CircTTC13 promotes sorafenib resistance in hepatocellular carcinoma through the inhibition of ferroptosis by targeting the miR-513a-5p/SLC7A11 axis
Abstract The high mortality rate from hepatocellular carcinoma (HCC) is due primarily to challenges in early diagnosis and the development of drug resistance in advanced stages. Many first-line chemotherapeutic drugs induce ferroptosis, a form of programmed cell death dependent on ferrous iron-media...
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BMC
2025-01-01
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| Series: | Molecular Cancer |
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| Online Access: | https://doi.org/10.1186/s12943-024-02224-3 |
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| author | Ying Zhang Ruiwei Yao Mingyi Li Chongkai Fang Kunliang Feng Xiuru Chen Jinan Wang Rui Luo Hanqian Shi Xinqiu Chen Xilin Zhao Hanlin Huang Shuwei Liu Bing Yin Chong Zhong |
| author_facet | Ying Zhang Ruiwei Yao Mingyi Li Chongkai Fang Kunliang Feng Xiuru Chen Jinan Wang Rui Luo Hanqian Shi Xinqiu Chen Xilin Zhao Hanlin Huang Shuwei Liu Bing Yin Chong Zhong |
| author_sort | Ying Zhang |
| collection | DOAJ |
| description | Abstract The high mortality rate from hepatocellular carcinoma (HCC) is due primarily to challenges in early diagnosis and the development of drug resistance in advanced stages. Many first-line chemotherapeutic drugs induce ferroptosis, a form of programmed cell death dependent on ferrous iron-mediated oxidative stress, suggesting that drug resistance and ensuing tumor progression may in part stem from reduced ferroptosis. Since circular RNAs (circRNAs) have been shown to influence tumor development, we examined whether specific circRNAs may regulate drug-induced ferroptosis in HCC. Through circRNA sequencing, we identified a novel hsa_circ_0000195 (circTTC13) that is overexpressed in HCC tissues. This overexpression is linked to higher tumor grade, more advanced tumor stage, decreased ferroptosis, and poorer overall survival. Overexpression of CircTTC13 in HCC cell lines and explant tumors was associated with increased proliferation rates, enhanced metastatic capacity, and resistance to sorafenib, while also inhibiting ferroptosis. Conversely, circTTC13 silencing reduced malignant characteristics and promoted ferroptosis. In silico analysis, luciferase assays, and fluorescence in situ hybridization collectively demonstrated that circTTC13 directly targets and reduces miR-513a-5p expression, which in turn leads to the upregulation of the negative ferroptosis regulator SLC7A11. Moreover, the inhibition of SLC7A11 mirrored the effect of circTTC13 knockdown, whereas ferroptosis inhibition mimicked the effect of circTTC13 overexpression. Both circTTC13 and SLC7A11 were highly expressed in drug-resistant HCC cells, and circTTC13 silencing induced ferroptosis and reversed sorafenib resistance in explant tumors. These findings identify circTTC13 as a critical driver of HCC progression and resistance to drug-induced ferroptosis via upregulation of SLC7A11. The cicTTC13/miR-513a-5p/SLC7A11 axis represents a potential therapeutic target for HCC. |
| format | Article |
| id | doaj-art-50e4ec1633a8495485f2f14f3310a6b3 |
| institution | Kabale University |
| issn | 1476-4598 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Cancer |
| spelling | doaj-art-50e4ec1633a8495485f2f14f3310a6b32025-02-02T12:11:33ZengBMCMolecular Cancer1476-45982025-01-0124111810.1186/s12943-024-02224-3CircTTC13 promotes sorafenib resistance in hepatocellular carcinoma through the inhibition of ferroptosis by targeting the miR-513a-5p/SLC7A11 axisYing Zhang0Ruiwei Yao1Mingyi Li2Chongkai Fang3Kunliang Feng4Xiuru Chen5Jinan Wang6Rui Luo7Hanqian Shi8Xinqiu Chen9Xilin Zhao10Hanlin Huang11Shuwei Liu12Bing Yin13Chong Zhong14State Key Laboratory of Traditional Chinese Medicine Syndrome/The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese MedicineFirst Clinical Medical College, Guangzhou University of Chinese MedicineThe 3rd Ward of Radiotherapy Department, Guangzhou Institute of Cancer Research, the Affiliated Cancer Hospital, Guangzhou Medical UniversityScience and Technology Innovation Center, Guangzhou University of Chinese MedicineDepartment of Surgery, Baiyun Hospital of the First Affiliated Hospital of Guangzhou University of Chinese MedicineScience and Technology Innovation Center, Guangzhou University of Chinese MedicineState Key Laboratory of