Background:As a major histopathological subtype of gastric cancer(GC),stomach adenocarcinoma(STAD)is an important malignant tumor in the digestive system.Increasing evidence also indicates that endoplasmic reticulum(E...Background:As a major histopathological subtype of gastric cancer(GC),stomach adenocarcinoma(STAD)is an important malignant tumor in the digestive system.Increasing evidence also indicates that endoplasmic reticulum(ER)stress plays a pivotal role in the pathogenesis and progression of GC.Therefore,this study aims to screen and identify vital ER stress-related genes that could contribute to the malignant development and poor prognosis for STAD.Methods:A novel ER stress-related risk score signature was developed employingmachine learning techniques.Then,a prognostic prediction nomogram was also built based on the clinicopathological characteristics and the risk score signature.The tumor immune microenvironment characteristics and pathway enrichment analysis in different risk groups were also explored.Furthermore,through the single-cell RNA sequencing(scRNA-seq)analysis,the study highlightedCytochrome P450 Family 19 SubfamilyAMember 1(CYP19A1)as the pivotal research target and detected its effect on cell proliferation by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazoliumbromide(MTT)and the expression of ER stress-related genes by RT-qPCR in STAD.Results:Based on the evaluation of five screened key ER stressrelated genes(AKR1B1,SERPINE1,ADCYAP1,MATN3,CYP19A1),our ER stress-related risk score signature offers a novel approach for assessing STAD prognosis hazards.The novel prognostic prediction nomogram based on the signature also accurately predicted the survival outcomes of patients with STAD.Furthermore,the expression of CYP19A1 is significantly higher in STAD tissues than in normal tissues.High expression of CYP19A1 was related to a poor survival outcome for patients with STAD.Besides,compared to normal gastric epithelial cells,the expression of CYP19A1 was significantly higher in STAD cell lines.Silencing the expression of CYP19A1 significantly inhibited the cell proliferation ability and decreased the expression of ER stress-related genes,including ATF4,DDIT3 and XBP1 in STAD.Conclusions:In conclusion,our study developed a novel prognosis prediction signature and identified the novel diagnostic and therapeutic target CYP19A1 for patients with STAD.展开更多
Myocardial fibrosis is a major pathogenic factor contributing to cardiac remodeling and heart failure. Recent research has indicated that micro RNAs play a crucial role in the progression of cardiac fibrosis. Bone mor...Myocardial fibrosis is a major pathogenic factor contributing to cardiac remodeling and heart failure. Recent research has indicated that micro RNAs play a crucial role in the progression of cardiac fibrosis. Bone morphogenetic protein and activin membrane-bound inhibitor(BAMBI) have been shown to alleviate myocardial fibrosis by inhibiting the transforming growth factor β1(TGF-β1) signaling pathway. Therefore, the current study aimed to elucidate the post-transcriptional regulation of BAMBI by miR-19a-3p and its role in TGF-β1-induced cardiac fibroblast activation. We found that transverse aortic constriction induced both myocardial interstitial and perivascular collagen deposition. Quantitative reverse transcription-PCR(q RT-PCR) analysis showed that the expression level of miR-19a-3p was increased in the myocardial tissues of cardiac fibrosis, and TGF-β1 induced an upregulation in miR-19a-3p expression in cardiac fibroblasts. The dual-luciferase reporter assay and q RT-PCR verified that miR-19a-3p directly bound to the 3 ′ untranslated regions of BAMBI m RNA, thereby reducing BAMBI expression and diminishing its ability to inhibit the TGF-β1 signaling pathway. Furthermore,overexpression of miR-19a-3p mimic increased the activation of TGF-β1/SMAD2/3 pathway signaling,promoting cardiac fibroblast activation. However, this activation was blocked by BAMBI overexpression. These findings imply that miR-19a-3p enhances the activation of TGF-β1/SMAD2/3 by inhibiting BAMBI, further boosting the activation of cardiac fibroblasts and contributing to myocardial fibrosis.展开更多
基金Natural Science Foundation of Liaoning Province(2022-MS-083)Application Basic Research Plan of Liaoning Province(2023JH2/101300084).
