The distinct responsiveness of cytokeratin 19-positive hepatocellular carcinoma to regorafenib
Abstract Cytokeratin 19-positive (CK19+) hepatocellular carcinoma (HCC) is an aggressive subtype characterized by early recurrence and chemotherapy tolerance. However, there is no specific therapeutic option for CK19+ HCC. The correlation between tumor recurrence and expression status of CK19 were s...
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2021
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oai:doaj.org-article:0c2f2212cdcf45f8b489bd90246896042021-11-21T12:03:25ZThe distinct responsiveness of cytokeratin 19-positive hepatocellular carcinoma to regorafenib10.1038/s41419-021-04320-42041-4889https://doaj.org/article/0c2f2212cdcf45f8b489bd90246896042021-11-01T00:00:00Zhttps://doi.org/10.1038/s41419-021-04320-4https://doaj.org/toc/2041-4889Abstract Cytokeratin 19-positive (CK19+) hepatocellular carcinoma (HCC) is an aggressive subtype characterized by early recurrence and chemotherapy tolerance. However, there is no specific therapeutic option for CK19+ HCC. The correlation between tumor recurrence and expression status of CK19 were studied in 206 patients undergoing liver transplantation for HCC. CK19−/+ HCC cells were isolated to screen effective antitumor drugs. The therapeutic effects of regorafenib were evaluated in patient-derived xenograft (PDX) models from 10 HCC patients. The mechanism of regorafenib on CK19+ HCC was investigated. CK19 positiveness indicated aggressiveness of tumor and higher recurrence risk of HCC after liver transplantation. The isolated CK19+ HCC cells had more aggressive behaviors than CK19− cells. Regorafenib preferentially increased the growth inhibition and apoptosis of CK19+ cells in vitro, whereas sorafenib, apatinib, and 5-fluorouracil did not. In PDX models from CK19−/+ HCC patients, the tumor control rate of regorafenib achieved 80% for CK19+ HCCs, whereas 0% for CK19− HCCs. RNA-sequencing revealed that CK19+ cells had elevated expression of mitochondrial ribosomal proteins, which are essential for mitochondrial function. Further experiments confirmed that regorafenib attenuated the mitochondrial respiratory capacity in CK19+ cells. However, the mitochondrial respiration in CK19− cells were faint and hardly repressed by regorafenib. The mitochondrial respiration was regulated by the phosphorylation of signal transducer and activator of transcription 3 (STAT3), which was inhibited by regorafenib in CK19+ cells. Hence, CK19 could be a potential marker of the therapeutic benefit of regorafenib, which facilitates the individualized therapy for HCC. STAT3/mitochondria axis determines the distinct response of CK19+ cells to regorafenib treatment.Jianyong ZhuoDi LuZuyuan LinXinyu YangModan YangJianguo WangYaoye TaoXue WenHuihui LiZhengxing LianBeini CenSiyi DongXuyong WeiHaiyang XieShusen ZhengYouqing ShenXiao XuNature Publishing GrouparticleCytologyQH573-671ENCell Death and Disease, Vol 12, Iss 12, Pp 1-13 (2021) |
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DOAJ |
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DOAJ |
| language |
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| topic |
Cytology QH573-671 |
| spellingShingle |
Cytology QH573-671 Jianyong Zhuo Di Lu Zuyuan Lin Xinyu Yang Modan Yang Jianguo Wang Yaoye Tao Xue Wen Huihui Li Zhengxing Lian Beini Cen Siyi Dong Xuyong Wei Haiyang Xie Shusen Zheng Youqing Shen Xiao Xu The distinct responsiveness of cytokeratin 19-positive hepatocellular carcinoma to regorafenib |
| description |
Abstract Cytokeratin 19-positive (CK19+) hepatocellular carcinoma (HCC) is an aggressive subtype characterized by early recurrence and chemotherapy tolerance. However, there is no specific therapeutic option for CK19+ HCC. The correlation between tumor recurrence and expression status of CK19 were studied in 206 patients undergoing liver transplantation for HCC. CK19−/+ HCC cells were isolated to screen effective antitumor drugs. The therapeutic effects of regorafenib were evaluated in patient-derived xenograft (PDX) models from 10 HCC patients. The mechanism of regorafenib on CK19+ HCC was investigated. CK19 positiveness indicated aggressiveness of tumor and higher recurrence risk of HCC after liver transplantation. The isolated CK19+ HCC cells had more aggressive behaviors than CK19− cells. Regorafenib preferentially increased the growth inhibition and apoptosis of CK19+ cells in vitro, whereas sorafenib, apatinib, and 5-fluorouracil did not. In PDX models from CK19−/+ HCC patients, the tumor control rate of regorafenib achieved 80% for CK19+ HCCs, whereas 0% for CK19− HCCs. RNA-sequencing revealed that CK19+ cells had elevated expression of mitochondrial ribosomal proteins, which are essential for mitochondrial function. Further experiments confirmed that regorafenib attenuated the mitochondrial respiratory capacity in CK19+ cells. However, the mitochondrial respiration in CK19− cells were faint and hardly repressed by regorafenib. The mitochondrial respiration was regulated by the phosphorylation of signal transducer and activator of transcription 3 (STAT3), which was inhibited by regorafenib in CK19+ cells. Hence, CK19 could be a potential marker of the therapeutic benefit of regorafenib, which facilitates the individualized therapy for HCC. STAT3/mitochondria axis determines the distinct response of CK19+ cells to regorafenib treatment. |
| format |
article |
| author |
Jianyong Zhuo Di Lu Zuyuan Lin Xinyu Yang Modan Yang Jianguo Wang Yaoye Tao Xue Wen Huihui Li Zhengxing Lian Beini Cen Siyi Dong Xuyong Wei Haiyang Xie Shusen Zheng Youqing Shen Xiao Xu |
| author_facet |
Jianyong Zhuo Di Lu Zuyuan Lin Xinyu Yang Modan Yang Jianguo Wang Yaoye Tao Xue Wen Huihui Li Zhengxing Lian Beini Cen Siyi Dong Xuyong Wei Haiyang Xie Shusen Zheng Youqing Shen Xiao Xu |
| author_sort |
Jianyong Zhuo |
| title |
The distinct responsiveness of cytokeratin 19-positive hepatocellular carcinoma to regorafenib |
| title_short |
The distinct responsiveness of cytokeratin 19-positive hepatocellular carcinoma to regorafenib |
| title_full |
The distinct responsiveness of cytokeratin 19-positive hepatocellular carcinoma to regorafenib |
| title_fullStr |
The distinct responsiveness of cytokeratin 19-positive hepatocellular carcinoma to regorafenib |
| title_full_unstemmed |
The distinct responsiveness of cytokeratin 19-positive hepatocellular carcinoma to regorafenib |
| title_sort |
distinct responsiveness of cytokeratin 19-positive hepatocellular carcinoma to regorafenib |
| publisher |
Nature Publishing Group |
| publishDate |
2021 |
| url |
https://doaj.org/article/0c2f2212cdcf45f8b489bd9024689604 |
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