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.
Highlights
Cytokeratin 19 (CK19) is a marker for early hepatoblasts, hepatic progenitor cells, and cholangiocytes [1, 2]
P value Taken together, these results suggest that CK19+ hepatocellular carcinoma (HCC) cells have (n = 157)
Mitochondrial ribosomal proteins were involved in the response of CK19+ HCC cells to regorafenib Because of the specific inhibitory effects of regorafenib on CK19+ cells, we further investigated the underlying mechanisms
Summary
Cytokeratin 19 (CK19) is a marker for early hepatoblasts, hepatic progenitor cells, and cholangiocytes [1, 2]. The CK19-related gene signature has strongly overlapped with previously described more aggressive HCC subclass, such as “Hoshida_S2” [10], “Chiang_Proliferation” [11], “iCluster subtype” [12], and “Shimada_MS1” [13]. Using microarrays and microRNA profiling in a Caucasian cohort of 242 consecutive HCC samples, Govaere et al [14] reported the distinct molecular profile of CK19+ HCCs, which was different from other HCC types. Taking these into consideration, CK19+ HCC should be diagnosed and treated as a unique subtype. It is necessary to identify specific therapeutic options for CK19+ HCC
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