Bufalin induces protective autophagy by Cbl-b regulating mTOR and ERK signaling pathways in gastric cancer cells.

Bufalin, a natural small-molecule compound derived from the traditional Chinese medicine Chan su, has shown promising anti-cancer effects against a broad variety of cancer cells through different mechanisms. It has been reported to induce autophagy in gastric cancer cells. However, the molecular mechanism involved is not fully elucidated. In the present study, we aimed to investigate the molecular mechanism by which bufalin induce autophagy in human gastric cancer cells. We found that bufalin induced apoptosis and autophagy in gastric cancer cells, and autophagy prevented human gastric cancer cells from undergoing apoptosis. Bufalin treatment changed the expression of autophagy-related proteins. Moreover, phosphorylated Akt, mTOR, and p70S6K were all significantly decreased, while phosphorylated ERK1/2 was increased by bufalin. Pretreatment of MGC803 cells with the ERK1/2-specific inhibitor PD98059 led to the down-regulation of LC3 II. Further study showed that Cbl-b positively regulated autophagy by suppressing mTOR and enhancing ERK1/2 activation. Therefore, our data provide evidence that bufalin induces autophagy in MGC803 cells via both Akt/mTOR/p70S6K and ERK signaling pathways, and Cbl-b-mediated suppression of mTOR and activation of ERK1/2 might play an important role.

Correlation between PARP-1 Val762Ala polymorphism and the risk of lung cancer in a Chinese population.

The aim of this study was to investigate the relationship of the PARP-1 Val762Ala (rs1136410 T>C) polymorphism and the risk of lung cancer. A population-based case-control study of 373 lung cancer patients and 360 healthy control subjects (individually matched on age and gender) in a Chinese population was conducted. Genomic DNA was extracted by the phenol-chloroform method from the peripheral blood. PARP-1 Val762Ala polymorphism was identified using polymerase chain reaction-restriction fragments length polymorphism technique. After adjusting for age, tobacco smoking, gender, smoking index, and drinking status, logistic regression analysis demonstrated that CC genotype in PARP-1 Val762Ala polymorphism had an increased risk of lung cancer compared with TT genotype (OR = 1.59, 95 % CI = 1.03 ~ 2.50, P = 0.048), a statistically difference that still existed when merging CC and TC genotypes (OR = 1.56, 95 % CI = 1.03 ~ 2.44, P = 0.042). However, no obvious difference was found between TT and TC (OR = 1.54, 95 % CI = 0.96 ~ 2.44, P = 0.073). Subgroup analysis by histological type indicated that adenocarcinoma patients had higher frequencies of CC or TC+CC genotypes than healthy controls (CC: OR = 1.85, 95 % CI = 1.12 ~ 3.03, P = 0.015; TC+CC: OR = 1.67, 95 % CI = 1.06 ~ 2.63, P = 0.027, respectively), but no statistically significant difference within each genotype in squamous cell carcinoma or small cell lung cancer (all P > 0.05). Our findings support the view that PARP-1 Val762Ala polymorphism may contribute to an increased risk of lung cancer in the Chinese population, especially for adenocarcinoma.

Prognostic role of the let-7 family in various carcinomas: A meta-analysis update.

PURPOSE: The role of let-7 family members in cancer prognosis has been the subject of increasing interest; however, the correlation between let-7 expression and cancer prognosis remains unknown. The goal of this study was to investigate the prognostic role of let-7 expression by performing a meta-analysis update of 31 studies. METHODS: All relevant studies were searched on PubMed and Web of Science. The pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated, and subgroup analysis was performed for overall survival (OS) and disease-free survival (DFS) to evaluate the relationship between high let-7 expression and cancer prognosis. Heterogeneity and publication bias were also investigated. RESULTS: We discovered that high let-7 expression can predict a better OS (pooled HR=0.69, 95% CI 0.60-0.80, transformed from lnHR and its 95% CI) and DFS (pooled HR=0.72, 95% CI 0.54-0.96, transformed from lnHR and its 95% CI) in various carcinomas, especially in digestive cancer. Subgroup analysis showed that high let-7 expression was significantly associated with a better DFS in Asians (pooled HR=0.50, 95% CI 0.39-0.64, transformed from lnHR and its 95% CI). CONCLUSIONS: This meta-analysis showed that high let-7 expression is a prognostic factor for better OS and DFS in cancer patients, with particularly better DFS among the Asian populations. These results suggest that clinicians should treat patients with low let-7 expression more carefully. Future studies in large-scale populations among different ethnicities and regions are needed to definitively determine if let-7 expression can be used as a predicative biomarker for clinical assessment.

