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Background: Gastric adenocarcinoma of the fundic gland type (GA-FG) is a newly described variant of gastric adenocarcinoma with lack of knowledges regarding its genetic features., Methods: We performed whole-genome sequencing (WGS) in formalin-fixed paraffin-embedded (FFPE) tumor tissues and matched adjacent noncancerous specimens from 21 patients with GA-FG, and integrated published datasets from 1105 patients with traditional gastric adenocarcinoma with the purpose of dissecting genetic determinants both common to conventional gastric adenocarcinoma and unique to GA-FG disease., Results: We characterized the genomic architecture of GA-FG disease, revealing the predominant proportion of C > T substitution among the six types of SNVs. GNAS was the most significantly mutated driver gene (14.29%). 42.8% of samples harbored "Kataegis." Distinct genomic alterations between GA-FG and conventional gastric cancer were identified. Specifically, low mutational burden and relatively moderate mutational frequencies of significantly mutated driver genes, coupled with the absence of non-silent alterations of formerly well-known drivers such as TP53, PIK3CA and KRAS were identified in GA-FG patients. Oncogenic signaling pathway analysis revealed mutational processes associated with focal adhesions and proteoglycans in cancer, highlighting both common and specific procedures during the development of GA-FG and conventional gastric cancer., Conclusion: Our study is the first to comprehensively depict the genomic landscape highlighting the multidimensional perturbations in GA-FG patients. These discoveries offered mechanistic insights for novel diagnostic and therapeutic strategies for patients with such disease., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Objective: A Mendelian randomization (MR) analysis was performed to assess the relationship between tea consumption and cancer. Methods: There were 100 639 participants with the information of gene sequencing of whole genome in the China Kadoorie Biobank. After excluding those with cancer at baseline survey, a total of 100 218 participants were included in this study. The baseline information about tea consumption were analyzed, including daily tea consumption or not, cups of daily tea consumption, and grams of daily tea consumption. We used the two-stage least square method to evaluate the associations between three tea consumption variables and incidence of cancer and some subtypes, including stomach cancer, liver and intrahepatic bile ducts cancer, colorectal cancer, tracheobronchial and lung cancer, and female breast cancer. Multivariable MR and analysis only among nondrinkers were used to control the impact of alcohol consumption. Sensitivity analyses were also performed, including inverse variance weighting, weighted median, and MR-Egger. Results: We used 54, 42, and 28 SNPs to construct non-weighted genetic risk scores as instrumental variables for daily tea consumption or not, cups of daily tea consumption, and grams of daily tea consumption, respectively. During an average of (11.4±3.0) years of follow-up, 6 886 cases of cancer were recorded. After adjusting for age, age 2 , sex, region, array type, and the first 12 genetic principal components, there were no significant associations of three tea consumption variables with the incidence of cancer and cancer subtypes. Compared with non-daily tea drinkers, the HR (95% CI ) of daily tea drinkers for cancer and some subtypes, including stomach cancer, liver and intrahepatic bile ducts cancer, colorectal cancer, tracheobronchial and lung cancer, and female breast cancer, are respectively 0.99 (0.78-1.26), 1.17 (0.58-2.36), 0.86 (0.40-1.84), 0.85 (0.42-1.73), 1.39 (0.85-2.26) and 0.63 (0.28-1.38). After controlling the impact of alcohol consumption and performing multiple sensitivity analyses, the results were similar. Conclusion: There is no causal relationship between tea consumption and risk of cancer in population in China.

