Hydroxychloroquine (HCQ) Modulates Autophagy and Oxidative DNA Damage Stress in Hepatocellular Carcinoma to Overcome Sorafenib Resistance via TLR9/SOD1/hsa-miR-30a-5p/Beclin-1 Axis
Sorafenib is used for treating advanced hepatocellular carcinoma (HCC), but some patients acquire sorafenib resistance. We investigated the mechanisms underlying acquired sorafenib resistance in HCC cells and targeted them to re-sensitize them to sorafenib. In silico analysis indicated that toll-lik...
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MDPI AG
2021-06-01
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| Online Access: | https://www.mdpi.com/2072-6694/13/13/3227 |
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| author | Ming-Yao Chen Vijesh Kumar Yadav Yi Cheng Chu Jiann Ruey Ong Ting-Yi Huang Kwai-Fong Lee Kuen-Haur Lee Chi-Tai Yeh Wei-Hwa Lee |
| author_facet | Ming-Yao Chen Vijesh Kumar Yadav Yi Cheng Chu Jiann Ruey Ong Ting-Yi Huang Kwai-Fong Lee Kuen-Haur Lee Chi-Tai Yeh Wei-Hwa Lee |
| author_sort | Ming-Yao Chen |
| collection | DOAJ |
| description | Sorafenib is used for treating advanced hepatocellular carcinoma (HCC), but some patients acquire sorafenib resistance. We investigated the mechanisms underlying acquired sorafenib resistance in HCC cells and targeted them to re-sensitize them to sorafenib. In silico analysis indicated that toll-like receptor (TLR)-9 was significantly overexpressed, and that miRNA (hsa-miR-30a-5p) was downregulated in sorafenib-resistant HCC cells, which modulated HCC cell proliferation, oxidative stress, and apoptosis. TLR9 overexpression increased HCC cell proliferation, whereas TLR9 inhibition from hydroxychloroquine (HCQ) decreased HCC cell proliferation, tumor growth, oxidative stress marker (SOD1), and the formation of autophagosome bodies (reduced ATG5 and Beclin-1 expression). Moreover, HCQ treatment reduced epithelial–mesenchymal transition, leading to decreased clonogenicity, migratory ability, and invasiveness. HCQ targeted and reduced the self-renewal capacity phenotype by inhibiting tumorsphere generation. Both in vitro and in vivo results demonstrated the synergistic effect of the HCQ–sorafenib combination on sorafenib-resistant HCC (Huh7-SR) cells, increasing their sensitivity to treatment by modulating TLR9, autophagy (ATG5 and Beclin-1), oxidative stress (SOD1), and apoptosis (c-caspase3) expression and thus overcoming the drug resistance. This study’s findings indicate that TLR9 overexpression occurs in sorafenib-resistant HCC cells and that its downregulation aids HCC suppression. Moreover, HCQ treatment significantly increases sorafenib’s effect on sorafenib-resistant HCC cells. |
| first_indexed | 2024-03-10T09:59:43Z |
| format | Article |
| id | doaj.art-73d596a59b6e40499a8e37f31b19113a |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T09:59:43Z |
| publishDate | 2021-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-73d596a59b6e40499a8e37f31b19113a2023-11-22T02:04:18ZengMDPI AGCancers2072-66942021-06-011313322710.3390/cancers13133227Hydroxychloroquine (HCQ) Modulates Autophagy and Oxidative DNA Damage Stress in Hepatocellular Carcinoma to Overcome Sorafenib Resistance via TLR9/SOD1/hsa-miR-30a-5p/Beclin-1 AxisMing-Yao Chen0Vijesh Kumar Yadav1Yi Cheng Chu2Jiann Ruey Ong3Ting-Yi Huang4Kwai-Fong Lee5Kuen-Haur Lee6Chi-Tai Yeh7Wei-Hwa Lee8Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, TaiwanDivision of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, TaiwanDepartment of Medicine, St. George’s University School of Medicine, St. George SW17 0RE, GrenadaDepartment of Emergency Medicine, Taipei Medical University-Shuang Ho Hospital, New Taipei City 23516, TaiwanBiobank management Center, Taipei Medical University-Shuang Ho Hospital, New Taipei City 23561, TaiwanBiobank management Center, Taipei Medical University-Shuang