Cytokeratin 10 and Cytokeratin 19: Predictive Markers for Poor Prognosis in Hepatocellular Carcinoma Patients after Curative Resection

Abstract

Purpose: Cytokeratin 10 (CK10) was found to be expressed differently in human hepatocellular carcinoma (HCC) cell lines with different metastatic potentials in our previous research.The aim of this study was to assess the value of CK10 alone or in combination with cytokeratin 19 (CK19) in predicting tumor recurrence after curative resection in HCC patients. Experimental Design: CK10 expression in stepwise metastatic HCC cell lines and tumor tissues from 50 HCC patients was investigated using immunofluorescence assay, quantitative real-time reverse transcription-PCR, and Western blot analyses. Tumor tissue microarrays of 300 HCC patients who underwent curative resection between 1997 and 2000 were used to detect the expressions of CK10 and CK19. Clinicopathologic data for these patients were evaluated. The prognostic significance was assessed using Kaplan-Meier survival estimates and log-rank tests. Results: CK10 was overexpressed in the high metastatic HCC cell line and in tumor tissues of recurrent patients. Both univariate and multivariate analyses revealed that CK10 was a significant predictor for overall survival (OS) and disease-free survival, and that CK19 was a significant predictor for OS. CK10 expression was correlated with poor prognosis regardless of a-fetoprotein, tumor-node-metastasis stage, and vascular invasion. The 7-year OS and diseasefree survival rates in CK10 + and/or CK19 + patients were 30.0% and 37.6%, respectively, which were significantly lower than that of CK10 -/CK19 -patients (56.1% and 60.0%, respectively;Conclusion: CK10 is associated with HCC invasiveness. CK10 alone, or in combination with CK19, can be a novel predictor for poor prognosis of HCC patients after curative resection.Hepatocellular carcinoma (HCC) is one of the most prevalent tumor types; its incidence and mortality rates have increased in recent years (1).The high rate of recurrence or metastases after curative resection has hindered improvements in HCC survival (2, 3). Molecular signatures that define the risk of recurrence and metastatic potential of HCC have been difficult to identify. Such markers would allow appropriate therapeutic regimens to be applied earlier in the disease course. Although several prognostic biomarkers in HCC have been reported recently (4 -7), there still remains a lack of ideal biomarkers available that can be widely used in clinical settings (8, 9). Cytokeratins are typical epithelial cell markers expressed in a tissue-specific and differentiation-dependent manner. It has been reported that cytokeratins were extensively present in many malignant epithelial cells (10 -13) and tended to be altered in association with increases in metastatic ability and malignancy (14). Several cytokeratins were proven to be present in HCC (15,16) and relate with poor prognosis and metastatic potential (17 -22).In our previous research, cytokeratin 10 (CK10) expression was detected by in vitro phage display and proteomics technology in MHCC97-H but not in MHCC97-L, two human HCC cell lines created at ...

Epidermal growth factor induces cytokeratin 19 expression accompanied by increased growth abilities in human hepatocellular carcinoma

“…8,11,12 In accordance with these reports, CK19 positivity significantly correlated with the 2-year DFS rate. 8,11 Although the 5-year DFS and OS rate was not significantly correlated with CK19 positivity in this study, both of them tended to be lower in CK19-positive HCC group. Because this study dealt with relatively limited number of cases and the follow up periods were not sufficient, a significant difference might not be obtained.…”

“…In most of the EGF and CK19-positive HCC N Yoneda et al CK19-positive cases, CK19 expression in HCC was not diffusely observed, and CK19-positive cells were aggregated in focal areas in a single section (Figure 6b). On the basis of previous reports, 8,11,12 CK19-positive HCC was defined as such tumor that o5% of total carcinoma cells showed positive immunoreactivity of CK19 in this study. According to this definition, 9 (12%) of 78 cases of surgically resected HCC samples corresponded to CK19-positive HCC.…”

“…[5][6][7][8][9][10] The expression of CK19 in HCC is implicated as a novel predictor for the poor prognosis of the patients after curative resection. 8,11,12 Although the clinical significance of CK19-positive HCC seems to be establishing, the mechanism underlying the development of CK19-positive HCC remains to be unclear.…”

Tumor initiation and progression in hepatocellular carcinoma: risk factors, classification, and therapeutic targets

“…Lee et al showed significant survival differences between HCC patients with a hepatocyte-like phenotype and a hepatoblast-like phenotype [70,71] . Other studies suggest that HCC positive for Keratin 19 (KRT19), which is a progenitor cell marker, have a higher rate of recurrence after resection or transplantation [72][73][74] . Other fetal markers such as AFP and epithelial cell adhesion molecule (EpCAM) are of prognostic value as well, since EpCAM+/AFP+HCC is associated with poor survival [75] .…”

1047 Keratin 19: A Key Role Player in the Invasion of Human Hepatocellular Carcinomas

“…[2][3][4][5][6] In 2006, our group was the first to describe the clinicopathological and prognostic relevance of K19 in a Caucasian series of HCCs as it was linked with a high recurrence after transplantation. 7 Subsequently, we started a prospective study on a Caucasian series of 242 consecutive HCC samples with a different range of aetiologies and performed a detailed evaluation of the clinicopathological relevance of K19.…”