Early initiation of fluorouracil-based adjuvant chemotherapy improves survival in patients with resectable gastric cancer.

PURPOSE: Several clinical trials have suggested that adjuvant chemotherapy improves the survival of patients with resected gastric cancer, but the optimal time at which to initiate post-operative adjuvant chemotherapy has not been studied. This study investigated the association between time to adjuvant chemotherapy and survival in gastric cancer. METHODS: We retrospectively identified 266 patients with stage IB-IIIC gastric cancer who received fluorouracil-based adjuvant chemotherapy after radical gastrectomy. Overall survival (OS) was compared between patients grouped according to time from surgery to adjuvant chemotherapy (<45 and ≥45 days). The Cox proportional hazards model was used to analyze the effects of time to initiation of chemotherapy and other clinical covariates on survival. RESULTS: Of 266 patients, 141 (53%) started adjuvant chemotherapy within 45 days after surgery and 125 (47%) started adjuvant chemotherapy more than 45 days after surgery. The 3-year OS rates were 81.2 and 65.8% for patients starting chemotherapy within 45 days and after 45 days, respectively (p=0.006). Multivariate analysis identified early initiation of adjuvant chemotherapy, completion of the planned chemotherapy, and early-stage disease as favorable prognostic factors in terms of OS (p<0.05). Subgroup analysis suggested that starting chemotherapy within 45 days after surgery was associated with significant OS benefit compared with initiation of chemotherapy after 45 days from surgery in most subgroups. CONCLUSIONS: This retrospective analysis suggests that delaying adjuvant chemotherapy for longer than 45 days after surgery may be associated with poorer survival in patients with resected gastric cancer.

Interaction among Caveolin-1 genotypes (rs3807987/rs7804372), H. pylori infection, and risk of gastric cancer in a Chinese population.

Caveolin-1, a candidate tumor suppressor, interacts with a number of transducing molecules and plays a regulatory role in several signaling pathways. Recently, a study revealed that Cav-1 G14713A (rs3807987)/T29107A (rs7804372) polymorphisms might be associated with the susceptibility to certain cancers. In this study, we evaluated the interaction among Caveolin-1 genotypes (rs3807987/rs7804372) and Helicobacter pylori infection and increased risk of gastric cancer among the Chinese population. Blood specimens were collected from 412 gastric cancer cases to 412 noncancer controls between January 2004 and December 2012 in Liaoning Province, China. Caveolin-1 genotypes (rs3807987/rs7804372) were determined by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Enzyme-linked immunosorbent assays were used to measure serum levels of anti-H. pylori IgG. Odds ratio and 95 % confidence interval were calculated using multivariate logistic regression adjusted by sex and age. There were significant differences between gastric cancer and control groups in the distribution of their genotypes and allelic frequencies of the Cav-1 G14713A (rs3807987) and T29107A (rs7804372) polymorphisms, respectively. An elevated risk of gastric cancer was observed in patients with H. pylori infection combined with the Cav-1 G14713A, but not T29107A genotypes. The A allele of G14713A shows an interaction with H. pylori infection that increases the risk of gastric cancer.