Ho Hospital, New Taipei City 23561, TaiwanGraduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110, TaiwanDepartment of Medical Research & Education, Taipei Medical University Shuang Ho Hospital, New Taipei City 23561, TaiwanDepartment of Pathology, Taipei Medical University Shuang Ho Hospital, New Taipei City 23561, TaiwanSorafenib is used for treating advanced hepatocellular carcinoma (HCC), but some patients acquire sorafenib resistance. We investigated the mechanisms underlying acquired sorafenib resistance in HCC cells and targeted them to re-sensitize them to sorafenib. In silico analysis indicated that toll-like receptor (TLR)-9 was significantly overexpressed, and that miRNA (hsa-miR-30a-5p) was downregulated in sorafenib-resistant HCC cells, which modulated HCC cell proliferation, oxidative stress, and apoptosis. TLR9 overexpression increased HCC cell proliferation, whereas TLR9 inhibition from hydroxychloroquine (HCQ) decreased HCC cell proliferation, tumor growth, oxidative stress marker (SOD1), and the formation of autophagosome bodies (reduced ATG5 and Beclin-1 expression). Moreover, HCQ treatment reduced epithelial–mesenchymal transition, leading to decreased clonogenicity, migratory ability, and invasiveness. HCQ targeted and reduced the self-renewal capacity phenotype by inhibiting tumorsphere generation. Both in vitro and in vivo results demonstrated the synergistic effect of the HCQ–sorafenib combination on sorafenib-resistant HCC (Huh7-SR) cells, increasing their sensitivity to treatment by modulating TLR9, autophagy (ATG5 and Beclin-1), oxidative stress (SOD1), and apoptosis (c-caspase3) expression and thus overcoming the drug resistance. This study’s findings indicate that TLR9 overexpression occurs in sorafenib-resistant HCC cells and that its downregulation aids HCC suppression. Moreover, HCQ treatment significantly increases sorafenib’s effect on sorafenib-resistant HCC cells.https://www.mdpi.com/2072-6694/13/13/3227hepatocellular carcinomaTLR9HCQautophagyoxidative stresssorafenib resistance |
| spellingShingle | Ming-Yao Chen Vijesh Kumar Yadav Yi Cheng Chu Jiann Ruey Ong Ting-Yi Huang Kwai-Fong Lee Kuen-Haur Lee Chi-Tai Yeh Wei-Hwa Lee Hydroxychloroquine (HCQ) Modulates Autophagy and Oxidative DNA Damage Stress in Hepatocellular Carcinoma to Overcome Sorafenib Resistance via TLR9/SOD1/hsa-miR-30a-5p/Beclin-1 Axis Cancers hepatocellular carcinoma TLR9 HCQ autophagy oxidative stress sorafenib resistance |
| title | Hydroxychloroquine (HCQ) Modulates Autophagy and Oxidative DNA Damage Stress in Hepatocellular Carcinoma to Overcome Sorafenib Resistance via TLR9/SOD1/hsa-miR-30a-5p/Beclin-1 Axis |
| title_full | Hydroxychloroquine (HCQ) Modulates Autophagy and Oxidative DNA Damage Stress in Hepatocellular Carcinoma to Overcome Sorafenib Resistance via TLR9/SOD1/hsa-miR-30a-5p/Beclin-1 Axis |
| title_fullStr | Hydroxychloroquine (HCQ) Modulates Autophagy and Oxidative DNA Damage Stress in Hepatocellular Carcinoma to Overcome Sorafenib Resistance via TLR9/SOD1/hsa-miR-30a-5p/Beclin-1 Axis |
| title_full_unstemmed | Hydroxychloroquine (HCQ) Modulates Autophagy and Oxidative DNA Damage Stress in Hepatocellular Carcinoma to Overcome Sorafenib Resistance via TLR9/SOD1/hsa-miR-30a-5p/Beclin-1 Axis |
| title_short | Hydroxychloroquine (HCQ) Modulates Autophagy and Oxidative DNA Damage Stress in Hepatocellular Carcinoma to Overcome Sorafenib Resistance via TLR9/SOD1/hsa-miR-30a-5p/Beclin-1 Axis |
| title_sort | hydroxychloroquine hcq modulates autophagy and oxidative dna damage stress in hepatocellular carcinoma to overcome sorafenib resistance via tlr9 sod1 hsa mir 30a 5p beclin 1 axis |
| topic | hepatocellular carcinoma TLR9 HCQ autophagy oxidative stress sorafenib resistance |
| url | https://www.mdpi.com/2072-6694/13/13/3227 |
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