2. Academic Validation
  3. 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.
PMID: 34785656 DOI: 10.1038/s41419-021-04320-4
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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