Elevated serum CA19-9 level is a promising predictor for poor prognosis in patients with resectable pancreatic ductal adenocarcinoma: a pilot study.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive human cancers. Several studies have reported that the carbohydrate antigen 19-9 (CA19-9) level is a useful marker for predicting the prognosis for PDAC after resection. However, the cutoff value of CA19-9 used to predict prognosis varied among these reports. The aims of this study were to evaluate whether the serum CA19-9 level is a significant predictor for survival and to determine the optimal cutoff value of CA19-9 for predicting prognosis. METHODS: A total of 120 consecutive patients who underwent surgery for potentially resectable primary PDAC were retrospectively analyzed. The variables included the following: age, sex, the location of the tumor, the maximal tumor size, the histological differentiation, the margin status, the tumor stage, serum CA19-9 levels, and serum total bilirubin (TBil) levels. RESULTS: The overall 1-year survival rate was 62.5%. The receiver operating characteristic (ROC) curve indicated a significant result for the level of CA19-9 in predicting death within 1 year after surgery (Area under the curve (AUC), 0.612; 95% confidence interval (CI), 0.505-0.720; P = 0.040). The optimal cutoff point was 338.45 U/mL (sensitivity, 60.0%; specificity, 66.7%; accuracy, 64.2%). The strongest univariate predictor among the categorized CA19-9 values was CA19-9 greater than or equal to 338.45 U/mL. In the multivariate Cox proportional hazards mode analysis, the serum CA19-9 level, age and the histological differentiation were significant independent prognostic factors that were associated with the overall survival. CONCLUSIONS: The preoperative elevated CA19-9 level is a promising independent factor for predicting a poor prognosis in PDAC, and the optimal cutoff value is 338.45 U/mL.

The Chinese Society of Clinical Oncology (CSCO): Clinical guidelines for the diagnosis and treatment of gastric cancer, 2023.

The 2023 update of the Chinese Society of Clinical Oncology (CSCO) Clinical Guidelines for Gastric Cancer focuses on standardizing cancer diagnosis and treatment in China, reflecting the latest advancements in evidence-based medicine, healthcare resource availability, and precision medicine. These updates address the differences in epidemiological characteristics, clinicopathological features, tumor biology, treatment patterns, and drug selections between Eastern and Western gastric cancer patients. Key revisions include a structured template for imaging diagnosis reports, updated standards for molecular marker testing in pathological diagnosis, and an elevated recommendation for neoadjuvant chemotherapy in stage III gastric cancer. For advanced metastatic gastric cancer, the guidelines introduce new recommendations for immunotherapy, anti-angiogenic therapy and targeted drugs, along with updated management strategies for human epidermal growth factor receptor 2 (HER2)-positive and deficient DNA mismatch repair (dMMR)/microsatellite instability-high (MSI-H) patients. Additionally, the guidelines offer detailed screening recommendations for hereditary gastric cancer and an appendix listing drug treatment regimens for various stages of gastric cancer. The 2023 CSCO Clinical Guidelines for Gastric Cancer updates are based on both Chinese and international clinical research and expert consensus to enhance their applicability and relevance in clinical practice, particularly in the heterogeneous healthcare landscape of China, while maintaining a commitment to scientific rigor, impartiality, and timely revisions.

The role of E3 ubiquitin ligase Cbl proteins in ß-elemene reversing multi-drug resistance of human gastric adenocarcinoma cells.

Recent studies indicate that ß-elemene, a compound isolated from the Chinese herbal medicine Curcuma wenyujin, is capable of reversing tumor MDR, although the mechanism remains elusive. In this study, ß-Elemene treatment markedly increased the intracellular accumulation of doxorubicin (DOX) and rhodamine 123 in both K562/DNR and SGC7901/ADR cells and significantly inhibited the expression of P-gp. Treatment of SGC7901/ADR cells with ß-elemene led to downregulation of Akt phosphorylation and significant upregulation of the E3 ubiquitin ligases, c-Cbl and Cbl-b. Importantly, ß-elemene significantly enhanced the anti-tumor activity of DOX in nude mice bearing SGC7901/ADR xenografts. Taken together, our results suggest that ß-elemene may target P-gp-overexpressing leukemia and gastric cancer cells to enhance the efficacy of DOX treatment.

Corrigendum: DYNC1I1 Promotes the Proliferation and Migration of Gastric Cancer by Up-Regulating IL-6 Expression.

[This corrects the article DOI: 10.3389/fonc.2019.00491.].

