Nonenzymatic function of Aldolase A downregulates miR-145 to promote the Oct4/DUSP4/TRAF4 axis and the acquisition of lung cancer stemness
| العنوان: | Nonenzymatic function of Aldolase A downregulates miR-145 to promote the Oct4/DUSP4/TRAF4 axis and the acquisition of lung cancer stemness |
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| المؤلفون: | Hsing Fang Tsai, Yu Chan Chang, Michael Hsiao, Chi Long Chen, Chih Yeu Fang, Jean Chiou, Chih Jen Yang, Yi Fang Yang |
| المصدر: | Cell Death & Disease Cell Death and Disease, Vol 11, Iss 3, Pp 1-15 (2020) |
| بيانات النشر: | Nature Publishing Group UK, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Male, Cancer Research, Lung Neoplasms, TRAF4, Immunology, Down-Regulation, Mice, SCID, Article, Cellular and Molecular Neuroscience, Mice, In vivo, Mice, Inbred NOD, Cell Line, Tumor, Fructose-Bisphosphate Aldolase, medicine, Animals, Humans, Glycolysis, lcsh:QH573-671, Lung cancer, Transcription factor, Cell Proliferation, Gene knockdown, TNF Receptor-Associated Factor 4, biology, lcsh:Cytology, Cancer stem cells, Aldolase A, Cell Biology, medicine.disease, Cancer metabolism, In vitro, MicroRNAs, biology.protein, Cancer research, Neoplastic Stem Cells, Dual-Specificity Phosphatases, Heterografts, Mitogen-Activated Protein Kinase Phosphatases, Octamer Transcription Factor-3, Signal Transduction |
| الوصف: | Drug resistance remains a serious issue of clinical importance and is a consequence of cancer stemness. In this study, we showed that the level of Aldolase A (ALDOA) expression is significantly associated with the IC50 value of chemotherapy drugs in lung cancer. Our data revealed that ALDOA overexpression resulted in a significant increase of lung tumor spheres. The use of ingenuity pathway analysis (IPA) resulted in the identification of POU5F1 (Oct4) as the leading transcription factor of ALDOA. We observed high expression of ALDOA, Oct4 and stemness markers in collected spheroid cells. DUSP4 and TRAF4 were confirmed as major downstream targets of the ALDOA-Oct4 axis. Knockdown of these molecules significantly decreased the stemness ability of cells. In addition, we investigated whether miR-145 targets the 3′-UTR of Oct4 and is regulated by ALDOA due to the involvement of ALDOA in glycolysis and metabolic reprogramming. Furthermore, we constructed several mutant forms of ALDOA that disrupted its enzymatic activity and showed that they still induced significant in vitro sphere formation and in vivo tumorigenicity. These results demonstrated that ALDOA-mediated spheroid formation is independent of its enzymatic activity. In the clinical component, we also showed that the combination of ALDOA and TRAF4 or DUSP4 is positively correlated with poor overall survival in a xenograft model and cancer patients through immunohistochemical analyses. The results of our study revealed novel functional roles of ALDOA in inducing cancer stemness via the inhibition of miR-145 expression and the activation of Oct4 transcription. These findings offer new therapeutic strategies for modulation of lung cancer stemness to enhance chemotherapeutic responses in lung cancer patients. |
| اللغة: | English |
| تدمد: | 2041-4889 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::cec8a869af3fce7ad1fd0185bb66d6bbTest http://europepmc.org/articles/PMC7080828Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....cec8a869af3fce7ad1fd0185bb66d6bb |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20414889 |
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