Background: The incidence of gastric cancer (GC) ranks fourth among all malignant tumors worldwide, and the fatality rate ranks second among all malignant tumors. Several Chinese traditional medicines have been used in the treatment of advanced gastric cancer. This study aims to investigate the effect of combinational use of natural product cryptotanshinone (CTS) with anti-cancer drug trifluorothymidine (FTD) in GC., Methods: Cell Counting Kit-8 assay was used to detect the inhibitory effect of the combinational or separate use of FTD and CTS on the growth of HGC-27 and AGS GC cells. The combined index of FTD and CTS was calculated using CompuSyn software. To understand the mechanism, we applied flow cytometry to study the cell cycle and cell apoptosis after treatment. We also investigated the amount of FTD incorporated into the DNA by immunofluorescence assay. The expression of relevant proteins was monitored using western blot. Furthermore, the effect of using TAS-102 in combination with CTS was studied in xenograft tumor nude mice model., Results: FTD and CTS inhibited the growth of GC cells in a dose-dependent manner, respectively. They both exhibited low to sub-micromolar potency in HGC-27 and AGS cells. The combination of FTD and CTS showed synergistic anticancer effect in HGC-27 cells and AGS cells. Our mechanism studies indicate that FTD could block HGC-27 cells at G2/M phase, while CTS could block HGC-27 cells at G1/G0 phase, while FTD combined with CTS could mainly block HGC-27 cells at G2 phase. FTD in combination with CTS significantly increased the apoptosis of HGC-27 cells. We observed that CTS treatment increased the incorporation of FTD into the DNA HGC-27 cell. FTD treatment activated STAT3 phosphorylation in HGC-27 cells, while CTS treatment down-regulated the concentration of p-STAT3. Interestingly, the combination of CTS and FTD reduced STAT3 phosphorylation induced by FTD. In the in vivo experiments, we observed that the combination of TAS-102 with CTS was significantly more potent than TAS-102 on tumor growth inhibition., Conclusions: FTD combined with CTS has a synergistic anti-gastric cancer effect as shown by in vitro and in vivo experiments, and the combined treatment of FTD and CTS will be a promising treatment option for advanced gastric cancer.

Aim: We compared endoscopic "calabash" ligation and resection (ECLR) and endoscopic submucosal excision (ESE) in treating endophytic gastric stromal tumors (GSTs) ≤15 mm in diameter originating from the muscularis propria., Methods: We performed a retrospective study and included patients who visited our hospital for removal of small endophytic GSTs (diameter ≤ 15 mm) confirmed by postoperative pathological reports between February 2019 and December 2020. Patients were assigned to the study (received ECLR) or control (accepted ESE) groups, and their medical records were reviewed. Age, sex, GST size, resection outcomes, procedure measurements, lengths of hospital stays, medical expenses, intraoperative and postoperative complications, and follow-up outcomes were documented and compared between the two groups. Propensity score matching was used to avoid retrospective biases., Results: A total of 277 patients were included in the analysis, with 135 in the study group and 142 in the control group. After propensity score matching, 119 cases in each group were finally included in the study. Compared to the control group, the study group had significantly shorter procedure durations and lengths of hospital stays, as well as reduced medical expenses. Compared to the control group, the study group also had significantly lower incidence rates of intraoperative stomach perforation, postoperative intraperitoneal infection, and postoperative electrocoagulation syndrome, as well as a lower intensity of postoperative pain. There were no significant differences in the other measurements between the two groups., Conclusion: ECLR is an effective and safe procedure for treating patients with endophytic GSTs ≤15 mm in diameter originating from the muscularis propria., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Gastric cancer (GC) is a highly aggressive malignant tumor, and, therefore, the prognosis evaluation of this disease is important. Proteasome activator subunit 3 (PSME3) is highly expressed in GC; however, its exact role in GC has yet to be clarified. The gene expression profiles for GC were downloaded to find a candidate prognostic biomarker, and PSME3 was selected. The expression level of the PSME3 gene in GC tissues was analyzed using a public database. The biological processes and signal pathways that PSME3 was involved in were further analyzed. Immunohistochemical staining of 181 GC tissues was performed to detect the expression of the PSME3 protein. The correlation between PSME3 expression and GC prognosis and its clinical and pathological parameters were investigated. It was found that PSME3 mRNA expression was higher in GC than in adjacent gastric tissues, and high PSME3 expression was significantly correlated with tumor stage, histological subtype, lymph node metastasis status, and Helicobacter pylori infection in patients with GC (all p<0.01). Bioinformatics showed that PSME3 mainly played an oncogenic role in the development of GC by regulating the cell cycle and inhibiting apoptosis. The PSME3 protein was overexpressed in 64.6% (117/181) of the analyzed samples, and overexpression of PSME3 was associated with a significantly poor prognosis. In addition, multivariate analysis suggested that PSME3 overexpression, tumor, node, metastasis stage, and tumor size are independent prognostic biomarkers for GC. We conclude that the overexpression of PSME3 was associated with a poor prognosis in patients with GC, and PSME3 might play an oncogenic role in the occurrence and development of GC.