Kang-Ai Injection Inhibits Gastric Cancer Cells Proliferation through IL-6/STAT3 Pathway.

OBJECTIVE: To explore the mechanisms underlying the proliferative inhibition of Chinese herbal medicine Kang-Ai injection (KAI) in gastric cancer cells. METHODS: Gastric cancer cell lines MGC803 and BGC823 were treated by 0, 0.3%, 1%, 3% and 10% KAI for 24, 48 and 72 h, respectively. The cell proliferation was evaluated by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay. The apoptosis and cell cycle were evaluated by flow cytometry. Interleukin (IL)-6 mRNA and protein expression levels were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and enzyme-linked immune sorbent assay (ELISA), respectively. The protein expression levels of cyclin A, cyclin E, cyclin B1, cyclin D1, p21, retinoblastoma (RB), protein kinase B (AKT), extracellular regulated protein kinases (ERK), signal transducer and activator of transcription (STAT) 1 and STAT3 were detected by Western blot. RESULTS: KAI inhibited the proliferation of MGC803 and BGC823 gastric cancer cells in dose- and time-dependent manner. After treated with KAI for 48 h, the proportion of G1 phase was increased, expression level of cyclin D1 and phosphorylation-RB were down-regulated, whereas the expression of p21 was up-regulated (all P<0.01). Furthermore, 48-h treatment with KAI decreased the phosphorylation level of STAT3, inhibited the mRNA and protein expressions of IL-6 (all P<0.01). IL-6 at dose of 10 ng/mL significantly attenuated the proliferative effect of both 3% and 10% KAI, and recovered KAI-inhibited STAT3 phosphorylation and cyclin D1 expression level (all P<0.01). CONCLUSION: KAI exerted an anti-proliferative function by inhibiting IL-6/STAT3 signaling pathway followed by the induction of G1 phase arrest in gastric cancer cells.

Ubiquitin ligase c-Cbl is involved in tamoxifen-induced apoptosis of MCF-7 cells by downregulating the survival signals.

BACKGROUND: Tamoxifen (TAM) is a nonsteroidal antiestrogen that has been widely used in the treatment of breast cancer through its anti-estrogen activity. Recent studies show that TAM is cytotoxic to both estrogen receptor (ER)-positive and ER-negative cells via the induction of apoptosis. However, the molecular mechanisms of this effect are not well understood. In the present study, we investigated the roles of c-Src, ERK, AKT and c-Cbl ubiquitin ligases during TAM-induced apoptosis of MCF-7 cells. MATERIAL AND METHODS: MCF-7 cell proliferation and apoptosis were measured by 3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, and flow cytometry, respectively. c-Cbl expression, and the activity of c-Src, ERK, AKT were assayed by Western blotting. Overexpression of the wild and the dominant-negative type of c-Cbl (70Z/Cbl) were achieved by transient transfection of plasmids encoding c-Cbl and 70Z/Cbl, respectively, and were confirmed by Western blotting. Statistical analysis was performed using the t-test, and a p-value <0.05 was considered to be statistically significant. RESULTS: A high concentration of TAM (25 µM) induced a time-dependent apoptosis of MCF-7 cells. ERK1/2 and AKT were activated during TAM-induced apoptosis. The ERK1/2 inhibitor PD98059, the PI3K/Akt inhibitor LY294002, and the c-Src inhibitor PP2 all enhanced TAM action. Moreover, the ubiquitin ligase c-Cbl was up-regulated during this process. Over-expression of c-Cbl significantly enhanced the apoptosis-inducing effects of TAM, while 70Z/Cbl suppressed the apoptosis-inducing effects of TAM. Further investigation revealed that, overexpression of c-Cbl significantly downregulated the c-Src protein levels and TAM-induced AKT activity. But 70Z/Cbl significantly upregulated TAM-induced ERK and AKT activity. CONCLUSIONS: This study demonstrates that c-Src, ERK, and AKT played a protective role during TAM-induced apoptosis, and that c-Cbl sensitized MCF-7 cells to TAM by modulating the expression of c-Src, and TAM-induced ERK and AKT activity.

