RESUMO
Despite the exact biological role of HNF1 homolog A (HNF1A) in the regulatory mechanism of glioblastoma (GBM), the molecular mechanism, especially the downstream regulation as a transcription factor, remains to be further elucidated. Immunohistochemistry was used to detect the expression and clinical relevance of HNF1A in GBM patients. CCK8, TUNEL, and subcutaneous tumor formation in nude mice were used to evaluate the effect of HNF1A on GBM in vitro and in vivo. The correction between HNF1A and epidermal growth factor receptor pathway substrate 8 (EPS8) was illustrated by bioinformatics analysis and luciferase assay. Further mechanism was explored that the transcription factor HNF1A regulated the expression of EPS8 and downstream signaling pathways by directly binding to the promoter region of EPS8. Our comprehensive analysis of clinical samples in this study showed that upregulated expression of HNF1A was associated with poor survival in GBM patients. Further, we found that knockdown of HNF1A markedly suppressed the malignant phenotype of GBM cells in vivo and in vitro as well as promoted apoptosis of tumor cells, which was reversed by upregulation of HNF1A. Mechanistically, HNF1A could significantly activate PI3K/AKT signaling pathway by specifically binding to the promoter regions of EPS8. Moreover, overexpression of EPS8 was able to reverse the apoptosis of tumor cells caused by HNF1A knockdown, thereby exacerbating the GBM progression. Correctively, our study has clarified the explicit mechanism by which HNF1A promotes GBM malignancy and provides a new therapeutic target for further clinical application.
Assuntos
Glioblastoma , Proteínas Proto-Oncogênicas c-akt , Animais , Camundongos , Humanos , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Glioblastoma/genética , Glioblastoma/patologia , Camundongos Nus , Proliferação de Células , Linhagem Celular Tumoral , Transdução de Sinais , Fatores de Transcrição/metabolismo , Regulação Neoplásica da Expressão Gênica , Fator 1-alfa Nuclear de Hepatócito/genética , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismoRESUMO
Objectives: Protein post-translational modifications (PTMs) are closely associated with tumorigenesis, targeting PTMs of key proteins might be the focus of antitumor drug discovery. This study aimed to analyze the research progress on protein PTMs in tumorigenesis by performing qualitative and quantitative evaluations. Methods: The Web of Science Core Collection was selected as the database, and Science Citation Index Expanded was selected as the citation index. Visualization tools such as VOSviewer, CiteSpace, HistCite, and Online Analysis Platform of Bibliometrics were used to deeply explore the information of the retrieved research papers and analyze them in terms of research trends and main aspects of research. Results: The search yielded 3777 relevant articles. The results showed that the total number of PTMs related papers in cancer field has been increasing annually, with the largest number of papers published in the United States of America. The co-word cluster analysis showed that the research on PTMs and tumorigenesis was primarily focused on the following four areas, mechanism, histone, P53, key Technologies. Tumor metabolism, autophagy, and protein-protein interaction, histone ubiquitination have become new research topics. Conclusion: This study provides an important reference for the research direction and selection of topics of interest in the PTMs of cancer field.
