ABSTRACT
Colorectal cancer (CRC) ranks as the third most prevalent cancer globally and stands as the second principal contributor to cancer-related fatalities. Recently, emerging research has emphasized the role of pan apoptosis (PANoptosis) in tumor development and anti-tumor therapy. In the course of this investigation, we meticulously identified and conducted a correlation analysis between differentially expressed genes associated with PANoptosis in CRC (CPAN_DEGs) and the proportion of immune cells. Subsequently, we formulated a prognostic score based on the CPAN_DEGs. Further our analysis revealed a noteworthy reduction in UNC5D mRNA expression within HCT116, HT29 and SW480 cells, as validated by qRT-PCR assay. Furthermore, scrutinizing the TCGA database unveiled a distinctive trend wherein individuals with the low UNC5D expression exhibited significantly reduced overall survival compared to their counterparts with the high UNC5D levels. The drug susceptibility analysis of UNC5D was further performed, which showed that UNC5D was corassociated with the sensitivity of CRC to 6-Thioguanine. The outcomes of our investigation underscore the mechanisms by which PANoptosis influences immune dysregulation as well as prognostic outcome in CRC.
Subject(s)
Colorectal Neoplasms , Computational Biology , Gene Expression Regulation, Neoplastic , Humans , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Computational Biology/methods , Prognosis , Apoptosis/genetics , Cell Line, Tumor , Gene Expression Profiling , HCT116 CellsABSTRACT
BACKGROUND: The relationships between urinary polycyclic aromatic hydrocarbon (PAH) metabolites and hyperlipidemia have not been thoroughly studied. The primary goal of this research focused on investigating the linkage between PAH metabolite concentrations in urine and hyperlipidemia prevalence within US adults. METHODS: A cross-sectional analysis was conducted using data from the 2007-2016 National Health and Nutrition Examination Survey (NHANES). Logistic regression models were used to assess correlations between urinary PAH metabolite levels and the risk of hyperlipidemia, while restricted cubic spline models were used to examine doseâresponse relationships. Subgroup and interaction analyses were performed to further elucidate these associations. Weighted quantile sum (WQS) regression analyzed the cumulative impact of various urinary PAH metabolites on hyperlipidemia risk. RESULTS: This study included 7,030 participants. Notably, individuals in the highest quintile of urinary PAH metabolite concentrations exhibited a significantly elevated prevalence of hyperlipidemia, even after comprehensive adjustments (odds ratio [OR]: 1.33, 95% confidence interval [CI]: 1.01-1.75). Moreover, elevated levels of 1-hydroxyphenanthrene and 2-hydroxynaphthalene in the fourth quintile and 2-hydroxyfluorene in the third, fourth, and fifth quintiles demonstrated positive correlations with the prevalence of hyperlipidemia. These associations persisted across subgroup analyses. Additionally, a positive correlation between the urinary PAH metabolite mixture and hyperlipidemia (positive model: OR = 1.04, 95% CI: 1.00-1.09) was observed in the WQS model, and 2-hydroxynaphthalene showed the most substantial contribution. CONCLUSION: The cross-sectional analysis identified a significant correlation between urinary PAH metabolite and hyperlipidemia prevalence within the US demographic, with 2-hydroxynaphthalene being the predominant influencer. These findings underscore the need to mitigate PAH exposure as a preventive measure for hyperlipidemia.