[Cisplatin enhances TRAIL-induced apoptosis in gastric cancer cells through clustering death receptor 4 into lipid rafts].

OBJECTIVE: Gastric cancer cells are insensitive to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). To sensitize gastric cancer cells to TRAIL, we treated gastric cancer MGC803 cells with TRAIL and cisplatin. METHODS: Cell proliferation was measured using MTT assay. Cell apoptosis was determined by flow cytometry. Expression of proteins was analyzed by Western blot. The distribution of lipid rafts and death receptors was analyzed by immunofluorescence microscopy. MGC803 cells were pretreated with 50 mg/L nystatin for 1 h, and followed by the treatment of cisplatin and TRAIL. RESULTS: 100 µg/L TRAIL resulted in (8.51 ± 3.45)% inhibition of cell proliferation and caused (3.26 ± 0.89)% cell apoptosis in MGC803 cells. Compared with the treatment with cisplatin alone, treatment with TRAIL (100 µg/L) and cisplatin (8.49 mg/L, IC(50) dose of 24 h) led to a dramatic increase in both inhibition of cell proliferation [(52.58 ± 4.57)% vs. (76.43 ± 5.35)%, P < 0.05] and cell apoptosis [(23.10 ± 3.41)% vs. (42.56 ± 4.11)%, P < 0.05]. Moreover, cleavage of caspase-8 and caspase-3 was detected. TRAIL (100 µg/L) did not induce obvious lipid rafts aggregation and death receptor 4 (DR4) clustering, while cisplatin (8.49 mg/L) significantly promoted the localization of DR4 in aggregated lipid rafts. Pretreatment with 50 mg/L nystatin, a cholesterol-sequestering agent, triggered (3.66 ± 0.52)% cell apoptosis after 24 h. Pretreatment with nystatin for 1 h before the addition of 8.49 mg/L cisplatin for 24 h caused a decreased tendency to cell apoptosis [(25.74 ± 3.28)% vs. (22.76 ± 2.97)%]. While, pretreatment with nystatin before the addition of cisplatin and TRAIL, the proportion of apoptotic cells decreased from (43.16 ± 4.26)% to (31.52 ± 3.99)% (P < 0.05). CONCLUSION: Cisplatin enhances TRAIL-induced apoptosis in gastric cancer MGC803 cells through clustering death receptors into lipid rafts.

Protective autophagy antagonizes oxaliplatin-induced apoptosis in gastric cancer cells.

Oxaliplatin-based chemotherapy is used for treating gastric cancer. Autophagy has been extensively implicated in cancer cells; however, its function is not fully understood. Our study aimed to determine if oxaliplatin induce autophagy in gastric cancer MGC803 cells and to assess the effect of autophagy on apoptosis induced by oxaliplatin. MGC803 cells were cultured with oxaliplatin. Cell proliferation was measured using MTT assay, and apoptosis was determined by flow cytometry. Protein expression was detected by Western blot. Autophagy was observed using fluorescent microscopy. Our results showed that the rate of apoptosis was 9.73% and 16.36% when MGC803 cells were treated with 5 and 20 µg/mL oxaliplatin for 24 h, respectively. In addition, caspase activation and poly ADP-ribose polymerase (PARP) cleavage were detected. Furthermore, when MGC803 cells were treated with oxaliplatin for 24 h, an accumulation of punctate LC3 and an increase of LC3-II protein were also detected, indicating the activation of autophagy. Phosphorylation of Akt and mTOR were inhibited by oxaliplatin. Compared to oxaliplatin alone, the combination of autophagy inhibitor chlorochine and oxaliplatin significantly enhanced the inhibition of cell proliferation and the induction of cell apoptosis. In conclusion, oxaliplatin-induced protective autophagy partially prevents apoptosis in gastric cancer MGC803 cells. The combination of autophagy inhibitor and oxaliplatin may be a new therapeutic option for gastric cancer.

[Identification of B Antigen Weak Expression Caused by 5873CT Mutation in Blood Group Gene Based on Sequencing Technique].

