resection rate and R0 resection rate than NSC. The overall survival (OS) rate in NIPS group was better than that in NSC group. Multivariate analysis revealed that the P stage, ascites response, conversion surgery rate and R0 resection rate were independent prognostic factors. Subgroup analysis indicated that NIPS showed a survival benefit over NSC only in patients with cT3-4a, P1-2, whose cytology turned negative, and who received conversion surgery; while not in patients with cT4b, P0 or P3, whose cytology did not turn negative, or who did not receive conversion surgery. Conclusions: NIPS is a safe and feasible treatment for GCPM, which showed more benefit than NSC.

Introduction It is worldwide accepted that lncRNA PTCSC3 is a tumor suppressor in glioma and thyroid cancer, whereas its role in the recurrence of gastric cancer is unknown. Patients and Methods We recruited 80 GC patients (46 males and 34 females, 44 to 68 years, 56.3±6.7 years) in our study. Two human GC cell lines AGS and SNU-1 were transfected with PTCSC3 and HOXA11-AS expression vectors. Then, qPCR was used to detect the level of relative mRNA. Both invasion and migration assays were performed to detect the effect of the lncRNA on gastric cancer cell motility. Results In the present study, we showed that PTCSC3 was downregulated in plasma of gastric cancer patients than in plasma of healthy controls. Follow-up study indicated that PTCSC3 was further downregulated in patients with distant-recurrence but not in patients with local recurrence only or non-recurrence. LncRNA HOXA11-AS was upregulated in plasma of gastric cancer cells than in plasma of healthy controls and was inversely correlated with PTCSC3 in plasma of gastric cancer patients. PTCSC3 overexpression mediated the downregulation of HOXA11-AS in gastric cancer cells, while HOXA11-AS overexpression failed to significantly affect PTCSC3. PTCSC3 overexpression led to inhibited, while HOXA11-AS overexpression led to promoted migration and invasion of gastric cancer cells. In addition, HOXA11-AS overexpression reduced the effects of PTCSC3 overexpression. Discussion Therefore, lncRNA PTCSC3 alleviates in the postoperative distant recurrence of gastric cancer possible by suppression of HOXA11-AS.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies because of its broad resistance to chemotherapy. Numerous evidence indicates that integrinβ1 is upregulated in some human cancers, and it is correlated with resistance to various therapies. However, the role of integrinβ1 in chemotherapy is not clear in pancreatic cancer. The present study evaluates the potential of integrinβ1 to predict chemoresistance and prognosis in patients and to modulate resistance to gemcitabine in PDAC cells. Primary drug-resistance (DR) cancer cells were isolated, and DR cells from MiaPaCa-2 and AsPC-1 parent cell lines (PCL) were selected. Integrinβ1 expression was determined using immunohistochemistry (IHC), quantitative real-time PCR (qRT-PCR) and Western blotting. Changes in drug response after knockdown of integrinβ1 via RNA interference (RNAi) were evaluated using the viability of cancer cells as colon formation, proliferation using Western blot of Ki-67 and apoptosis using cleaved caspase-3 immunofluorescence. qRT-PCR and Western blot also detected variations in the activities of cdc42 and AKT after integrinβ1 suppression. Patient survival and relative factors were assessed using Kaplan-Meier and Cox regression analyses. Integrinβ1 expression was upregulated in PDAC, which was significantly associated with intrinsic and acquired gemcitabine resistance and worse outcomes. The downregulation of integrinβ1 attenuated PDAC chemoresistance, and this attenuation partially correlated with reduced Cdc42 and AKT activity, which are target molecules of integrinβ1 in some human cancers. These findings identified integrinβ1 as a special marker of drug resistance and a serious prognosis, and they furthermore support the use of integrinβ1 as a novel potential therapeutic target to overcome chemotherapy resistance. The results also suggest a possible drug-resistant signalling pathway of integrinβ1 in PDAC.

The tripartite motif (TRIM) family comprises more than 70 members involved in the regulation of many cellular pathways. TRIM32 acts as an E3 ubiquitin ligase and has been reported to participate in many human cancers. Here, we aimed to investigate the role of TRIM32 in gastric cancer (GC) and the clinical implications. High expression of TRIM32 was observed in GC tissues and cell lines, and was significantly associated with poor prognosis. Knockdown TRIM32 expression remarkably suppressed the proliferation, migration, and invasion of GC cells in vitro and tumour growth in vivo, whereas overexpression of TRIM32 yielded the opposite results. Western blotting and quantitative reverse‐transcription PCR (qRT‐PCR) analyses revealed that up‐regulation of TRIM32 significantly enhanced expression of β‐catenin protein and of its downstream targets TCF1, cyclin D1, Axin2 and MMP7 mRNAs. Moreover, we found that the mechanism behind the TRIM32‐promoted GC progression was related to the β‐catenin signalling pathway. Collectively, these data suggest that TRIM32 promotes GC cell proliferation, migration, and invasion by activating the β‐catenin signalling pathway.