文摘Background:As a major histopathological subtype of gastric cancer(GC),stomach adenocarcinoma(STAD)is an important malignant tumor in the digestive system.Increasing evidence also indicates that endoplasmic reticulum(ER)stress plays a pivotal role in the pathogenesis and progression of GC.Therefore,this study aims to screen and identify vital ER stress-related genes that could contribute to the malignant development and poor prognosis for STAD.Methods:A novel ER stress-related risk score signature was developed employingmachine learning techniques.Then,a prognostic prediction nomogram was also built based on the clinicopathological characteristics and the risk score signature.The tumor immune microenvironment characteristics and pathway enrichment analysis in different risk groups were also explored.Furthermore,through the single-cell RNA sequencing(scRNA-seq)analysis,the study highlightedCytochrome P450 Family 19 SubfamilyAMember 1(CYP19A1)as the pivotal research target and detected its effect on cell proliferation by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazoliumbromide(MTT)and the expression of ER stress-related genes by RT-qPCR in STAD.Results:Based on the evaluation of five screened key ER stressrelated genes(AKR1B1,SERPINE1,ADCYAP1,MATN3,CYP19A1),our ER stress-related risk score signature offers a novel approach for assessing STAD prognosis hazards.The novel prognostic prediction nomogram based on the signature also accurately predicted the survival outcomes of patients with STAD.Furthermore,the expression of CYP19A1 is significantly higher in STAD tissues than in normal tissues.High expression of CYP19A1 was related to a poor survival outcome for patients with STAD.Besides,compared to normal gastric epithelial cells,the expression of CYP19A1 was significantly higher in STAD cell lines.Silencing the expression of CYP19A1 significantly inhibited the cell proliferation ability and decreased the expression of ER stress-related genes,including ATF4,DDIT3 and XBP1 in STAD.Conclusions:In conclusion,our study developed a novel prognosis prediction signature and identified the novel diagnostic and therapeutic target CYP19A1 for patients with STAD.
基金National Natural Science Foundation of China (Grant Nos. 82070234 and 82100254)。
文摘Myocardial fibrosis is a major pathogenic factor contributing to cardiac remodeling and heart failure. Recent research has indicated that micro RNAs play a crucial role in the progression of cardiac fibrosis. Bone morphogenetic protein and activin membrane-bound inhibitor(BAMBI) have been shown to alleviate myocardial fibrosis by inhibiting the transforming growth factor β1(TGF-β1) signaling pathway. Therefore, the current study aimed to elucidate the post-transcriptional regulation of BAMBI by miR-19a-3p and its role in TGF-β1-induced cardiac fibroblast activation. We found that transverse aortic constriction induced both myocardial interstitial and perivascular collagen deposition. Quantitative reverse transcription-PCR(q RT-PCR) analysis showed that the expression level of miR-19a-3p was increased in the myocardial tissues of cardiac fibrosis, and TGF-β1 induced an upregulation in miR-19a-3p expression in cardiac fibroblasts. The dual-luciferase reporter assay and q RT-PCR verified that miR-19a-3p directly bound to the 3 ′ untranslated regions of BAMBI m RNA, thereby reducing BAMBI expression and diminishing its ability to inhibit the TGF-β1 signaling pathway. Furthermore,overexpression of miR-19a-3p mimic increased the activation of TGF-β1/SMAD2/3 pathway signaling,promoting cardiac fibroblast activation. However, this activation was blocked by BAMBI overexpression. These findings imply that miR-19a-3p enhances the activation of TGF-β1/SMAD2/3 by inhibiting BAMBI, further boosting the activation of cardiac fibroblasts and contributing to myocardial fibrosis.