OBJECTIVE: To explore the role and significance of blood group genotyping and gene sequencing technology in the identification of blood group subtypes. METHODS: Blood type of the proband and his son were identified by blood type serology, and ABO genotyping and DNA sequencing were performed according to the results of serological expression pattern. RESULTS: The weak B antigen expression was found in the proband and his son by serological test, and was preliminarily identified as B3 subtype. The ABO blood group genotyping confirmed that the genotype of the proband and his son was B/O1 and B/O2, respectively. Finally, through gene sequencing, it was confirmed that the B101 allele of the proband and his son showed a heterozygous mutation of 5873CT. CONCLUSION: The combination of serology, genotyping and sequencing showed find new blood group gene mutation sites, which is important strategic significance for accurate blood group identification, personalized blood use and trasfusion safety, which is beneficial to clarify the molecular biological basis of ABO blood group subtypes.

FEN1 is a prognostic biomarker for ER+ breast cancer and associated with tamoxifen resistance through the ERα/cyclin D1/Rb axis.

BACKGROUND: Tamoxifen is an important choice in endocrine therapy for patients with oestrogen receptor-positive (ER+) breast cancer, and disease progression-associated resistance to tamoxifen therapy is still challenging. Flap endonuclease-1 (FEN1) is used as a prognostic biomarker and is considered to participate in proliferation, migration, and drug resistance in multiple cancers, especially breast cancer, but the prognostic function of FEN1 in ER+ breast cancer, and whether FEN1 is related to tamoxifen resistance or not, remain to be explored. METHODS: On-line database Kaplan-Meier (KM) plotter, GEO datasets, and immunohistochemistry were used to analyse the prognostic value of FEN1 in ER+ breast cancer from mRNA and protein levels. Cell viability assay and colony formation assays showed the response of tamoxifen in MCF-7 and T47D cells. Microarray data with FEN1 siRNA versus control group in MCF-7 cells were analysed by Gene Set Enrichment Analysis (GSEA). The protein levels downstream of FEN1 were detected by western blot assay. RESULTS: ER+ breast cancer patients who received tamoxifen for adjuvant endocrine therapy with poor prognosis showed a high expression of FEN1. MCF-7 and T47D appeared resistant to tamoxifen after FEN1 over-expression and increased sensitivity to tamoxifen after FEN1 knockdown. Importantly, FEN1 over-expression could activate tamoxifen resistance through the ERα/cyclin D1/Rb axis. CONCLUSIONS: As a biomarker of tamoxifen effectiveness, FEN1 participates in tamoxifen resistance through ERα/cyclin D1/Rb axis. In the future, reversing tamoxifen resistance by knocking-down FEN1 or by way of action as a small molecular inhibitor of FEN1 warrants further investigation.

Atezolizumab Monotherapy or Plus Chemotherapy in First-Line Treatment for Advanced Non-Small Cell Lung Cancer Patients: A Meta-Analysis.

Background: Atezolizumab plus chemotherapy has been recommended as a first-line treatment option for patients with advanced non-small cell lung carcinoma (NSCLC) irrespective of programmed cell death-ligand 1 (PD-L1) expression. Currently, little is known about the efficacy and treatment-related adverse effects (TRAEs) of subtracting chemotherapy from the combination for patients with high PD-L1 expression. Thus, we performed an indirect comparison between atezolizumab plus chemotherapy and atezolizumab alone. Methods: A total of five eligible randomized controlled trials (RCTs) were identified from PubMed, EMBASE, and Cochrane Central controlled trial registries, using keywords including atezolizumab, PD-1, PD-L1, NSCLC, and RCT. The clinical outcomes of objective response rate (ORR), progression-free survival (PFS), OS, and TRAEs were extracted and evaluated. Using indirect analysis, the efficacy and TRAEs were compared between arm A (atezolizumab plus chemotherapy) and arm C (atezolizumab), linked by arm B (chemotherapy). Results: Direct comparison revealed that both atezolizumab plus chemotherapy (HR 0.65, P = 0.003) and atezolizumab alone (HR 0.59, P = 0.010) significantly improved OS compared with chemotherapy. More importantly, the indirect comparison showed that atezolizumab plus chemotherapy was not superior to atezolizumab regarding OS (RR 1.10, P =0.695) and ORR (RR 1.11, P = 0.645). However, patients who received atezolizumab combined with chemotherapy experienced more ≥ grade 3 TRAEs (RR 4.23, P<0.001) and TRAEs leading to drug discontinuation (RR 3.60, P<0.001) than those treated with atezolizumab monotherapy. Conclusions: Atezolizumab monotherapy might be a better treatment option for patients with advanced NSCLC and high PD-L1 expression than atezolizumab plus chemotherapy.