Subject(s)
Hyperlipidemias , Nutrition Surveys , Polycyclic Aromatic Hydrocarbons , Humans , Hyperlipidemias/urine , Hyperlipidemias/epidemiology , Male , Female , Polycyclic Aromatic Hydrocarbons/urine , Middle Aged , Adult , Cross-Sectional Studies , Prevalence , Logistic Models , Odds Ratio , AgedABSTRACT
DC1 (Divergent C1) domain proteins are a new class of proteins that have been discovered in recent years, which play an important role in plant growth, development, and stress response. In order to better study the distribution and function of DC1 domain proteins in tomatoes, a genome-wide identification was conducted. It was found that there are twenty-one DC1 domain protein genes distributed on nine chromosomes of tomatoes, named SlCHP1-21. Phylogenetic analysis shows that twenty-one SlCHP genes are divided into six subfamilies. Most of the SlCHP genes in tomatoes have no or very short introns. All SlCHP proteins, with the exception of SlCHP8 and SlCHP17, contain variable amounts of C1 domain. Analysis of the SlCHP gene promoter sequence revealed multiple cis-elements responsive to plant stress. qRT-CR analysis showed that most members of SlCHP gene expressed in the roots. The SlCHP11, 13, 16, 17, and SlCHP20 genes showed specific responses to high temperature, low temperature, salt, and drought stress. In addition, the subcellular localization and interaction proteins of SlCHP were analyzed and predicted. Together, these results provides a theoretical basis for further exploration of the function and mechanism of the SlCHP gene in tomatoes.
Subject(s)
Solanum lycopersicum , Solanum lycopersicum/genetics , Plant Proteins/genetics , Plant Proteins/metabolism , Phylogeny , Stress, Physiological/genetics , Transcription Factors/metabolism , Gene Expression Regulation, Plant , Multigene FamilyABSTRACT
Cytokines are important components of the immune system that can predict or influence the development of liver diseases. IL-37, a new member of the IL-1 cytokine family, exerts potent anti-inflammatory and immunosuppressive effects inside and outside cells. IL-37 expression differs before and after liver lesions, suggesting that it is associated with liver disease; however, its mechanism of action remains unclear. This article mainly reviews the biological characteristics of IL-37, which inhibits hepatitis, liver injury, and liver fibrosis by inhibiting inflammation, and inhibits the development of hepatocellular carcinoma (HCC) by regulating the immune microenvironment. Based on additional evidence, combining IL-37 with liver disease markers for diagnosis and treatment can achieve more significant effects, suggesting that IL-37 can be developed into a powerful tool for the clinical adjuvant treatment of liver diseases, especially HCC.
Subject(s)
Carcinoma, Hepatocellular , Hepatitis , Liver Neoplasms , Humans , Carcinoma, Hepatocellular/pathology , Liver Neoplasms/pathology , Cytokines , Tumor MicroenvironmentABSTRACT
Photothermal therapy (PTT) is an extremely promising tumor therapeutic modality. However, excessive heat inevitably injures normal tissues near tumors, and the damage to cancer cells caused by mild hyperthermia is easily repaired by stress-induced heat shock proteins (HSPs). Thus, maximizing the PTT efficiency and minimizing the damage to healthy tissues simultaneously by adopting appropriate therapeutic temperatures is imperative. Herein, an innovative strategy is reported: ferroptosis-boosted mild PTT based on a single-atom nanozyme (SAzyme). The Pd SAzyme with atom-economical utilization of catalytic centers exhibits peroxidase (POD) and glutathione oxidase (GSHOx) mimicking activities, and photothermal conversion performance, which can result in ferroptosis featuring the up-regulation of lipid peroxides (LPO) and reactive oxygen species (ROS). The accumulation of LPO and ROS provides a powerful approach for cleaving HSPs, which enables Pd SAzyme-mediated mild-temperature PTT.
Subject(s)
Nanoparticles/chemistry , Palladium/chemistry , Photothermal Therapy , Temperature , Animals , Catalysis , Cell Line, Tumor , Cell Survival/drug effects , Dose-Response Relationship, Drug , Ferroptosis , Lipid Peroxides/metabolism , Mice , Oxidoreductases/chemistry , Oxidoreductases/metabolism , Palladium/metabolism , Palladium/pharmacology , Particle Size , Reactive Oxygen Species/metabolismABSTRACT
This study aims to explore the role of Gastrokin-2 (GKN2) in gastric cancer and its function in the progression and metastasis of gastric cancer. The expression of GKN2 in the patient samples was examined by qRT-PCR and western blot. The transcription factor NK6 Homeobox 2 (NKX6-2), which binds to the GKN2 promoter, was predicted by cBioportal and JSPAR. Binding between NKX6-2 and the GKN2 promoter was analyzed by dual-luciferase assay. MTT assay and transwell assay were used to detect changes in gastric cancer cell viability and migration after GKN2 overexpression, which was achieved by transfection of GKN2 overexpression vector. Akt signaling pathway markers were assessed by western blot. GKN2 is downregulated in gastric cancer and low GKN2 expression is correlated to poor survival, metastasis, and higher clinical stages. NKX6-2 binds the promoter region of GKN2 and regulate its expression. GKN2 overexpression inhibits the proliferation, migration, and invasion of gastric cancer cells, which was mediated by Akt signaling pathway. NKX6-2 regulated GKN2 inhibits the proliferation and invasion of gastric cancer cells by inhibiting Akt signaling pathway. GKN2 can be used as a potential diagnostic and therapeutic target for patients with clinical gastric cancer.