Background: The expression pattern and regulatory effect of microRNA-375 (miR-375) in human pancreatic cancer was explored. Methods: Gene expression of miR-375 was compared between pancreatic tumors and non-tumorous pancreatic tissues, as well as pancreatic cancer cell lines and normal epithelial cells. MiR-375 was downregulated in pancreatic cancer cell lines, Capan-1 and PANC-1 cells, to assess possible tumor suppressive effects on cancer proliferation, migration, cisplatin chemosensitivity and in vivo growth of tumor explant. The regulation of miR-375 on its target gene, homeobox B3 (HOXB3) gene, was assessed though luciferase activity assay and qRT-PCR. HOXB3 was also downregulated in Capan-1 and PANC-1 cells to assess its functional correlation with miR-375 on cancer regulation. Results: MiR-375 was upregulated in pancreatic tumors and pancreatic cancer cell lines. MiR-375 downregulation had tumor suppressive effects in Capan-1 and PANC-1 cells by reducing cancer proliferation & migration, increasing cisplatin sensitivity and inhibiting in vivo tumor explant growth. HOXB3 was directly bound by miR-375, and was negatively regulated by miR-375 in pancreatic cancer cells. Subsequent HOXB3 downregulation reversed the suppression of miR-375 downregulation on cancer proliferation, migration and cisplatin chemosensitivity in pancreatic cancer. Conclusion: MiR-375 is an oncogene in pancreatic cancer. Deregulation of miR-375 is inhibitory to the development of pancreatic cancer, and reversely regulated by HOXB3.

Background Nutrients such as ω-3 fatty acids including fish oil components eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) suppress the growth and promote apoptosis of tumor cells, improve immune function and reduce the effects of systemic inflammatory response syndrome. We sought to investigate the effect of ω-3 fish oil fat emulsion-based parenteral nutrition (PN) on nutritional state, immune function, inflammatory reaction, expression of tumor factors and complication incidence in patients after surgical resection of gastric cancer. Methods Forty-eight patients after surgical operation of gastric tumor in hospital were randomly divided into the control group and intervention group. Patients in both groups were treated with iso-nitrogen and iso-caloric parenteral nutrition support. In addition, the intervention group received ω-3 fish oil fat emulsion and the control group received soybean oil. The indicators of nutrition, immune function and inflammation in the two groups were detected on the day before the operation and postoperative day 6. The rate of complication was compared between the two groups. Results There was no significant difference in nutritional state, liver function and renal function between the two groups (P > 0.05). However, the levels of inflammatory markers were significantly decreased (P

Nasogastric tubes (NGT) have been routinely used after abdominal procedures, largely due to the accepted tradition, especially in China. However, studies recently questioned the role of routine NGT intubation by stating that it was overused and many complications occurred from its use. Herein, we performed a systematic review and a meta-analysis evaluating the role of NGT in decompression after elective colon and rectum surgery. Four fixed-effect models and three randomized-effect models were used for statistics pooling of the relative risks (RR) for the different outcomes. A total of seven articles (1,416 patients) fulfilled the inclusion criteria. Patients in NGT group had less vomiting (p

Acute pancreatitis (AP) is a common inflammatory disease mediated by damage to acinar cells and subsequent pancreatic inflammation with infiltration of leukocytes. The neuronal guidance protein, netrin-1, has been shown to control leukocyte trafficking and modulate inflammatory responses in several inflammation-based diseases. The present study was aimed toward investigating the effects of netrin-1 in an in vivo model of AP in mice. AP was induced in C57BL/6 mice by administration of two intraperitoneal injections of L-Arginine (4 g/kg). Mice were treated with recombinant mouse netrin-1 at a dose of 1 µg/mouse or vehicle (0.1% BSA) intravenously through the tail vein immediately after the second injection of L-Arginine, and every 24 h thereafter. Mice were sacrificed at several time intervals from 0 to 96 h after the induction of pancreatitis. Blood and tissue samples of pancreas and lung were collected and processed to determine the severity of pancreatitis biochemically and histologically. Immunohistochemical staining demonstrated that netrin-1 was mainly expressed in the islet cells of the normal pancreas and the AP model pancreas, and the pancreatic expression of netrin-1 was down-regulated at both the mRNA and protein levels during the course of AP. Exogenous netrin-1 administration significantly reduced plasma amylase levels, myeloperoxidase activity, pro-inflammatory cytokine production, and pancreas and lung tissue damages. Furthermore, netrin-1 administration did not cause significant inhibition of nuclear factor-kappa B activation in the pancreas of L-Arginine-induced AP. In conclusion, our novel data suggest that netrin-1 is capable of improving damage of pancreas and lung, and exerting anti-inflammatory effects in mice with severe acute pancreatitis. Thus, our results indicate that netrin-1 may constitute a novel target in the management of AP.