The Chinese Society of Clinical Oncology (CSCO): Clinical guidelines for the diagnosis and treatment of gastric cancer, 2021.

There exist differences in the epidemiological characteristics, clinicopathological features, tumor biological characteristics, treatment patterns, and drug selections between gastric cancer patients from the Eastern and Western countries. The Chinese Society of Clinical Oncology (CSCO) has organized a panel of senior experts specializing in all sub-specialties of gastric cancer to compile a clinical guideline for the diagnosis and treatment of gastric cancer since 2016 and renews it annually. Taking into account regional differences, giving full consideration to the accessibility of diagnosis and treatment resources, these experts have conducted expert consensus judgment on relevant evidence and made various grades of recommendations for the clinical diagnosis and treatment of gastric cancer to reflect the value of cancer treatment and meeting health economic indexes in China. The 2021 CSCO Clinical Practice Guidelines for Gastric Cancer covers the diagnosis, treatment, follow-up, and screening of gastric cancer. Based on the 2020 version of the CSCO Chinese Gastric Cancer guidelines, this updated guideline integrates the results of major clinical studies from China and overseas for the past year, focused on the inclusion of research data from the Chinese population for more personalized and clinically relevant recommendations. For the comprehensive treatment of non-metastatic gastric cancer, attentions were paid to neoadjuvant treatment. The value of perioperative chemotherapy is gradually becoming clearer and its recommendation level has been updated. For the comprehensive treatment of metastatic gastric cancer, recommendations for immunotherapy were included, and immune checkpoint inhibitors from third-line to the first-line of treatment for different patient groups with detailed notes are provided.

Bortezomib synergizes TRAIL-induced apoptosis in gastric cancer cells.

Background/Aims Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) as a newly identified biological agent has shown promising antitumor effects in a wide range of cancers. However, gastric cancer cells are less sensitive than other cancer cells to TRAIL-induced apoptosis.Here, we combined TRAIL with bortezomib, a proteasomal inhibitor to induce apoptosis in three gastric cancer cell lines.Methods After the cells were treated with TRAIL and/or bortezomib, the cell viability, apoptosis and cell cycle distribution were examined. The levels of death receptors and the mitochondrial membrane potential were also detected. The expression of apoptosis-associated proteins was determined by Western blot.Results Bortezomib at low concentration significantly(P<0.05) enhanced the cytotoxic effect of TRAIL by enhancing apoptosis as well as cell cycle arrest at G2/M phase. The enhancement of efficiency of TRAIL by bortezomib involved up-regulation of death receptor 4 and 5, as well as reduction of the mitochondrial membrane potential. Further study showed that combined treatment with TRAIL and bortezomib down-regulated anti-apoptotic protein cIAP-1, and over expression of cIAP-1 significantly(P\0.05) reduced the synergistic effect between TRAIL and bortezomib.Conclusions Bortezomib synergizes TRAIL-induced apoptosis in human gastric cancer cells. The synergistic effect between these two drugs is associated with up-regulation of death receptors and down-regulation of cIAP-1.The combination of TRAIL and bortezomib might be an effective regimen for the treatment of advanced gastric cancer.

[Expression of c-Cbl, Cbl-b, and epidermal growth factor receptor in gastric carcinoma and their clinical significance].