Subject(s)
Carrier Proteins/metabolism , Homeodomain Proteins/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Stomach Neoplasms/metabolism , Apoptosis , Cell Line, Tumor , Cell Movement , Cell Proliferation , Cell Survival , Computational Biology , Gene Expression Regulation, Neoplastic , Genes, Homeobox , HEK293 Cells , Humans , Neoplasm Invasiveness , Neoplasm Metastasis , Promoter Regions, Genetic , Signal TransductionABSTRACT
Endoscopic ultrasound-guided minimally invasive tissue acquisition can be performed by two approaches as follows: Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) and endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB). These have been evolved into leading approaches and widely used for the histological diagnosis of tumors in the gastrointestinal tract and adjacent organs. However, the role of EUS-FNA and EUS-FNB in disease diagnosis and evaluation remains controversial. Although the incidence of surgery-associated complications remains low, the consequences of needle tract seeding can be serious or even life-threatening. Recently, increasing case reports of needle tract seeding are emerging, especially caused by EUS-FNA. This complication needs serious consideration. In the present work, we integrated these case reports and the related literature, and summarized the relevant cases and technical characteristics of needle tract seeding caused by EUS-FNA and EUS-FNB. Collectively, our findings provided valuable insights into the prevention and reduction of such serious complication.
Subject(s)
Endoscopic Ultrasound-Guided Fine Needle Aspiration , Endosonography , Endoscopic Ultrasound-Guided Fine Needle Aspiration/adverse effects , Humans , Image-Guided Biopsy , NeedlesABSTRACT
BACKGROUND/AIMS: Approximately 20-30% of small bowel capsule endoscopies (SBCEs) do not reach the cecum at the completion of the examination. We aimed to determine whether hypokalemia influences the completion rate and small bowel transit time (SBTT) of SBCE. PATIENTS AND METHODS: From January to December 2017, 112 patients (18-75 years old) who underwent SBCE were assessed consecutively for enrolment in our study. On the day of the procedure, a blood test was performed prior to capsule ingestion. The completion rate, gastric transit time (GTT), SBTT, and diagnostic yield were recorded for each SBCE. RESULTS: The SBCE completion rate was lower in the hypokalemia group than that in the normal potassium group (55.6% (15/27) vs. 76.5% (65/85), P = 0.036). The median GTT was 55.5 ± 47.1 min in the hypokalemia group and 46.7 ± 44.5 min in the normal potassium group (P > 0.05). The median SBTT was 412.8 ± 123.3 min in the hypokalemia group and 367.3 ± 172.5 min in the normal potassium group (P > 0.05). The diagnostic yields of the hypokalemia and normal potassium groups were 74.1% and 78.8%, respectively (P = 1.00). CONCLUSION: Hypokalemia may decrease the SBCE completion rate. Physicians should consider the possibility of hypokalemia after bowel preparation because this condition is not rare. Potassium deficiencies should be rectified prior to performing SBCE procedures to increase the SBCE completion rate.
