Objective: Growing evidence indicates that FAT atypical cadherin 1(FAT1) has aberrant genetic alterations and exhibits potential tumor suppressive function in esophageal squamous cell carcinoma(ESCC). However, the rol...Objective: Growing evidence indicates that FAT atypical cadherin 1(FAT1) has aberrant genetic alterations and exhibits potential tumor suppressive function in esophageal squamous cell carcinoma(ESCC). However, the role of FAT1 in ESCC tumorigenesis remains not well elucidated. The aim of this study was to further investigate genetic alterations and biological functions of FAT1, as well as to explore its transcriptional regulation and downstream targets in ESCC.Methods: The mutations of FAT1 in ESCC were achieved by analyzing a combined study from seven published genomic data, while the copy number variants of FAT1 were obtained from an analysis of our previous data as well as of The Cancer Genome Atlas(TCGA) and Cancer Cell Line Encyclopedia(CCLE) databases using the cBioPortal. The transcriptional regulation of FAT1 expression was investigated by chromatin immunoprecipitation(ChIP) and the luciferase reporter assays. In-cell western, Western blot and reverse transcription-quantitative polymerase chain reaction(RT-qPCR) were used to assess the indicated gene expression. In addition, colony formation and Transwell migration/invasion assays were employed to test cell proliferation, migration and invasion.Finally, RNA sequencing was used to study the transcriptomes.Results: FAT1 was frequently mutated in ESCC and was deleted in multiple cancers. Furthermore, the transcription factor E2 F1 occupied the promoter region of FAT1, and depletion of E2 F1 led to a decrease in transcription activity and mRNA levels of FAT1. Moreover, we found that knockdown of FAT1 promoted KYSE30 and KYSE150 cell proliferation, migration and invasion;while overexpression of FAT1 inhibited KYSE30 and KYSE410 cell proliferation, migration and invasion. In addition, knockdown of FAT1 led to enrichment of the mitogen-activated protein kinase(MAPK) signaling pathway and cell adhesion process.Conclusions: Our data provided evidence for the tumor suppressive function of FAT1 in ESCC cells and elucidated the transcriptional regulation of FAT1 by E展开更多
Through bioinformatics predictions,we identified that GTF2I and FAT1 were downregulated in thyroid carcinoma(TC).Further,Pearson’s correlation coefficient revealed a positive correlation between GTF2I expression and ...Through bioinformatics predictions,we identified that GTF2I and FAT1 were downregulated in thyroid carcinoma(TC).Further,Pearson’s correlation coefficient revealed a positive correlation between GTF2I expression and FAT1 expression.Therefore,we selected them for this present study,where the effects of bone marrow mesenchymal stem cell-derived EVs(BMSDs-EVs)enriched with GTF2I were evaluated on the epithelial–to–mesenchymal transition(EMT)and stemness maintenance in TC.The under-expression of GTF2I and FAT1 was validated in TC cell lines.Ectopically expressed GTF2I and FAT1 were found to augment malignant phenotypes of TC cells,EMT,and stemness maintenance.Mechanistic studies revealed that GTF2I bound to the promoter region of FAT1 and consequently upregulated its expression.MSC-EVs could shuttle GTF2I into TPC-1 cells,where GTF2I inhibited TC malignant phenotypes,EMT,and stemness maintenance by increasing the expression of FAT1 and facilitating the FAT1-mediated CDK4/FOXM1 downregulation.In vivo experiments confirmed that silencing of GTF2I accelerated tumor growth in nude mice.Taken together,our work suggests that GTF2I transferred by MSC-EVs confer antioncogenic effects through the FAT1/CDK4/FOXM1 axis and may be used as a promising biomarker for TC treatment.展开更多
目的探讨胃腺癌伴肠母细胞分化(gastric adenocarcinoma with enteroblastic differentiation,GAED)的临床病理学特征及FAT1表达的意义。方法采用免疫组化EnVision两步法检测306例胃腺癌中SALL4、Glypican-3、AFP的表达,共诊断42例GAED...目的探讨胃腺癌伴肠母细胞分化(gastric adenocarcinoma with enteroblastic differentiation,GAED)的临床病理学特征及FAT1表达的意义。方法采用免疫组化EnVision两步法检测306例胃腺癌中SALL4、Glypican-3、AFP的表达,共诊断42例GAED,分析其临床病理学特征。免疫组化EnVision两步法检测GAED中CD10、CDX2、MUC-2和FAT1的表达,分析各标志物与GAED临床病理学特征的关系。结果GAED与同期普通型胃癌相比,具有更高的淋巴管血管侵犯和转移率,具有多种组织学形态。GAED不同程度表达SALL4、Glypican-3和AFP,三种标志物表达与肿瘤大小、T分期及血管、淋巴管侵犯具有相关性(P<0.05)。GAED中CDX-2高表达,FAT1表达明显降低(P<0.05)。结论GAED是一类侵袭性高、预后差的肿瘤,SALL4和Glypican-3联合检测可以提高诊断率。FAT1在GAED中发挥抑癌基因作用。GAED和肝样腺癌在形态学、免疫表型上有较大重叠性,应规范此类肿瘤的名称。展开更多
