1. Academic Validation
  2. The distinct responsiveness of cytokeratin 19-positive hepatocellular carcinoma to regorafenib

The distinct responsiveness of cytokeratin 19-positive hepatocellular carcinoma to regorafenib

  • Cell Death Dis. 2021 Nov 16;12(12):1084. doi: 10.1038/s41419-021-04320-4.
Jianyong Zhuo  # 1 2 Di Lu  # 1 Zuyuan Lin 1 Xinyu Yang 1 Modan Yang 1 Jianguo Wang 1 Yaoye Tao 1 Xue Wen 3 Huihui Li 1 Zhengxing Lian 1 Beini Cen 1 Siyi Dong 4 Xuyong Wei 1 Haiyang Xie 2 5 6 Shusen Zheng 2 4 5 6 7 Youqing Shen 8 Xiao Xu 9 10 11
Affiliations

Affiliations

  • 1 Department of Hepatobiliary and Pancreatic Surgery, Center for Integrated Oncology and Precision Medicine, the Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 2 Institute of Organ Transplantation, Zhejiang University School of Medicine, Hangzhou, China.
  • 3 Department of Pathology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 4 National Center for Healthcare Quality Management in Liver Transplant, Hangzhou, China.
  • 5 Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 6 National Health Commission Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China.
  • 7 Department of Hepatobiliary and Pancreatic Surgery, Shulan (Hangzhou) Hospital, Hangzhou, China.
  • 8 Center for Bionanoengineering and Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, China.
  • 9 Department of Hepatobiliary and Pancreatic Surgery, Center for Integrated Oncology and Precision Medicine, the Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China. zjxu@zju.edu.cn.
  • 10 Institute of Organ Transplantation, Zhejiang University School of Medicine, Hangzhou, China. zjxu@zju.edu.cn.
  • 11 National Center for Healthcare Quality Management in Liver Transplant, Hangzhou, China. zjxu@zju.edu.cn.
  • # Contributed equally.
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.

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