J Cancer 2020; 11(17):5069-5077. doi:10.7150/jca.44697

Review

CK19-positive Hepatocellular Carcinoma is a Characteristic Subtype

Jian-Yong Zhuo1,2#, Di Lu1,2#, Win-Yen Tan1,2, Shu-Sen Zheng1,2,3, You-Qing Shen4✉, Xiao Xu1,2✉

1. Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, Zhejiang Province, China.
2. NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, Hangzhou, 310003, Zhejiang Province, China.
3. Department of Hepatobiliary and Pancreatic Surgery, Shulan (Hangzhou) Hospital, Hangzhou, 310003, Zhejiang Province, China.
4. Center for Bionanoengineering and Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, 310003, Zhejiang Province, China.
#These authors contributed equally to this work.

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Citation:
Zhuo JY, Lu D, Tan WY, Zheng SS, Shen YQ, Xu X. CK19-positive Hepatocellular Carcinoma is a Characteristic Subtype. J Cancer 2020; 11(17):5069-5077. doi:10.7150/jca.44697. Available from http://www.jcancer.org/v11p5069.htm

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Abstract

The heterogeneity of hepatocellular carcinoma (HCC) commonly leads to therapeutic failure of HCC. Cytokeratin 19 (CK19) is well acknowledged as a biliary/progenitor cell marker and a marker of tumor stem cell. CK19-positive HCCs demonstrate aggressive behaviors and poor outcomes which including worse overall survival and early tumor recurrence after hepatectomy and liver transplantation. CK19-positive HCCs are resistant to chemotherapies as well as local treatment. This subset of HCC is thought to derive from liver progenitor cells and can be induced by extracellular stimulation such as hypoxia. Besides being a stemness marker, CK19 plays an important role in promoting malignant property of HCC. The regulatory network associated with CK19 expression has been summarized that extracellular stimulations which transmit into cytoplasm through signal transduction pathways (TGF-β, MAKP/JNK and MEK-ERK1/2), further induce important nuclear transcriptional factors (SALL4, AP1, SP1) to activate CK19 promoter. Novel noncoding RNAs are also involved in the regulation of CK19 expression. TGFβR1 becomes a therapeutic target for CK19-positive HCC. In conclusion, CK19 can be a potential biomarker for predicting poor prognosis after surgical and adjuvant therapies. CK19-pisitive HCCs exhibit distinctive molecular profiling, should be diagnosed and treated as a separate subtype of HCCs.

Keywords: cytokeratin 19, hepatocellular carcinoma, subtype