基金supported by the National Basic Research Program of China (973 Program) (No. 2015CB553906 and 2015CB553904)the National Natural Science Foundation of China (No. 81490753 and 81830086)the Education Department of Liaoning Province in China (Scientific Research Projects, No. L2016038)
文摘Objective: Growing evidence indicates that FAT atypical cadherin 1(FAT1) has aberrant genetic alterations and exhibits potential tumor suppressive function in esophageal squamous cell carcinoma(ESCC). However, the role of FAT1 in ESCC tumorigenesis remains not well elucidated. The aim of this study was to further investigate genetic alterations and biological functions of FAT1, as well as to explore its transcriptional regulation and downstream targets in ESCC.Methods: The mutations of FAT1 in ESCC were achieved by analyzing a combined study from seven published genomic data, while the copy number variants of FAT1 were obtained from an analysis of our previous data as well as of The Cancer Genome Atlas(TCGA) and Cancer Cell Line Encyclopedia(CCLE) databases using the cBioPortal. The transcriptional regulation of FAT1 expression was investigated by chromatin immunoprecipitation(ChIP) and the luciferase reporter assays. In-cell western, Western blot and reverse transcription-quantitative polymerase chain reaction(RT-qPCR) were used to assess the indicated gene expression. In addition, colony formation and Transwell migration/invasion assays were employed to test cell proliferation, migration and invasion.Finally, RNA sequencing was used to study the transcriptomes.Results: FAT1 was frequently mutated in ESCC and was deleted in multiple cancers. Furthermore, the transcription factor E2 F1 occupied the promoter region of FAT1, and depletion of E2 F1 led to a decrease in transcription activity and mRNA levels of FAT1. Moreover, we found that knockdown of FAT1 promoted KYSE30 and KYSE150 cell proliferation, migration and invasion;while overexpression of FAT1 inhibited KYSE30 and KYSE410 cell proliferation, migration and invasion. In addition, knockdown of FAT1 led to enrichment of the mitogen-activated protein kinase(MAPK) signaling pathway and cell adhesion process.Conclusions: Our data provided evidence for the tumor suppressive function of FAT1 in ESCC cells and elucidated the transcriptional regulation of FAT1 by E
基金supported by Shanghai Shenkang Hospital Development Center(No.SHDC12019X38).
文摘Through bioinformatics predictions,we identified that GTF2I and FAT1 were downregulated in thyroid carcinoma(TC).Further,Pearson’s correlation coefficient revealed a positive correlation between GTF2I expression and FAT1 expression.Therefore,we selected them for this present study,where the effects of bone marrow mesenchymal stem cell-derived EVs(BMSDs-EVs)enriched with GTF2I were evaluated on the epithelial–to–mesenchymal transition(EMT)and stemness maintenance in TC.The under-expression of GTF2I and FAT1 was validated in TC cell lines.Ectopically expressed GTF2I and FAT1 were found to augment malignant phenotypes of TC cells,EMT,and stemness maintenance.Mechanistic studies revealed that GTF2I bound to the promoter region of FAT1 and consequently upregulated its expression.MSC-EVs could shuttle GTF2I into TPC-1 cells,where GTF2I inhibited TC malignant phenotypes,EMT,and stemness maintenance by increasing the expression of FAT1 and facilitating the FAT1-mediated CDK4/FOXM1 downregulation.In vivo experiments confirmed that silencing of GTF2I accelerated tumor growth in nude mice.Taken together,our work suggests that GTF2I transferred by MSC-EVs confer antioncogenic effects through the FAT1/CDK4/FOXM1 axis and may be used as a promising biomarker for TC treatment.
文摘目的探讨胃腺癌伴肠母细胞分化(gastric adenocarcinoma with enteroblastic differentiation,GAED)的临床病理学特征及FAT1表达的意义。方法采用免疫组化EnVision两步法检测306例胃腺癌中SALL4、Glypican-3、AFP的表达,共诊断42例GAED,分析其临床病理学特征。免疫组化EnVision两步法检测GAED中CD10、CDX2、MUC-2和FAT1的表达,分析各标志物与GAED临床病理学特征的关系。结果GAED与同期普通型胃癌相比,具有更高的淋巴管血管侵犯和转移率,具有多种组织学形态。GAED不同程度表达SALL4、Glypican-3和AFP,三种标志物表达与肿瘤大小、T分期及血管、淋巴管侵犯具有相关性(P<0.05)。GAED中CDX-2高表达,FAT1表达明显降低(P<0.05)。结论GAED是一类侵袭性高、预后差的肿瘤,SALL4和Glypican-3联合检测可以提高诊断率。FAT1在GAED中发挥抑癌基因作用。GAED和肝样腺癌在形态学、免疫表型上有较大重叠性,应规范此类肿瘤的名称。
