Cadherin 17 is related to recurrence and poor prognosis of cytokeratin 19‑positive hepatocellular carcinoma

Abstract

Abstract.A previous study demonstrated that cytokeratin 19 (CK19) expression in hepatocellular carcinoma (HCC) is an indicator of HCC invasiveness, including lymph node metastasis (LNM), tumor infiltration/non-encapsulation and poor prognosis. The exact mechanism by which CK19 expression results in poor prognosis remains unclear. Through the use of an Affymetrix U133A oligonucleotide microarray [20 patients with hepatitis B virus (HBV)-HCC], it was demonstrated that cadherin 17 (CDH17) significantly correlated with CK19 expression (R 2 , 0.867; P<0.001) in HBV-HCC. Immunohistochemical analysis (114 patients with HBV-HCC) also demonstrated a significant correlation between CK19 and CDH17 expressions in primary tumor tissue (R 2 , 0.414; P<0.001). In addition, CK19 and CDH17 expressions levels revealed a significant association with LNM (P<0.001). Cox regression multivariate analysis demonstrated that indocyanine green retention at 15 min >10% and CDH17 expression were independent prognostic factors for disease free survival (P=0.010 and 0.002, respectively). In vitro studies showed that epidermal growth factor can induce the expression of both CK19 and CDH17, and CDH17 in turn can enhance the expression of CK19 in HCC. In summary, this study demonstrated that the early recurrence and poor prognosis of CK19(+) HCC may be due to the expression of CDH17, a gene known to be associated with vascular invasion, tumor metastasis, and advanced tumor stage of HCC. Thus, novel therapeutics by targeting CDH17 may be beneficial for CK19(+) HCC.

Keratin 19‐expressing hepatocellular carcinoma and small‐duct type intrahepatic cholangiocarcinoma show a similar postoperative clinical course but have distinct genetic features

“…Lymph node metastasis is generally uncommon in HCC, but was observed in 8% of K19 + HCC in our cohort. This figure was even higher (~22%) in previous studies . The postoperative prognosis and pattern of tumour recurrence of K19 + HCC were similar to those of S‐iCCA.…”

“…All these alterations increase the expression of TERT, and have been identified as independent prognostic factors for patients with HCC . Based on tumour cell phenotypes, approximately 10% of HCC cases express keratin 19 (K19), a cholangiocyte/stem‐cell marker . Multiple studies have demonstrated that the clinical outcome of K19 + HCC was worse than that of K19 − HCC and better than that of intrahepatic cholangiocarcinoma (iCCA), indicating that K19 + HCC is an intermediate group between HCC and iCCA …”

Associations between CD133, CK19 and G2/M in cirrhotic HCV (genotype-4) patients with or without accompanying tumor

“…Nevertheless, when CD133 was combined with G2/M phase the diagnostic performance was improved but still insignificant with poor AUC value (0.602) and somewhat better accuracy (62.5%). In harmony with Cai et al (2012), Kim et al (2011) and Lee et al (2018), addition of CK19 to CD133 resulted in further improvement with considerable excellent AUC (0.973) and high accuracy (90%).…”

“…CK19 + in HCC is also a stemness marker which revealed strongest correlation with invasion, increasing tumor size, decreasing tumor differentiation, metastasis, and micro vascular invasion and it is an important predictive factor for prognosis, patient survival and tumor recurrence (Kim et al, 2011). CK19 is reported as an indicator of HCC invasiveness (Lee et al, 2018), is correlated with clinicopathologic signs of tumor aggressiveness and has been related to mortality in HCC patients (Lee et al, 2018). Few research papers gathered studying CD133 and CK19 together in HCV patients.…”

GDF11 exhibits tumor suppressive properties in hepatocellular carcinoma cells by restricting clonal expansion and invasion

“…To gain more evidence, we performed the analysis of the messenger RNA levels of key molecular markers for aggressive cancers and stemness ( Figure 3B), cytokeratin 19 (ck19) has been closely related to poor prognosis and high recurrence in HCC [34], the effect on ck19 expression, induced by GDF11, was the most relevant, in terms of absolute values comparing with NT cells, prom1 (CD133) and epcam (EpCAM) also are well characterized stemness markers, being CD133 most significant in stages I, while the prognostic role of EpCAM is more effective in advanced stages [35], interestingly, the effect of GDF11 in epcam expression was different in the HCC cell lines studied here, Huh7 cells did not respond to the GDF11 treatment exhibiting no changes in the expression, however, Hep3B, which a more aggressive cell line, diminished the expression since 6 h of treatment, supporting the findings by Chang and coworkers [35]. These results strongly suggest that GDF11 antitumorigenic properties are more relevant in advanced tumors.…”