Targeting EGFR sensitizes 5-Fu-resistant colon cancer cells through modification of the lncRNA-FGD5-AS1-miR-330-3p-Hexokinase 2 axis
| العنوان: | Targeting EGFR sensitizes 5-Fu-resistant colon cancer cells through modification of the lncRNA-FGD5-AS1-miR-330-3p-Hexokinase 2 axis |
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| المؤلفون: | Shengnan Ren, Sujie Gao, Hong-Wei Yan, Yiting Liu, Xuebo Chen |
| المصدر: | Molecular Therapy Oncolytics Molecular Therapy: Oncolytics, Vol 23, Iss, Pp 14-25 (2021) |
| بيانات النشر: | American Society of Gene & Cell Therapy, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Cancer Research, Colorectal cancer, Biology, lncRNA-FGD5-AS1, medicine, Pharmacology (medical), 5-fluorouracil, Epidermal growth factor receptor, RC254-282, Oncogene, Competing endogenous RNA, Cancer, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, chemoresistance, medicine.disease, Non-coding RNA, miR-330-3p, Oncology, colon cancer, Cancer cell, Cancer research, biology.protein, Molecular Medicine, Hexokinase 2, Original Article, Erlotinib, Warburg effect, medicine.drug |
| الوصف: | 5-Fluorouracil (5-Fu) is a widely applied anti-cancer agent against colorectal cancer (CRC), yet a number of CRC patients have developed resistance to 5-Fu-based chemotherapy. The epidermal growth factor receptor (EGFR) is recognized as an oncogene that promotes diverse cancer progresses. In addition, long noncoding RNAs (lncRNAs) are essential regulators of cancers. Here we report that EGFR and lncRNA-FGD5-AS1 promoted 5-Fu resistance of CRC. By establishing the 5-Fu-resistant CRC cell line, we detected that EGFR, FGD5-AS1, and glucose metabolism were significantly elevated in 5-Fu-resistant CRC cells. A microRNA-microarray analysis revealed that miR-330-3p functions as a downstream effector of FGD5-AS1. FGD5-AS1 directly sponged miR-330-3p to form a competing endogenous RNA (ceRNA) network, leading to inhibition of miR-330-3p expression. Furthermore, bioinformatics analysis revealed that Hexokinase 2 (HK2) was a potential target of miR-330-3p, which was validated by luciferase assay. Rescue experiments demonstrated that FGD5-AS1 promotes glycolysis through modulating the miR-330-3p-HK2 axis, leading to 5-Fu resistance of CRC cancer cells. Finally, in vitro and in vivo xenograft experiments consistently demonstrated that inhibition of EGFR by the specific inhibitor erlotinib effectively enhanced the anti-tumor toxicity of 5-Fu by targeting the EGFR-FGD5-AS1-miR-330-3p-HK2 pathway. In summary, this study demonstrates new mechanisms of the EGFR-modulated 5-Fu resistance through modulating the noncoding RNA network, contributing to development of new approaches against chemoresistant CRC. Graphical abstract EGFR and FGD5-AS1 promote 5-Fu resistance of CRC. EGFR positively regulates FGD5-AS1. FGD5-AS1 promotes glucose metabolism, which is elevated in 5-Fu-resistant CRC cells, via sponging miR-330-3p-HK2. In vitro and in vivo experiments demonstrate that inhibiting EGFR by erlotinib effectively sensitizes 5-Fu-resistant CRC cells through the FGD5-AS1-miR-338-3p-HK2-glycolysis axis. |
| اللغة: | English |
| تدمد: | 2372-7705 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::981419df90ddc6a4604b5d5b5f8b58f0 http://europepmc.org/articles/PMC8455313 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....981419df90ddc6a4604b5d5b5f8b58f0 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 23727705 |
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