BACKGROUND AND OBJECTIVE: c-Cbl and Cbl-b are two ubiquitous members of the Casitas B-lineage lymphoma (Cbl) family, which play important roles in the downregulation of epidermal growth factor receptor (EGFR) by acting as E3 ubiquitin ligases and multiadaptor proteins. This study investigated the expression of c-Cbl, Cbl-b, and EGFR in gastric carcinoma and its clinical significance. METHODS: The expressions of c-Cbl, Cbl-b, and EGFR were detected by immunohistochemistry using tissue microarrays consisting of 124 specimens of gastric carcinoma and 16 specimens of normal gastric mucosa. The relationship between the expressions of c-Cbl, Cbl-b, and EGFR and clinicopathologic factors of gastric carcinoma were analyzed statistically. RESULTS: The positive rates of c-Cbl, Cbl-b, and EGFR were higher in the gastric carcinoma group than in the normal group (71.0% vs. 18.0%, P<0.01; 82.3% vs. 25.0%, P<0.01; 56.5% vs. 12.5%, P<0.01, respectively). The expression of c-Cbl was positively correlated with depth of invasion (r=0.219, P=0.015), and TNM staging (r=0.266, P=0.003). The expression of Cbl-b was positively correlated with lymph node metastasis (r=0.190, P<0.034) and TNM staging (r=0.298, P<0.001). The expression of EGFR was positively correlated with depth of invasion (r=0.286, P<0.001) and TNM staging (r=0.362, P=0.000). The expression of both c-Cbl and Cbl-b was positively correlated with EGFR (r=0.241, P=0.007; r=0.183, P=0.042, respectively). Synchronous strong-positive expressions of c-Cbl, Cbl-b, and EGFR were observed in 27 specimens of gastric carcinoma, most of which were at advanced stage. CONCLUSIONS: Overexpressions of c-Cbl, Cbl-b, and EGFR are closely related to the invasion and progression of gastric carcinoma. c-Cbl and Cbl-b may serve as novel molecular markers for gastric carcinoma.

FKBP10 Acts as a New Biomarker for Prognosis and Lymph Node Metastasis of Gastric Cancer by Bioinformatics Analysis and in Vitro Experiments.

PURPOSE: To explore the role of FKBP prolyl isomerase 10 (FKBP10) protein in the progression of gastric cancer. METHODS: Four independent gastric cancer databases (GSE27342, GSE29272, GSE54129 and TCGA-STAD) were used to identify differentially expressed genes (DEGs). Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis was used to identify the abnormally active pathways in patients with gastric cancer. Univariate Cox regression analysis was used to identify genes with stable prognostic value in gastric cancer patients based on three independent gastric cancer databases (GSE15459, GSE62254, TCGA-STAD). Gene set enrichment analysis (GSEA) was used to explore the possible pathways related to FKBP10. The reverse transcription-polymerase chain reaction (RT-PCR) was employed to determine the expression of FKBP10 mRNA in the HGC-27 and MKN-7 cell lines. Adhesion assay was used to detect changes in cell adhesion ability. FKBP10, ITGA1, ITGA2, ITGA5, ITGAV, ITGA6, P- AKT 473, P- AKT 308, AKT, and ß-actin were evaluated by Western blot (WB). RESULTS: We first performed differential expression genes (DEGs) screening of four independent GC databases (GSE27342, GSE29272, GSE54129 and TCGA-STAD). Eighty-nine genes showed consistent up-regulation in GC, the results of pathway analysis showed that they were related to "Focal adhesion". The prognostic value of these 89 genes was tested in three independent GC databases GSE15459, GSE62254 and TCGA-STAD cohort. Finally, 12 genes, in which the expression of FKBP10 was prominently increased in patients with lymph node metastasis (LNM), showed stable prognostic value. The following gene set enrichment analysis (GSEA) also showed that FKBP10 is mainly involved in cell adhesion process, while adhesion experiments confirmed that cell adhesion was down-regulated after silencing FKBP10 in GC cells, and adhesion-related molecules integrin αV and α6 were down-regulated. CONCLUSION: FKBP10 may be used as a marker for lymph node metastasis of GC and could be used as a potential target for future treatment of GC.