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 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.

Comparative Study between the 3D‐Liver Spheroid Models Developed from HepG2 and Immortalized Hepatocyte‐Like Cells with Primary Hepatic Stellate Coculture for Drug Metabolism Analysis and Anticancer Drug Screening

“…Therefore, the developed 3D‐HepG2 coculture model may be useful for investigating the role of CK19 in tumor and finding new target molecules against CK19‐positive HCC. [ 44 ]…”

“…Therefore, the developed 3D-HepG2 coculture model may be useful for investigating the role of CK19 in tumor and finding new target molecules against CK19-positive HCC. [44] ALB was used to investigate the liver function of all developed spheroid models. [17,23,45] To examine the liver function at different stages of spheroid growth, the supernatants were collected from day 5 (early-stage spheroids) to day 14 (late-stage spheroids).…”

Clonorchis sinensis infection amplifies hepatocellular carcinoma stemness, predicting unfavorable prognosis

“…sinensis not only serves as an independent risk factor for OS and RFS but also elevates the expression of HCC CSC markers, namely, CK19 and EpCAM. CK19+ HCC is an aggressive subtype characterized by its propensity for early recurrence, metastasis and chemotherapy tolerance as well as poor prognosis [ 45 – 48 ]. Oriana Miltiadous et al reported an independent association between CK19 and HCC recurrence, with a hazard ratio of 2.95 [ 49 ].…”

Prediction Model and Nomogram of Early Recurrence of Hepatocellular Carcinoma after Radiofrequency Ablation Based on Logistic Regression Analysis

“…After RFA treatment, liver cancer recurrence increased in patients. With respect to the recurrence of liver cancer, time is used as a dividing line in many studies (Shinkawa et al 2021;Zhuo et al 2021), and recurrence is divided into early and late recurrence. In this study, early recurrence was defined as within 24 mo after ablation.…”