BACKGROUND: The results of studies comparing Billroth-I (B-I) with Roux-en-Y (R-Y) reconstruction on the quality of life (QoL) are still inconsistent. The aim of this trial was to compare the long-term QoL of B-I with R-Y anastomosis after curative distal gastrectomy for gastric cancer. METHODS: A total of 140 patients undergoing curative distal gastrectomy with D2 lymphadenectomy in West China Hospital, Sichuan University from May 2011 to May 2014 were randomly assigned to the B-I group ( N  = 70) and R-Y group ( N  = 70). The follow-up time points were 1, 3, 6, 9, 12, 24, 36, 48, and 60 months after the operation. The final follow-up time was May 2019. The clinicopathological features, operative safety, postoperative recovery, long-term survival as well as QoL were compared, among which QoL score was the primary outcome. An intention-to-treat analysis was applied. RESULTS: The baseline characteristics were comparable between the two groups. There were no statistically significant differences in terms of postoperative morbidity and mortality rates, and postoperative recovery between the two groups. Less estimated blood loss and shorter surgical duration were found in the B-I group. There were no statistically significant differences in 5-year overall survival (79% [55/70] of the B-I group vs. 80% [56/70] of the R-Y group, P  = 0.966) and recurrence-free survival rates (79% [55/70] of the B-I group vs. 78% [55/70] of the R-Y group, P  = 0.979) between the two groups. The scores of the global health status of the R-Y group were higher than those of the B-I group with statistically significant differences (postoperative 1 year: 85.4 ± 13.1 vs . 88.8 ± 16.1, P  = 0.033; postoperative 3 year: 87.3 ± 15.2 vs . 92.8 ± 11.3, P  = 0.028; postoperative 5 year: 90.9 ± 13.7 vs . 96.4 ± 5.6, P  = 0.010), and the reflux (postoperative 3 year: 8.8 ± 12.9 vs . 2.8 ± 5.3, P  = 0.001; postoperative 5 year: 5.1 ± 9.8 vs . 1.8 ± 4.7, P  = 0.033) and epigastric pain (postoperative 1 year: 11.8 ± 12.7 vs. 6.1 ± 8.8, P  = 0.008; postoperative 3 year: 9.4 ± 10.6 vs. 4.6 ± 7.9, P  = 0.006; postoperative 5 year: 6.0 ± 8.9 vs . 2.7 ± 4.6, P  = 0.022) were milder in the R-Y group than those of the B-I group at the postoperative 1, 3, and 5-year time points. CONCLUSIONS: Compared with B-I group, R-Y reconstruction was associated with better long-term QoL by reducing reflux and epigastric pain, without changing survival outcomes. TRIAL REGISTRATION ChiCTR.org.cn, ChiCTR-TRC-10001434.
Humans ; Stomach Neoplasms/pathology* ; Anastomosis, Roux-en-Y/methods* ; Quality of Life ; Treatment Outcome ; Gastrectomy/methods* ; Postoperative Complications ; Gastroenterostomy/methods* ; Pain

Humans ; Female ; Breast Neoplasms/pathology* ; Retrospective Studies ; Prognosis ; Stomach Neoplasms/pathology* ; China/epidemiology*

BACKGROUND: Angiogenesis is described as a complex process in which new microvessels sprout from endothelial cells of existing vasculature. This study aimed to determine whether long non-coding RNA (lncRNA) H19 induced the angiogenesis of gastric cancer (GC) and its possible mechanism. METHODS: Gene expression level was determined by quantitative real-time polymerase chain reaction and western blotting. Cell counting kit-8, transwell, 5-Ethynyl-2'-deoxyuridine (EdU), colony formation assay, and human umbilical vein endothelial cells (HUVECs) angiogenesis assay as well as Matrigel plug assay were conducted to study the proliferation, migration, and angiogenesis of GC in vitro and in vivo . The binding protein of H19 was found by RNA pull-down and RNA Immunoprecipitation (RIP). High-throughput sequencing was performed and next Gene Ontology (GO) as well as Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis was conducted to analyze the genes that are under H19 regulation. Methylated RIP (me-RIP) assay was used to investigate the sites and abundance among target mRNA. The transcription factor acted as upstream of H19 was determined through chromatin immunoprecipitation (ChIP) and luciferase assay. RESULTS: In this study, we found that hypoxia-induced factor (HIF)-1α could bind to the promoter region of H19, leading to H19 overexpression. High expression of H19 was correlated with angiogenesis in GC, and H19 knocking down could inhibit cell proliferation, migration and angiogenesis. Mechanistically, the oncogenic role of H19 was achieved by binding with the N 6 -methyladenosine (m 6 A) reader YTH domain-containing family protein 1 (YTHDF1), which could recognize the m 6 A site on the 3'-untransated regions (3'-UTR) of scavenger receptor class B member 1 (SCARB1) mRNA, resulting in over-translation of SCARB1 and thus promoting the proliferation, migration, and angiogenesis of GC cells. CONCLUSION HIF-1α induced overexpression of H19 via binding with the promoter of H19, and H19 promoted GC cells proliferation, migration and angiogenesis through YTHDF1/SCARB1, which might be a beneficial target for antiangiogenic therapy for GC.
Humans ; Cell Line, Tumor ; Cell Proliferation/genetics* ; Endothelial Cells/metabolism* ; Gene Expression Regulation ; Gene Expression Regulation, Neoplastic/genetics* ; Hypoxia ; MicroRNAs/genetics* ; RNA ; RNA, Long Noncoding/metabolism* ; RNA-Binding Proteins/metabolism* ; Scavenger Receptors, Class B/metabolism* ; Stomach Neoplasms/genetics*