Subject(s)
Capsule Endoscopy/methods , Gastrointestinal Transit/physiology , Hypokalemia/complications , Intestine, Small/diagnostic imaging , Potassium Deficiency/therapy , Potassium/blood , Adolescent , Adult , Aged , Cathartics/standards , China/epidemiology , Female , Humans , Hypokalemia/diagnosis , Intestine, Small/physiopathology , Male , Middle Aged , Potassium Deficiency/epidemiology , Potassium Deficiency/prevention & control , Prospective StudiesABSTRACT
Bismuth + proton pump inhibitor (PPI) + amoxicillin + levofloxacin is one of the bismuth quadruple therapy regimens widely used for the eradication of H. pylori infection. The recommended dosage of levofloxacin is 500 mg once daily or 200 mg twice daily to eradicate H. pylori infection. The aim of the present open-label, randomized control trial was to compare the effectiveness, safety, and compliance of different dosages of levofloxacin used to cure Helicobacter pylori infection. Eligible patients were randomly assigned to receive esomeprazole, amoxicillin, colloidal bismuth pectin and levofloxacin 500 mg once/day (group A) or levofloxacin 200 mg twice/day (group B) for 14 days. The primary outcome was the eradication rates in the intention-to-treat (ITT) and per protocol (PP) analyses. Overall, 400 patients were enrolled. The eradication rates in group A and group B were 77.5% and 79.5% respectively, in the ITT analysis, and 82.9% and 86.4%, respectively, in the PP analysis. No significant differences were found between two groups in terms of eradication rate, adverse effects or compliance. Oral levofloxacin 200 mg twice daily was similar in efficacy for eradicating H. pylori infection to oral levofloxacin 500 mg once daily but with lower mean total costs.
Subject(s)
Anti-Ulcer Agents/therapeutic use , Helicobacter Infections/drug therapy , Helicobacter pylori/drug effects , Levofloxacin/therapeutic use , Adult , Amoxicillin/adverse effects , Amoxicillin/therapeutic use , Anti-Bacterial Agents/adverse effects , Bismuth/adverse effects , Bismuth/therapeutic use , Diarrhea/chemically induced , Dose-Response Relationship, Drug , Drug Administration Schedule , Drug Therapy, Combination/adverse effects , Esomeprazole/adverse effects , Esomeprazole/therapeutic use , Exanthema/chemically induced , Female , Helicobacter Infections/microbiology , Helicobacter pylori/physiology , Humans , Levofloxacin/adverse effects , Male , Middle Aged , Prospective Studies , Treatment OutcomeABSTRACT
Helicobacter pylori encoded CagA is presently the only known virulence factor that is injected into gastric epithelial cells where it destroys apical junctional complexes and induces dedifferentiation of gastric epithelial cells, leading to H. pylori-related gastric carcinogensis. However, little is known about the molecular mechanisms by which CagA mediates these changes. Caudal-related homeobox 2 (Cdx2) is an intestine-specific transcription factor highly expressed in multistage tissues of dysplasia and cancer. One specific target of Cdx2, Claudin-2, is involved in the regulation of tight junction (TJ) permeability. In this study, our findings showed that the activity of Cdx2 binding to Cdx binding sites of CdxA (GTTTATG) and CdxB (TTTTAGG) of probes corresponding to claudin-2 flanking region increased in AGS cells, infected with CagA positive wild-type strain of H. pylori, compared to CagA negative isogenic mutant-type strain. Moreover, Cdx2 upregulated claudin-2 expression at transcriptional level and translational level. In the meantime, we found that TJs of AGS cells, infected with CagA positive wild-type strain of H. pylori, compared to CagA negative isogenic mutant-type strain, were more severely destroyed, leading to wider cell gap, interference of contact, scattering and highly elevated migration of cells. Herein, this study is firstly demonstrated that H. pylori-encoded CagA disrupts TJs and induces invasiveness of AGS gastric carcinoma cells via Cdx2-dependent targeting of Claudin-2. This provides a new mechanism whereby CagA induced dedifferentiation of AGS cells, leading to malignant behavior of biology.
