CK19-positive Hepatocellular Carcinoma is a Characteristic Subtype

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.

Figure 1

Overview for the origin of CK19-positive HCC. CK19 expression vanishes in adults' hepatocytes. Once the liver is damaged by inflammation, a portion of hepatocyte will reverse into progenitor cells which express CK19. These progenitor cells will potentially differentiate into CK19-positive HCC cells. Notably, the hepatocytes develop into CK19-negative HCC cells preferentially under normal condition. The hypoxia stimulations including the oxygen-deficient environment in tumor and hypoxic status caused by local treatments such as TACE will, however, induce CK19-negative HCC cells to transform into CK19-positive HCC cells. Abbreviation: CK19-, CK19-negative; CK19+, CK19-positive.

Figure 2

Diagrammatic sketch of the regulatory network of CK19. Abbreviation: CK19, cytokeratin 19; TGFβ, transforming growth factor beta; TGFβR, transforming growth factor beta receptor; HGF, hepatocyte growth factor; MET, MET proto-oncogene receptor tyrosine kinase or hepatocyte growth factor receptor; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; PDGF, platelet derived growth factor; PDGFRα, platelet derived growth factor receptor alpha; Smad, drosophila mothers against decapentaplegic protein; MEK, mitogen-activated protein kinase kinase 7; ERK, mitogen-activated protein kinase 1; JNK, mitogen-activated protein kinase 8; JUN, Jun proto-oncogene AP-1 transcription factor subunit; FOS, Fos proto-oncogene AP-1 transcription factor subunit; AP1, activator protein 1; SP1, specificity protein 1; KLF4, Krüppel like factor 4; KLF10, Krüppel like factor 10; SALL4, spalt-like transcription factor 4; CDH17, cadherin 17; LamB1, laminin subunit beta 1; Src, SRC proto-oncogene non-receptor tyrosine kinase; miR-642, microRNA 642a; miR-141, microRNA 141; miR-200c, microRNA 200c; Lin00974, long intergenic non-protein coding RNA 974.