Humans ; Stomach Neoplasms/pathology* ; Neoadjuvant Therapy ; Chemotherapy, Adjuvant ; Gastrectomy ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Neoplasm Staging

BACKGROUND: A polygenic risk score (PRS) derived from 112 single-nucleotide polymorphisms (SNPs) for gastric cancer has been reported in Chinese populations (PRS-112). However, its performance in other populations is unknown. A functional PRS (fPRS) using functional SNPs (fSNPs) may improve the generalizability of the PRS across populations with distinct ethnicities. METHODS: We performed functional annotations on SNPs in strong linkage disequilibrium (LD) with the 112 previously reported SNPs to identify fSNPs that affect protein-coding or transcriptional regulation. Subsequently, we constructed an fPRS based on the fSNPs by using the LDpred2-infinitesimal model and then analyzed the performance of the PRS-112 and fPRS in the risk prediction of gastric cancer in 457,521 European participants of the UK Biobank cohort. Finally, the performance of the fPRS in combination with lifestyle factors were evaluated in predicting the risk of gastric cancer. RESULTS: During 4,582,045 person-years of follow-up with a total of 623 incident gastric cancer cases, we found no significant association between the PRS-112 and gastric cancer risk in the European population (hazard ratio [HR] = 1.00 [95% confidence interval (CI) 0.93-1.09], P = 0.846). We identified 125 fSNPs, including seven deleterious protein-coding SNPs and 118 regulatory non-coding SNPs, and used them to construct the fPRS-125. Our result showed that the fPRS-125 was significantly associated with gastric cancer risk (HR = 1.11 [95% CI, 1.03-1.20], P = 0.009). Compared to participants with a low fPRS-125 (bottom quintile), those with a high fPRS-125 (top quintile) had a higher risk of incident gastric cancer (HR = 1.43 [95% CI, 1.12-1.84], P = 0.005). Moreover, we observed that participants with both an unfavorable lifestyle and a high genetic risk had the highest risk of incident gastric cancer (HR = 4.99 [95% CI, 1.55-16.10], P = 0.007) compared to those with both a favorable lifestyle and a low genetic risk. CONCLUSION These results indicate that the fPRS-125 derived from fSNPs may act as an indicator to measure the genetic risk of gastric cancer in the European population.
Humans ; Prospective Studies ; Stomach Neoplasms/genetics* ; Genetic Predisposition to Disease/genetics* ; Risk Factors ; Multifactorial Inheritance/genetics* ; Polymorphism, Single Nucleotide/genetics* ; Genome-Wide Association Study