Subject(s)
Adenocarcinoma/microbiology , Antigens, Bacterial/genetics , Bacterial Proteins/genetics , Claudin-2/genetics , Helicobacter pylori/genetics , Homeodomain Proteins/genetics , Stomach Neoplasms/microbiology , Tight Junctions/microbiology , Adenocarcinoma/genetics , Adenocarcinoma/metabolism , Adenocarcinoma/pathology , Antigens, Bacterial/metabolism , Bacterial Proteins/metabolism , Binding Sites , CDX2 Transcription Factor , Cell Dedifferentiation , Cell Line, Tumor , Claudin-2/metabolism , Epithelial Cells/metabolism , Epithelial Cells/microbiology , Epithelial Cells/pathology , Gene Expression Regulation , Helicobacter pylori/growth & development , Helicobacter pylori/pathogenicity , Homeodomain Proteins/metabolism , Host-Pathogen Interactions , Humans , Neoplasm Invasiveness , Protein Binding , Signal Transduction , Stomach Neoplasms/genetics , Stomach Neoplasms/metabolism , Stomach Neoplasms/pathology , Tight Junctions/metabolism , Tight Junctions/pathologyABSTRACT
Trefoil factor 1 (TFF1) is a small cysteine-rich secreted protein which is principally expressed in the superficial cells of gastric mucosa. In gastric cancer, TFF1 is downregulated and plays an important role. Gastrokine 1 (GKN1) is a secreted protein with similar expression and biological functions to TFF1. This study aimed to determine the expression and biological functions of TFF1 and the relationships between TFF1 and GKN1 in gastric cancer. RT-PCR and immunohistochemistry were performed to detect TFF1 expression in gastric cancer cell lines and tissues. The transfected and co-transfected AGS cells which stably expressed TFF1 or both TFF1 and GKN1 were generated. Phenotypic changes such as cell viability, apoptosis and cell cycle modulation were assayed in the transfected cells. We found that TFF1 expression was significantly downregulated or lost in gastric cancer cell lines, gastric dysplasia and cancer. Restoration of TFF1 expression in AGS cells suppressed tumor cell viability and arrested AGS cells in the G1-S transition phase after olomoucine treatment. However, TFF1 was unable to induce cell apoptosis. In co-transfected cells, we found that TFF1 and GKN1 did not directly interact at the protein level. GKN1 was unable to cooperate with TFF1 on cell viability suppression, cell apoptosis and differentiation. Together, these results indicate that TFF1 expression is significantly downregulated in gastric cancer. TFF1 inhibited cell proliferation by delaying G1-S phase transition but not by inducing apoptosis. TFF1 may not interact or cooperate with GKN1 at the protein and functional level.
Subject(s)
Peptide Hormones/metabolism , Stomach Neoplasms/genetics , Stomach Neoplasms/metabolism , Tumor Suppressor Proteins/metabolism , Adult , Aged , Apoptosis/genetics , Case-Control Studies , Cell Cycle/genetics , Cell Line, Tumor , Cell Proliferation , Female , Gastric Mucosa/metabolism , Humans , Immunoprecipitation , Male , Middle Aged , Peptide Hormones/genetics , Stomach Neoplasms/pathology , Trefoil Factor-1 , Tumor Suppressor Proteins/geneticsABSTRACT
BACKGROUND/AIMS: Gastrokine-1 is a novel protein that plays an important role in the maintenance of the integrity of the gastric mucosa. However, whether Helicobacter pylori infection and non-steroidal anti-inflammatory drugs, which are known to cause gastric mucosal injuries, affect gastrokine-1 expression in the gastric mucosa is unknown. The aim of the present study was to determine gastric mucosal expression of gastrokine-1 in patients with Helicobacter pylori infection or long-term non-steroidal anti-inflammatory drug administration. MATERIAL AND METHODS: A total of 40 patients with functional dyspepsia (20 with