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Melatonin Sensitizes Hepatocellular Carcinoma Cells to Chemotherapy Through Long Non-Coding RNA RAD51-AS1-Mediated Suppression of DNA Repair
DNA repair systems are abnormally active in most hepatocellular carcinoma (HCC) cells due to accumulated mutations, resulting in elevated DNA repair capacity and resistance to chemotherapy and radiotherapy. Thus, targeting DNA repair mechanisms is a common treatment approach in HCC to sensitize canc...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6162454/ https://www.ncbi.nlm.nih.gov/pubmed/30201872 http://dx.doi.org/10.3390/cancers10090320 |
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author | Chen, Chin-Chuan Chen, Chi-Yuan Wang, Shu-Huei Yeh, Chau-Ting Su, Shih-Chi Ueng, Shir-Hwa Chuang, Wen-Yu Hsueh, Chuen Wang, Tong-Hong |
author_facet | Chen, Chin-Chuan Chen, Chi-Yuan Wang, Shu-Huei Yeh, Chau-Ting Su, Shih-Chi Ueng, Shir-Hwa Chuang, Wen-Yu Hsueh, Chuen Wang, Tong-Hong |
author_sort | Chen, Chin-Chuan |
collection | PubMed |
description | DNA repair systems are abnormally active in most hepatocellular carcinoma (HCC) cells due to accumulated mutations, resulting in elevated DNA repair capacity and resistance to chemotherapy and radiotherapy. Thus, targeting DNA repair mechanisms is a common treatment approach in HCC to sensitize cancer cells to DNA damage. In this study, we examined the anti-HCC effects of melatonin and elucidated the regulatory mechanisms. The results of functional assays showed that in addition to inhibiting the proliferation, migration, and invasion abilities of HCC cells, melatonin suppressed their DNA repair capacity, thereby promoting the cytotoxicity of chemotherapy and radiotherapy. Whole-transcriptome and gain- and loss-of-function analyses revealed that melatonin induces expression of the long noncoding RNA RAD51-AS1, which binds to RAD51 mRNA to inhibit its translation, effectively decreasing the DNA repair capacity of HCC cells and increasing their sensitivity to chemotherapy and radiotherapy. Animal models further demonstrated that a combination of melatonin and the chemotherapeutic agent etoposide (VP16) can significantly enhance tumor growth inhibition compared with monotherapy. Our results show that melatonin is a potential adjuvant treatment for chemotherapy and radiotherapy in HCC. |
format | Online Article Text |
id | pubmed-6162454 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-61624542018-10-02 Melatonin Sensitizes Hepatocellular Carcinoma Cells to Chemotherapy Through Long Non-Coding RNA RAD51-AS1-Mediated Suppression of DNA Repair Chen, Chin-Chuan Chen, Chi-Yuan Wang, Shu-Huei Yeh, Chau-Ting Su, Shih-Chi Ueng, Shir-Hwa Chuang, Wen-Yu Hsueh, Chuen Wang, Tong-Hong Cancers (Basel) Article DNA repair systems are abnormally active in most hepatocellular carcinoma (HCC) cells due to accumulated mutations, resulting in elevated DNA repair capacity and resistance to chemotherapy and radiotherapy. Thus, targeting DNA repair mechanisms is a common treatment approach in HCC to sensitize cancer cells to DNA damage. In this study, we examined the anti-HCC effects of melatonin and elucidated the regulatory mechanisms. The results of functional assays showed that in addition to inhibiting the proliferation, migration, and invasion abilities of HCC cells, melatonin suppressed their DNA repair capacity, thereby promoting the cytotoxicity of chemotherapy and radiotherapy. Whole-transcriptome and gain- and loss-of-function analyses revealed that melatonin induces expression of the long noncoding RNA RAD51-AS1, which binds to RAD51 mRNA to inhibit its translation, effectively decreasing the DNA repair capacity of HCC cells and increasing their sensitivity to chemotherapy and radiotherapy. Animal models further demonstrated that a combination of melatonin and the chemotherapeutic agent etoposide (VP16) can significantly enhance tumor growth inhibition compared with monotherapy. Our results show that melatonin is a potential adjuvant treatment for chemotherapy and radiotherapy in HCC. MDPI 2018-09-10 /pmc/articles/PMC6162454/ /pubmed/30201872 http://dx.doi.org/10.3390/cancers10090320 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Chen, Chin-Chuan Chen, Chi-Yuan Wang, Shu-Huei Yeh, Chau-Ting Su, Shih-Chi Ueng, Shir-Hwa Chuang, Wen-Yu Hsueh, Chuen Wang, Tong-Hong Melatonin Sensitizes Hepatocellular Carcinoma Cells to Chemotherapy Through Long Non-Coding RNA RAD51-AS1-Mediated Suppression of DNA Repair |
title | Melatonin Sensitizes Hepatocellular Carcinoma Cells to Chemotherapy Through Long Non-Coding RNA RAD51-AS1-Mediated Suppression of DNA Repair |
title_full | Melatonin Sensitizes Hepatocellular Carcinoma Cells to Chemotherapy Through Long Non-Coding RNA RAD51-AS1-Mediated Suppression of DNA Repair |
title_fullStr | Melatonin Sensitizes Hepatocellular Carcinoma Cells to Chemotherapy Through Long Non-Coding RNA RAD51-AS1-Mediated Suppression of DNA Repair |
title_full_unstemmed | Melatonin Sensitizes Hepatocellular Carcinoma Cells to Chemotherapy Through Long Non-Coding RNA RAD51-AS1-Mediated Suppression of DNA Repair |
title_short | Melatonin Sensitizes Hepatocellular Carcinoma Cells to Chemotherapy Through Long Non-Coding RNA RAD51-AS1-Mediated Suppression of DNA Repair |
title_sort | melatonin sensitizes hepatocellular carcinoma cells to chemotherapy through long non-coding rna rad51-as1-mediated suppression of dna repair |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6162454/ https://www.ncbi.nlm.nih.gov/pubmed/30201872 http://dx.doi.org/10.3390/cancers10090320 |
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