BACKGROUND: Cancer stem-like cells (CSCs) are a small subset of cells in tumors that exhibit self-renewal and differentiation properties. CSCs play a vital role in tumor formation, progression, relapse, and therapeutic resistance. B7-H3, an immunoregulatory protein, has many protumor functions. However, little is known about the mechanism underlying the role of B7-H3 in regulating gastric cancer (GC) stemness. Our study aimed to explore the impacts of B7-H3 on GC stemness and its underlying mechanism. METHODS: GC stemness influenced by B7-H3 was detected both in vitro and in vivo . The expression of stemness-related markers was examined by reverse transcription quantitative polymerase chain reaction, Western blotting, and flow cytometry. Sphere formation assay was used to detect the sphere-forming ability. The underlying regulatory mechanism of B7-H3 on the stemness of GC was investigated by mass spectrometry and subsequent validation experiments. The signaling pathway (Protein kinase B [Akt]/Nuclear factor erythroid 2-related factor 2 [Nrf2] pathway) of B7-H3 on the regulation of glutathione (GSH) metabolism was examined by Western blotting assay. Multi-color immunohistochemistry (mIHC) was used to detect the expression of B7-H3, cluster of differentiation 44 (CD44), and Nrf2 on human GC tissues. Student's t -test was used to compare the difference between two groups. Pearson correlation analysis was used to analyze the relationship between two molecules. The Kaplan-Meier method was used for survival analysis. RESULTS: B7-H3 knockdown suppressed the stemness of GC cells both in vitro and in vivo . Mass spectrometric analysis showed the downregulation of GSH metabolism in short hairpin B7-H3 GC cells, which was further confirmed by the experimental results. Meanwhile, stemness characteristics in B7-H3 overexpressing cells were suppressed after the inhibition of GSH metabolism. Furthermore, Western blotting suggested that B7-H3-induced activation of GSH metabolism occurred through the AKT/Nrf2 pathway, and inhibition of AKT signaling pathway could suppress not only GSH metabolism but also GC stemness. mIHC showed that B7-H3 was highly expressed in GC tissues and was positively correlated with the expression of CD44 and Nrf2. Importantly, GC patients with high expression of B7-H3, CD44, and Nrf2 had worse prognosis ( P = 0.02). CONCLUSIONS B7-H3 has a regulatory effect on GC stemness and the regulatory effect is achieved through the AKT/Nrf2/GSH pathway. Inhibiting B7-H3 expression may be a new therapeutic strategy against GC.
Humans ; Cell Line, Tumor ; Neoplasm Recurrence, Local ; NF-E2-Related Factor 2/metabolism* ; Proto-Oncogene Proteins c-akt/metabolism* ; Signal Transduction ; Stomach Neoplasms

Objective: To investigate the molecular mechanism of how lactate induces high mobility group box 1 (HMGB1) release. Methods: Gastric cancer HGC-27 cells were divided into the control group and the lactate group (The cells were treated with lactate for 6 h). The level of HMGB1 in the cell culture medium was detected by enzyme-linked immunosorbent assay (ELISA), the localization of HMGB1 was detected using laser confocal microscopy, and the nuclear translocation of HMGB1 was detected using the nucleoplasmic separation assay. The phosphorylation and acetylation levels of HMGB1 were determined by co-immunoprecipitation, and Western blot was used to measure the phosphorylation of Akt and protein kinase C (PKC). HGC-27 cells were first treated with lactate and LY294002, the inhibitor of Akt, and then the phosphorylation of HMGB1 and Akt was analyzed by co-immunoprecipitation and Western blot, respectively. The localization of HMGB1 in cells was detected by laser confocal microscopy. EdU and Transwell assays were used to detect the proliferation and migration abilities of HGC-27 cells, respectively. HGC-27 cells were then injected into the BALB/C null mice for subcutaneous tumor implantation. Mice in the lactate group were intraperitoneally injected with lactate (0.2 g/kg/2 d), while those in the control group were intraperitoneally injected with an equal amount of PBS for 20 consecutive days. ELISA was used to detect the HMGB1 levels in the blood samples taken from the medial canthus vein of the mice, while co-immunoprecipitation and Western blot were used to detect the phosphorylation of HMGB1 and Akt in tumor tissue proteins, respectively. Results: The release levels of HMGB1 in the lactate group were (2 995.00±660.91) pg/ml and (696.33±22.03) pg/ml, after lactate treatment for 6 h and 12 h, respectively, both higher than those in the control group (485.00±105.83) pg/ml (P<0.001 and P=0.028, respectively). After lactate treatment for 6 h, the relative expression of HMGB1 protein in the cytoplasm of HGC-27 cells was 1.13±0.09, higher than that of the control group (0.83±0.07, P=0.001), while the relative expression of HMGB1 in the nucleus was 0.79±0.06, lower than that of the control group (1.07±0.06, P=0.007). The phosphorylation level of HMGB1 reached 1.41±0.09, which was higher than that of the control group (0.97±0.10, P=0.031). The phosphorylation level of Akt was 11.16±0.06, higher than that of the control group (0.91±0.022, P=0.002). The phosphorylation level and nuclear translocation of HMGB1 induced by lactate decreased obviously after Akt inhibition; the proliferation and migration abilities induced by lactate were also obviously inhibited after Akt inhibition. In vivo, the HMGB1 level in the peripheral blood was (1 280.70±389.66) pg/ml in the lactate group, which was obviously higher than that in the control group (595.11±44.75) pg/ml (P=0.008), and the phosphorylation levels of HMGB1 and Akt in tumor tissues in the lactate group were obviously enhanced compared with the control group. Conclusion: Lactate induces HMGB1 release through enhancing HMGB1 phosphorylation via the Akt signaling pathway.
Mice ; Animals ; Stomach Neoplasms/pathology* ; Proto-Oncogene Proteins c-akt/metabolism* ; HMGB1 Protein/metabolism* ; Phosphorylation ; Lactic Acid ; Mice, Inbred BALB C ; Signal Transduction

