Epigenetically regulated PAX6 drives cancer cells toward a stem-like state via GLI-SOX2 signaling axis in lung adenocarcinoma
| العنوان: | Epigenetically regulated PAX6 drives cancer cells toward a stem-like state via GLI-SOX2 signaling axis in lung adenocarcinoma |
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| المؤلفون: | Chandra Goparaju, Mohammad O. Hoque, Jun Chieh J. Tsay, Wikum Dinalankara, Luigi Marchionni, William N. Rom, Harvey I. Pass, Zahra Maleki, Akira Ooki |
| المصدر: | Oncogene |
| بيانات النشر: | Springer Science and Business Media LLC, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, Homeobox protein NANOG, cancer stem cell, Cancer Research, Lung Neoplasms, PAX6 Transcription Factor, SOX2, Adenocarcinoma of Lung, Biology, Zinc Finger Protein GLI1, Article, Epigenesis, Genetic, Mice, 03 medical and health sciences, Genetics, medicine, Animals, Humans, Lung cancer, Molecular Biology, Transcription factor, Regulation of gene expression, Oncogene, SOXB1 Transcription Factors, Oncogenes, DNA Methylation, medicine.disease, PAX6, 3. Good health, Gene Expression Regulation, Neoplastic, lung cancer, 030104 developmental biology, embryonic structures, Cancer cell, DNA methylation, Neoplastic Stem Cells, Cancer research, Heterografts, sense organs, GLI, Signal Transduction |
| الوصف: | It remains unclear whether PAX6 acts as a crucial transcription factor for lung cancer stem cell (CSC) traits. We demonstrate that PAX6 acts as an oncogene responsible for induction of cancer stemness properties in lung adenocarcinoma (LUAD). Mechanistically, PAX6 promotes GLI transcription, resulting in SOX2 upregulation directly by the binding of GLI to the proximal promoter region of the SOX2 gene. The overexpressed SOX2 enhances the expression of key pluripotent factors (OCT4 and NANOG) and suppresses differentiation lineage factors (HOPX and NKX2-1), driving cancer cells toward a stem-like state. In contrast, in the differentiated non-CSCs, PAX6 is transcriptionally silenced by its promoter methylation. In human lung cancer tissues, the positive linear correlations of PAX6 expression with GLI and SOX2 expression and its negative correlations with HOPX and NKX2-1 expression were observed. Therapeutically, the blockade of the PAX6-GLI-SOX2 signaling axis elicits a long-lasting therapeutic efficacy by limiting CSC expansion following chemotherapy. Furthermore, a methylation panel including the PAX6 gene yielded a sensitivity of 79.1% and specificity of 83.3% for cancer detection using serum DNA from stage IA LUAD. Our findings provide a rationale for targeting the PAX6-GLI-SOX2 signaling axis with chemotherapy as an effective therapeutic strategy and support the clinical utility of PAX6 gene promoter methylation as a biomarker for early lung cancer detection. |
| تدمد: | 1476-5594 0950-9232 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3f5c1cae74425493e3165e3d1f0f9792Test https://doi.org/10.1038/s41388-018-0373-2Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....3f5c1cae74425493e3165e3d1f0f9792 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14765594 09509232 |
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