Traditional Chinese Medicine Syndrome/The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese MedicineFirst Clinical Medical College, Guangzhou University of Chinese MedicineFirst Clinical Medical College, Guangzhou University of Chinese MedicineFirst Clinical Medical College, Guangzhou University of Chinese MedicineState Key Laboratory of Traditional Chinese Medicine Syndrome/The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese MedicineFirst Clinical Medical College, Guangzhou University of Chinese MedicineFirst Clinical Medical College, Guangzhou University of Chinese MedicineFirst Clinical Medical College, Guangzhou University of Chinese MedicineState Key Laboratory of Traditional Chinese Medicine Syndrome/The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese MedicineAbstract The high mortality rate from hepatocellular carcinoma (HCC) is due primarily to challenges in early diagnosis and the development of drug resistance in advanced stages. Many first-line chemotherapeutic drugs induce ferroptosis, a form of programmed cell death dependent on ferrous iron-mediated oxidative stress, suggesting that drug resistance and ensuing tumor progression may in part stem from reduced ferroptosis. Since circular RNAs (circRNAs) have been shown to influence tumor development, we examined whether specific circRNAs may regulate drug-induced ferroptosis in HCC. Through circRNA sequencing, we identified a novel hsa_circ_0000195 (circTTC13) that is overexpressed in HCC tissues. This overexpression is linked to higher tumor grade, more advanced tumor stage, decreased ferroptosis, and poorer overall survival. Overexpression of CircTTC13 in HCC cell lines and explant tumors was associated with increased proliferation rates, enhanced metastatic capacity, and resistance to sorafenib, while also inhibiting ferroptosis. Conversely, circTTC13 silencing reduced malignant characteristics and promoted ferroptosis. In silico analysis, luciferase assays, and fluorescence in situ hybridization collectively demonstrated that circTTC13 directly targets and reduces miR-513a-5p expression, which in turn leads to the upregulation of the negative ferroptosis regulator SLC7A11. Moreover, the inhibition of SLC7A11 mirrored the effect of circTTC13 knockdown, whereas ferroptosis inhibition mimicked the effect of circTTC13 overexpression. Both circTTC13 and SLC7A11 were highly expressed in drug-resistant HCC cells, and circTTC13 silencing induced ferroptosis and reversed sorafenib resistance in explant tumors. These findings identify circTTC13 as a critical driver of HCC progression and resistance to drug-induced ferroptosis via upregulation of SLC7A11. The cicTTC13/miR-513a-5p/SLC7A11 axis represents a potential therapeutic target for HCC.https://doi.org/10.1186/s12943-024-02224-3Hepatocellular carcinomaFerroptosiscircTTC13SLC7A11SorafenibcircRNA |
| spellingShingle | Ying Zhang Ruiwei Yao Mingyi Li Chongkai Fang Kunliang Feng Xiuru Chen Jinan Wang Rui Luo Hanqian Shi Xinqiu Chen Xilin Zhao Hanlin Huang Shuwei Liu Bing Yin Chong Zhong CircTTC13 promotes sorafenib resistance in hepatocellular carcinoma through the inhibition of ferroptosis by targeting the miR-513a-5p/SLC7A11 axis Molecular Cancer Hepatocellular carcinoma Ferroptosis circTTC13 SLC7A11 Sorafenib circRNA |
| title | CircTTC13 promotes sorafenib resistance in hepatocellular carcinoma through the inhibition of ferroptosis by targeting the miR-513a-5p/SLC7A11 axis |
| title_full | CircTTC13 promotes sorafenib resistance in hepatocellular carcinoma through the inhibition of ferroptosis by targeting the miR-513a-5p/SLC7A11 axis |
| title_fullStr | CircTTC13 promotes sorafenib resistance in hepatocellular carcinoma through the inhibition of ferroptosis by targeting the miR-513a-5p/SLC7A11 axis |
| title_full_unstemmed | CircTTC13 promotes sorafenib resistance in hepatocellular carcinoma through the inhibition of ferroptosis by targeting the miR-513a-5p/SLC7A11 axis |
| title_short | CircTTC13 promotes sorafenib resistance in hepatocellular carcinoma through the inhibition of ferroptosis by targeting the miR-513a-5p/SLC7A11 axis |
| title_sort | circttc13 promotes sorafenib resistance in hepatocellular carcinoma through the inhibition of ferroptosis by targeting the mir 513a 5p slc7a11 axis |
| topic | Hepatocellular carcinoma Ferroptosis circTTC13 SLC7A11 Sorafenib circRNA |
| url | https://doi.org/10.1186/s12943-024-02224-3 |
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