Objective: To identify new prognostic markers and therapeutic targets for gastric adenocarcinoma. Methods: The public datasets of gastric adenocarcinoma collected from GEO database (GSE33335 and GSE63089) were downloaded for analysis. There were 70 GC tissues and paired normal tissues in the two profile datasets. Differentially expressed genes (DEGs) between GC tissues and normal stomach tissues were selected by the R software. Protein-protein interaction (PPI) of these DEGs were visualized by the Search Tool for the Retrieval of Interacting Genes (STRING). The key gene sets were analyzed by Cytoscape and Molecular Complex Detection (MCODE). The mRNA and protein expression levels of prognosis related genes identified by public database were confirmed by using GC tissues and paired normal tissues collected from July 2019 to September 2019 in Affiliated Hospital of Nantong University. Results: DEGs were identified in the two datasets by using R software. A total of 128 DEGs were detected, including 85 up-regulated genes ( log (2) FC >1.2 and FDR <0.01) and 43 down-regulated genes ( log (2) FC <-1.2 and FDR <0.01) in the GC tissues. PPI network model and MCODE model were established by using the Online String tool and Cytoscape software, and 27 key genes were obtained, including 25 genes related with prognosis of GC patients ( P <0.05). We identified 14 significant DEGs in GC tissues, including cyclin B1 (CCNB1), polo-like kinase 1 (PLK1) and pituitary-tumor transforming gene (PTTG1), which were significantly enriched in the cell cycle pathway through KEGG pathway enrichment analysis. The positive expression rate of PTTG1 in GC tissues was 68.8% (22/32), significantly higher than 18.8% (6/32) in normal gastric tissues ( P <0.05). Conclusions: The expression of PTTG1 is different in GC and gastric tissues, implicates it is the key gene in gastric carcinogenesis. The prognoses of GC patients with higher PTTG1 expression are worse. PTTG1 might participate in the development of gastric adenocarcinoma by regulating cell cycle.

Background: Phosphatidylinositol-3,4,5-trisphosphate dependent Rac exchange factor 1 (PREX1) was reported to be overexpressed in some cancers and involved in cancer development, but its expression and significance in gastric cancer remain unclear., Aim: To evaluate the expression of PREX1 in gastric cancer and its significance in the development of gastric cancer, especially to evaluate the potential mechanism of PREX1 in gastric cancer., Methods: Bioinformatic analysis was performed in order to examine the expression of PREX1 in gastric cancer. The relationship between the survival rate of gastric cancer patients and PREX1 expression was assessed by Kaplan Meier portal. The Gene Set Enrichment Analysis and the correlation between PREX1 and transforming growth factor (TGF) β1 pathway-related mediators were evaluated by cBioPortal for Cancer Genomics. Western blotting and reverse transcriptase polymerase chain reaction assay were used to test the role of TGFβ1 on the expression of PREX1. Western blotting and dual-luciferase reporter system was used to evaluate the effect of PREX1 on the activation of TGFβ1 pathway. Wound healing and Transwell assay were used to assess the effect of PREX1 on the metastasis activity of gastric cancer cells., Results: PREX1 was overexpressed in the gastric tumors, and the expression levels were positively associated with the development of gastric cancer. Also, the high expression of PREX1 revealed poor prognosis, especially for those advanced and specific intestinal gastric cancer patients. PREX1 was closely involved in the positive regulation of cell adhesion and positively correlated with TGFβ1-related mediators. Furthermore, TGFβ1 could induce the expression of PREX1 at both the protein and mRNA level. Also, PREX1 could activate the TGFβ1 pathway. The induced PREX1 could increase the migration and invasion activity of gastric cancer cells., Conclusion: PREX1 is overexpressed in gastric cancer, and the high level of PREX1 predicts poor prognosis. PREX1 is closely associated with TGFβ signaling and promotes the metastasis of gastric cancer cells., Competing Interests: Conflict-of-interest statement: The authors declare no conflict of interest., (©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.)

Gastric cancer (GC) is one of the most common digestive malignancies globally, and the prognosis of patients with advanced tumors remains poor. Isocryptotanshinone (ICTS), isolated from Salvia miltiorrhiza, was found to inhibit the proliferation of lung and breast cancer cells. However, whether ICTS has anticancer activities against GC is unknown. In the present study, we reported that the proliferation of GC cells was inhibited by ICTS in a dose- and time-dependent manner. After treatment with ICTS, GC cells were arrested in the G1/G0 phase of cell cycle and the apoptotic cells were induced in a dose-dependent manner. Additionally, ICTS suppressed the expression of cell cycle- and apoptosis-associated proteins (e.g., Cyclin D1, phosphorylated Rb, E2F1, Mcl-1, Bcl-2, and Survivin). ICTS inhibited the phosphorylation of STAT3 in a dose-dependent manner. Down-regulated STAT3 attenuated the expression of Cyclin D1, p-Rb, and Survivin, which remarkably increased the sensitivity of ICTS in GC cells; overexpression of STAT3 restored the cell growth and proliferation and the protein expression suppressed by ICTS. ICTS also suppressed the xenograft tumor growth in BALB/c nude mice. Together, these data indicate that ICTS inhibits GC proliferation by inducing G1/G0 cell cycle arrest and apoptosis via inhibiting the STAT3 signaling pathway.