Helicobacter pylori-negative chronic gastritis, and 20 with Helicobacter pylori-positive chronic gastritis), and 37 Helicobacter pylori-negative long-term non-steroidal anti-inflammatory drug users (26 with aspirin, 11 with selective cyclooxygenase-2 inhibitors) were selected. In addition, 20 Helicobacter pylori-negative healthy volunteers were recruited as controls. All subjects underwent endoscopies with biopsies taken from the antrum and the sites with lesions. Gastric mucosal changes were detected endoscopically and histologically, and gastrokine-1 protein expression in the antral mucosa was analyzed by immunohistochemistry. RESULTS: Expression of gastrokine-1 protein was decreased in Helicobacter pylori-positive chronic gastritis compared with Helicobacter pylori-negative subjects and the healthy controls. Similarly, gastrokine-1 expression in non-steroidal anti-inflammatory drug users was also decreased, compared with the healthy controls, but there was no significant difference in gastrokine-1 expression between the aspirin group and selective cyclooxygenase-2 inhibitor group. Moreover, gastrokine-1 expression levels tended to be associated with the severity of chronic gastritis. CONCLUSIONS: Both Helicobacter pylori infection and long-term non-steroidal anti-inflammatory drug administration downregulate gastrokine-1 expression in the gastric mucosa, which may contribute to the gastric mucosal injuries induced by these two factors.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Gastric Mucosa/drug effects , Gastritis/metabolism , Helicobacter Infections/metabolism , Helicobacter pylori , Peptide Hormones/metabolism , Aspirin/administration & dosage , Case-Control Studies , Cyclooxygenase 2 Inhibitors/administration & dosage , Down-Regulation , Dyspepsia/metabolism , Dyspepsia/microbiology , Gastric Mucosa/metabolism , Gastritis/microbiology , Gene Expression Regulation , Helicobacter Infections/microbiology , Humans , Immunohistochemistry , Peptide Hormones/geneticsABSTRACT
BACKGROUND: Gastrokine-1 (GKN1), a secreted protein, is specifically expressed in gastric mucosa to protect and maintain the integrity of gastric epithelium. The present study investigated differential expression of GKN1 in normal, precancerous, and cancerous gastric tissues, and explored the biological functions of GKN1 protein in gastric cancer cells. METHODS: RT-PCR, Western blot, and immunohistochemistry were performed to detect GKN1 expression in normal, precancerous, cancerous gastric tissues and seven gastric cancer cell lines. Gene transfection was used to restore GKN1 expression in gastric cancer AGS cells. Phenotypic changes (i.e., cell viability, apoptosis, cell cycle modulation, and sensitivity of gastric cancer cells to fluorouracil (5-FU)) were assayed in the transfected cells. DNA microarrays were used to analyze expression changes of apoptosis-related genes. RESULTS: Significant downregulation or absence of GKN1 expression in seven gastric cancer cell lines were detected and progressive decrease of GKN1 expression from normal mucosa, precancerous tissue, to cancer tissues was observed. Moreover, restoration of GKN1 expression suppressed gastric cancer cell viability and induced the cells to undergo apoptosis. GKN1 expression also enhanced tumor cell sensitivity to 5-FU treatment. Moreover, it was found that GKN1 expression in AGS cells modulated expression of 19 apoptosis-related genes. CONCLUSIONS: Expression of GKN1 is progressively lost from normal mucosa, precancerous to cancerous gastric tissues, while restoration of GKN1 expression induces gastric cancer cells to undergo apoptosis, and enhances sensitivity of gastric cancer cells to 5-FU-induced apoptosis.