China is a country with a high incidence of gastric cancer, and the majority of patients are in the advanced stage. The peritoneum is the most common site of metastasis and recurrence in advanced gastric cancer. Attention to the standardized diagnosis and treatment of peritoneal metastases of gastric cancer is expected to significantly improve the prognosis and quality of life of some patients. Based on evidence-based medicine and the internationally accepted Delphi method, this consensus revises the Chinese expert consensus on the prevention and treatment of peritoneal metastasis of gastric cancer (2017 edition), reaches a preliminary consensus on the definition, classification, risk factors, diagnosis and prediction, grade assessment, prevention, treatment and management of complications of peritoneal metastasis of gastric cancer, and provides guidance for clinical work.
Humans ; Peritoneum/pathology* ; Peritoneal Neoplasms/therapy* ; Stomach Neoplasms/pathology* ; Consensus ; East Asian People ; Quality of Life ; China

Circulating tumor cell (CTC), as a novel tumor marker, has the characteristics of non-invasive, dynamic monitoring and high accuracy, and provides precise molecular characteristics of tumors and helps understand the changes in tumor development. Therefore, CTC has important clinical value in the dynamic monitoring of tumor progression. In order to standardize and guide the application of CTC detection in the diagnosis and treatment of gastrointestinal neoplasms, Gastric Cancer Group of Oncology Branch of Chinese Medical Association, Colorectal Cancer Professional Committee of Chinese Medical Doctor Association, Colorectal Cancer Professional Committee of Chinese Anti-Cancer Association, Gastric Cancer Professional Committee of Chinese Anti-Cancer Association, Digestive Tract Polyp and Precancerous Lesion Professional Committee of Chinese Anti-Cancer Association, jointly convened some domestic experts to discuss and formulate the Chinese expert consensus on the application of circulating tumor cell detection in the diagnosis and treatment of gastrointestinal neoplasms (2023 edition). The consensus provides opinions on the detection technology and clinical application of CTC detection in the diagnosis and treatment of gastrointestinal neoplasms, including the prediction of tumor prognosis, the monitoring of tumor recurrence and metastasis, the evaluation of treatment response, and the additional diagnostic value, providing guidance for clinical application.
Humans ; Stomach Neoplasms/therapy* ; Neoplastic Cells, Circulating/pathology* ; Consensus ; Neoplasm Recurrence, Local ; Colorectal Neoplasms/therapy*

OBJECTIVE: Xiaotan Sanjie recipe (XTSJ), a Chinese herbal compound medicine, exerts a significant inhibitory effect on gastric cancer (GC) metastasis. This work investigated the mechanism underlying the XTSJ-mediated inhibition of GC metastasis. METHODS: The effect of XTSJ on GC metastasis and the associated mechanism were investigated in vitro, using GC cell lines, and in vivo, using a GC mouse model, by focusing on the expression of Glc-N-Ac-transferase V (GnT-V; encoded by MGAT5). RESULTS: The migration and invasion ability of GC cells decreased significantly after XTSJ administration, which confirmed the efficacy of XTSJ in treating GC in vitro. XTSJ increased the accumulation of E-cadherin at junctions between GC cells, which was reversed by MGAT5 overexpression. XTSJ administration and MGAT5 knockdown alleviated the structural abnormality of the cell-cell junctions, while MGAT5 overexpression had the opposite effect. MGAT5 knockdown and XTSJ treatment also significantly increased the accumulation of proteins associated with the E-cadherin-mediated adherens junction complex. Furthermore, the expression of MGAT5 was significantly lower in the lungs of BGC-823-MGAT5 + XTSJ mice than in those of BGC-823-MGAT5 + solvent mice, indicating that the ability of gastric tumors to metastasize to the lung was decreased in vivo following XTSJ treatment. CONCLUSION XTSJ prevented GC metastasis by inhibiting the GnT-V-mediated E-cadherin glycosylation and promoting the E-cadherin accumulation at cell-cell junctions. Please cite this article as: Huang N, He HW, He YY, Gu W, Xu MJ, Liu L. Xiaotan Sanjie recipe, a compound Chinese herbal medicine, inhibits gastric cancer metastasis by regulating GnT-V-mediated E-cadherin glycosylation. J Integr Med. 2023; 21(6): 561-574.
Male ; Mice ; Animals ; Stomach Neoplasms/genetics* ; Drugs, Chinese Herbal/pharmacology* ; Glycosylation ; Cell Line, Tumor ; Cadherins/metabolism*