Background: Adenocarcinoma of esophagogastric junction (AEG) was initially proposed in 1999 by Siewert. During recent decades, the incidence and prevalence of AEG were arising globally whereas the incidence of gastric cancer is gradually declining. Complete blood counting and liver function tests, as the routine examination of immune and nutritional status, were reported to be the predictors of overall survival (OS) in some tumors. However, little is known about the prognostic significance of these indexes in AEG patients. The purpose of this study was to assess the prediction of preoperative pre-albumin, hemoglobin, and prognostic nutritional index (PNI) for survival outcomes in AEG patients., Methods: A retrospective cohort of 101 AEG patients followed by radical surgery was recruited between January and July 2010. Clinical and laboratory data were obtained and used to evaluate the predictive value through survival analysis. Receiver operating characteristic (ROC) curve analysis determined 200 mg/L, 120 g/L, 5 cm, and 51 as the cutoff values of pre-albumin, hemoglobin, tumor size, and PNI, respectively., Results: Univariate analysis revealed that AEG patients with hemoglobin ≥120 g/L, albumin ≥40 g/L, pre-albumin ≥200 g/L, PNI ≥51, and tumor size <5 cm had longer OS (P < 0.05). Additionally, pre-albumin, tumor size, and TNM stage were demonstrated to be independent prognostic indicators by multivariate analysis with Cox regression, and the performance of pre-albumin for predicting OS in AEG patients was further identified by ROC curves (P = 0.006)., Conclusions: Preoperative pre-albumin was an independent prognostic factor, and a high level of pre-albumin predicted longer OS in AEG patients.

Background: The most common malignancy to cause gastric outlet obstruction is primary gastric adenocarcinoma and it is followed by carcinoma of the pancreas and gallbladder. Herein, we report a case of gastric outlet obstruction secondary to metastatic lobular breast carcinoma., Case Presentation: Fifty-seven year old Caucasian female with recently diagnosed metastatic lobular breast carcinoma to skin was referred to gastroenterology for evaluation of dyspepsia and dysphagia. She has past medical history significant for acid reflux and Clostridium difficile colitis. Computed tomography of her abdomen showed diffused bowel wall thickening without evidence of bowel obstruction. Due to persistent abdominal pain, an upper endoscopy was performed. The upper endoscopy showed gastritis and gastric stenosis in the gastric antrum. These lesions were biopsied and dilated with a balloon dilator. The biopsy of the gastric antrum later showed a metastatic carcinoma of breast origin with typical tumor morphology and immune-phenotype., Conclusions: Differentiating metastatic breast carcinoma from primary gastric adenocarcinoma cannot be done using histological examination alone. Immunohistochemistry is needed to differentiate the two based on staining for estrogen and progesterone receptors. The presence of gross cystic disease fluid protein 15 is also suggestive of metastatic breast carcinoma. The stomach has a significant capacity to distend (up to 2-4 L of food) and malignant gastric outlet obstruction is often undetected clinically until a high-grade obstruction develops. Our case demonstrates valuable teaching point in terms of broadening our differentials for gastric outlet obstruction. When patients present with gastric outlet obstruction, both non-malignant and malignant causes of gastric outlet obstruction should be considered. Once adenocarcinoma has been determined to be the cause of gastric outlet obstruction, further immunohistochemistry is needed to differentiate breast carcinoma from other carcinomas.