Subject(s)
Gene Expression Regulation, Neoplastic , Peptide Hormones , Stomach Neoplasms , Adult , Aged , Apoptosis/drug effects , Cell Line, Tumor , Cell Survival , Epithelium/metabolism , Female , Fluorouracil/pharmacology , Gastric Mucosa/metabolism , Humans , Male , Middle Aged , Neoplasm Staging , Peptide Hormones/genetics , Peptide Hormones/metabolism , Stomach Neoplasms/genetics , Stomach Neoplasms/metabolism , Stomach Neoplasms/pathologyABSTRACT
BACKGROUND: Abberant aryl hydrocarbon receptor (AhR) expression and AhR pathway activation are involved in gastric carcinogenesis. However, the relationship between AhR pathway activation and gastric cancer progression is still unclear. In present study, we used 2,3,7,8-tetrachlorodibenzo-para-dioxin (TCDD), a classic and most potent ligand of AhR, to activate AhR pathway and investigated the effect of AhR pathway activation on human gastric cancer AGS cell invasion and explored the corresponding mechanism. RESULTS: To determine whether AhR pathway can be activated in AGS cells, we examined the expression of CYP1A1, a classic target gene of AhR pathway, following TCDD exposure. RT-PCR and western blot analysis showed that both CYP1A1 mRNA and protein expression were increased in a dose-dependent manner following TCDD treatment and AhR antagonist resveratrol (RSV) could reverse this TCDD-induced CYP1A1 expression. To determine whether TCDD treatment of AGS cells results in an induction of MMP-9 expression, we detected MMP-9 mRNA using RT-PCR and detected MMP-9 enzymatic activity using gelatin zymography. The results showed that both MMP-9 mRNA expression and enzymatic activity were gradually increased with the concentration increase of TCDD in media and these changes could be reversed by RSV treatment in a dose-dependent manner. To examine whether AhR activation-induced MMP-9 expression and activity in AGS cells results in increased migration and invasion, we performed wound healing migration assay and transwell migration and invasion assay. After TCDD treatment, the migration distance and the migration and invasion abilities of AGS cells were increased with a dose-dependent manner. To demonstrate AhR activation-induced MMP-9 expression is mediated by c-Jun, siRNA transfection was performed to silence c-Jun mRNA in AGS cells. The results showed that MMP-9 mRNA expression and activity in untreated control AGS cells were very weak; After TCDD (10 nmol/L) treatment, MMP-9 mRNA expression and activity were significant increased; This TCDD-induced MMP-9 expression and activity increase could be abolished by c-Jun siRNA transfection. CONCLUSION: AhR pathway activation enhances gastric cancer cell invasiveness likely through a c-Jun-dependent induction of MMP-9. Our results provide insight into the mechanism and function of the AhR pathway and its impact on gastric cancer progression.
Subject(s)
Matrix Metalloproteinase 9/metabolism , Proto-Oncogene Proteins c-jun/metabolism , Receptors, Aryl Hydrocarbon/physiology , Signal Transduction/physiology , Blotting, Western , Cell Line, Tumor , Cell Movement/drug effects , Cytochrome P-450 CYP1A1/genetics , Cytochrome P-450 CYP1A1/metabolism , Dose-Response Relationship, Drug , Gene Expression Regulation, Neoplastic/drug effects , Humans , Matrix Metalloproteinase 9/genetics , Neoplasm Invasiveness , Polychlorinated Dibenzodioxins/pharmacology , Proto-Oncogene Proteins c-jun/genetics , RNA, Small Interfering/genetics , Receptors, Aryl Hydrocarbon/agonists , Receptors, Aryl Hydrocarbon/antagonists & inhibitors , Resveratrol , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction/drug effects , Stilbenes/pharmacology , Stomach Neoplasms/genetics , Stomach Neoplasms/metabolism , Stomach Neoplasms/pathology , TransfectionABSTRACT
AIM: To determine the functional significance of aryl hydrocarbon receptor (AhR) in gastric carcinogenesis, and to explore the possible role of AhR in gastric cancer (GC) treatment. METHODS: RT-PCR, real-time PCR, and Western blotting were performed to detect AhR expression in 39 GC tissues and five GC cell lines. AhR protein was detected by immunohistochemistry (IHC) in 190 samples: 30 chronic superficial gastritis (CSG), 30 chronic atrophic gastritis (CAG), 30 intestinal metaplasia (IM), 30 atypical hyperplasia (AH), and 70 GC. The AhR agonist tetrachlorodibenzo-para-dioxin (TCDD) was used to treat AGS cells. MTT assay and flow cytometric analysis were performed to measure the viability, cell cycle and apoptosis of AGS cells. RESULTS: AhR expression was significantly increased in GC tissues and GC cell lines. IHC results indicated that the levels of AhR expression gradually increased, with the lowest levels in CSG, followed by CAG, IM, AH and GC. AhR expression and nuclear translocation were significantly higher in GC than in precancerous tissues. TCDD inhibited proliferation of AGS cells via induction of growth arrest at the G1-S phase. CONCLUSION: AhR plays an important role in gastric carcinogenesis. AhR may be a potential therapeutic target for GC treatment.