Research Paper Volume 12, Issue 1 pp 156—177
Over-expression of EGFR regulated by RARA contributes to 5-FU resistance in colon cancer
- 1 Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin 150040, People’s Republic of China
- 2 Department of Pathology, Harbin Medical University Cancer Hospital, Harbin 150040, People’s Republic of China
received: June 18, 2019 ; accepted: December 5, 2019 ; published: January 2, 2020 ;https://doi.org/10.18632/aging.102607
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Copyright © 2020 Gu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
A promising new strategy for cancer therapy is to target the autophagic pathway. However, comprehensive characterization of autophagy genes and their clinical relevance in cancer is still lacking. Here, we systematically characterized alterations of autophagy genes in multiple cancer lines by analyzing data from The Cancer Genome Atlas and CellMiner database. Interactions between autophagy genes and clinically actionable genes (CAGs) were identified by analyzing co-expression, protein-protein interactions (PPIs) and transcription factor (TF) data. A key subnetwork was identified that included 18 autophagy genes and 22 CAGs linked by 28 PPI pairs and 1 TF-target pair, which was EGFR targeted by RARA. Alterations in the expression of autophagy genes were associated with patient survival in multiple cancer types. RARA and EGFR were associated with worse survival in colorectal cancer patients. The regulatory role of EGFR in 5-FU resistance was validated in colon cancer cells in vivo and in vitro. EGFR contributed to 5-FU resistance in colon cancer cells through autophagy induction, and EGFR overexpression in 5-FU resistant colon cancer was regulated by RARA. The present study provides a comprehensive analysis of autophagy in different cancer cell lines and highlights the potential clinical utility of targeting autophagy genes.
ATG: Autophagy-related genes; ChIP: Chromatin immunoprecipitation; AO/EB staining: Acridine Orange/Ethidium Bromide staining; EGFR: Epidermal growth factor receptor; RARA: Retinoic acid receptor-α; CAGs: Clinically actionable genes; PPIs: Protein-protein interactions; TF: Transcription factor; PCC: Pearson correlation coefficient; STAD: Stomach adenocarcinoma; LGG: Lower grade glioma; BLCA: Bladder urothelial carcinoma; KIRP: Kidney renal papillary cell carcinoma; PI3K: Phosphatidylinositide 3 kinase.