Pyloric gland adenoma (PGA) is a rare neoplasm demonstrating gastric epithelial differentiation. In this series, we studied 41 PGAs from 36 patients. We compared them to 28 gastric foveolar type gastric adenomas (GTAs) from 25 patients. PGAs occurred in an older population with a mean age of 73 compared with 48 in GTAs (P<0.001). There was a significant female predominance, particularly for gastric PGAs. Morphologically, PGAs were characterized by closely packed pyloric gland-type tubules with a monolayer of cuboidal to low columnar epithelial cells containing round nuclei and pale to eosinophilic cytoplasm with a ground glass appearance. The cells lacked an apical mucin cap, a feature distinct from GTAs. An immunohistochemical panel of mucin core peptides (MUCs) and CDX2 was performed on a subset of the lesions. All PGAs expressed MUC6 with coexpression of MUC5AC, whereas GTAs expressed predominantly MUC5AC without MUC6. Both lesions lacked CDX2 and MUC2 except in areas of intestinal metaplasia (IM) found in some PGAs. Histologic features consistent with conventional dysplasia were found in 26 (63.4%) PGAs. Using a 2-tier grading system, 5 (12.2%) cases demonstrated low-grade dysplasia whereas 21 (51.2%) cases showed high-grade dysplasia including 5 (12.2%) cases with an associated intramucosal or more deeply invasive adenocarcinoma. This was significantly different from GTAs; all cases showed only low-grade dysplasia (P<0.001). In addition, 60% of gastric PGAs were associated with IM in the surrounding mucosa and 40% of lesions arose in a background of autoimmune gastritis, whereas these 2 conditions were only associated with 1 case (3%) of GTA. In summary, PGA is a distinct entity. Despite its bland histologic appearance, it is much more likely to be accompanied by background IM and autoimmune gastritis and can evolve into invasive adenocarcinoma displaying pyloric gland differentiation.

We describe an exceedingly rare case of severe gastritis that was temporally associated with primary Epstein-Barr virus (EBV) infection. The patient was a 59-year-old immunocompetent man who presented with intermittent fever of unknown origin and epigastric pain for 18 days. A computed tomographic scan of the abdomen showed diffuse thickening of the gastric wall and esophagogastroduodenoscopy revealed numerous ulcers in the stomach. Histologic examination of gastric biopsies showed a dense and diffuse atypical lymphoid infiltrate in the lamina propria with erosions and focal lymphoepithelial lesions. No lymphoid follicles or Helicobacter microorganisms were identified. Immunohistochemical studies demonstrated the lymphoid infiltrate to consist of mixed T and B cells. Immunoglobulin heavy chain gene arrangement analysis showed a polyclonal pattern. The plasma cells present in the biopsies exhibited no light chain restriction as determined by in situ hybridization. Concurrent clinical work-up revealed peripheral lymphocytosis with atypical lymphocytes and positive serum IgM antibody to EBV capsid antigen in the absence of IgG antibody. These findings indicated that the gastric abnormalities were related to primary EBV infection as the predominant manifestation of infectious mononucleosis. This was further confirmed by subsequent in situ hybridization showing numerous EBV-positive lymphocytes in the gastric mucosa. The patient's symptoms were spontaneously resolved with only supportive treatment. A follow-up endoscopy 2 months later showed completely normal gastric mucosa and he remained well with no gastrointestinal complaints for 2 and a half years. This case illustrates the importance of a high index of suspicion to avoid misdiagnosis of gastric lymphoma that requires more aggressive therapies.

To uncover the mechanisms relating to the anticancer effect of retinoic acids in gastric cancer cells, the mediation of activator protein-1 (AP-1) activity repression by retinoic acid receptors (RARs) was investigated. All-trans retinoic acid (ATRA) inhibited AP-1 activity in BGC-823 cells (RARalpha(+), RARbeta(+)), but not in MKN-45 cells (RARalpha(lo), RARbeta(-)). Transient transfection of RARbeta expression vector into MKN-45 cells significantly resulted in direct repression of AP-1 activity in a receptor concentration-dependent manner, and this could be strengthened by ATRA. Stable transfection of RARbeta into MKN-45 cells directly inhibited cell growth and colony formation, and ATRA also enhanced these effects. Transient transfection of RARalpha into MKN-45 cells however, displayed receptor concentration-dependent AP-1 activity inhibition only in the presence of ATRA. Stable transfection of RARalpha into MKN-45 cells resulted in ATRA-dependent inhibition of cell growth and colony formation. For AP-1 binding activity induced by TPA, the repressive effect of ATRA was only observed in BGC-823 and RARalpha and RARbeta stably transfected MKN-45 cells, but not in intact MKN-45 cells. This indicates the necessity for sufficient cellular RARalpha and/or RARbeta in order for AP-1 activity repression to occur. Deletion of DNA binding domain (DBD) of RARbeta, but not ligand binding domain (LBD), eliminated the anti-AP-1 function of RARbeta. It is therefore concluded that both RARalpha and RARbeta are mediators in the anticancer function of ATRA via AP-1 activity inhibition, and that RARbeta, not RARalpha, can inhibit AP-1 activity to a certain extent directly by itself. Thus DBD, not LBD, is critical for anti-AP-1 activity.

Aim: To investigate the effects of all-trans retinoic acid (ATRA) on metastasis and its related proteins in human gastric cancer cells in vivo and in vitro., Methods: Gastric cancer cells, MGC80-3 and SGC-7901, were inoculated into spleen subcapsule of nude mice, respectively. Nude mice were administered with ATRA (0.7 mg/kg, ig) every other day. Six weeks later, nude mice were sacrificed. All the tumors formed in spleen and in liver were removed. Some of them were fixed, and then embedded. Others were kept in liquid nitrogen for further use. Expression level of proteins in tumor and in cell was analyzed by Western blot. Microvessel in tumor section was shown by immunohistochemistry and adhesive ability of cell to amnion was measured by adhesion assay., Results: When inoculated nude mice were treated with ATRA, the xenograft tumors in spleen and metastatic tumors in liver were suppressed by 50 % respectively, and inhibition of microvessel formation in xenograft and metastatic tumors was also observed obviously. Although ATRA regulated expression of nm23 and mts1/p16 proteins at different patterns in vivo and in vitro, high ratio of nm23:mts1/p16 was in association with low adhesive activity of cells. In addition, ATRA induced ICAM-1 protein expression in vivo and in vitro., Conclusion: ATRA inhibits the growth of xenograft tumors and their metastasis to liver. This process may be associated with regulation of metastatic related proteins, including nm23, mts1/p16, and ICAM-1 in vivo and in vitro.

Aim: To evaluate the role of RARalpha gene in mediating the growth inhibitory effect of all-trans retinoic acid (ATRA) on gastric cancer cells., Methods: The expression levels of retinoic acid receptors (RARs) in gastric cancer cells were detected by Northern blot. Transient transfection and chlorophenicol acetyl transferase (CAT) assay were used to show the transcriptional activity of beta retinoic acid response element (betaRARE) and AP-1 activity. Cell growth inhibition was determined by MTT assay and anchorage-independent growth assay, respectively. Stable transfection was performed by the method of Lipofectamine, and the cells were screened by G418., Results: ATRA could induce expression level of RARalpha in MGC80-3, BGC-823 and SGC-7901 cells obviously, resulting in growth inhibition of these cell lines. After sense RARalpha gene was transfected into MKN-45 cells that expressed rather low level of RARalpha and could not be induced by ATRA, the cell growth was inhibited by ATRA markedly. In contrast, when antisense RARalpha gene was transfected into BGC-823 cells, a little inhibitory effect by ATRA was seen, compared with the parallel BGC-823 cells. In transient transfection assay, ATRA effectively induced transcriptional activity of betaRARE in MGC80-3, BGC-823, SGC-7902 and MKN/RARalpha cell lines, but not in MKN-45 and BGC/aRARalpha cell lines. Similar results were observed in measuring-antiAP-1 activity by ATRA in these cancer cell lines., Conclusion: ATRA inhibits the growth of gastric cancer cells by up-regulating the level of RARalpha RARalpha is the major mediator of ATRA action in gastric cancer cells; and adequate level of RARalpha is required for ATRA effect on gastric cancer cells.

Retinoic acid can induce growth inhibition and apoptosis, and regulate cell cycle in many types of cancer cell lines. In this study, we investigated the role of all-trans retinoic acid (ATRA) and its mechanism of action in human gastric cancer cell lines. Our results demonstrated that ATRA effectively inhibited growth in three of four gastric cancer cell lines by induction of G0/G1 arrest, and did not induce apoptosis in four gastric cancer cell lines. In RA-sensitive cell lines, ATRA-induced G0/G1 arrest is associated with down regulaton of c-myc and hyperphosphorylated Rb expression, and up regulation of p21WAF1/CIP1 and p53 expression. There were no significant changes in cyclin D1 or CDK4 expression induced by ATRA. Futhermore, expression of these genes were not regulated by ATRA in ATRA-resistant gastric cancer cell line. These results indicate that growth inhibition, rather than apoptosis, is correlated with G0/G1 arrest of these cell lines, more important molecules related cell cycle, including c-myc, p21WAF1/CIP1, p53 and Rb, are involveed in regulation of cell cycle in gastric cancer cells.