Abstract Background. Osteopontin (OPN) plays important roles in tumor progression and metastasis through binding to CD44 and integrin. The goal of this study was to elucidate the prognostic significance of OPN and CD44 in hepatocellular carcinoma patients. Methods. Tumor tissue microarray was used to detect the expression levels of OPN and CD44 in 302 hepatocellular carcinoma patients undergoing curative resection between 1997 and 2000 at our institute. Clinicopathologic data for these patients were investigated. The prognostic effects of OPN and CD44 were evaluated using the Kaplan–Meier method and compared using the log-rank test. The Spearman rank test and Fisher's exact test were applied to demonstrate correlations. Results. Both OPN and CD44 were independent predictors for overall survival and disease-free survival. When OPN and CD44 were taken into consideration together, the predictive range was extended and the sensitivity was improved, especially for those patients with normal serum α-fetoprotein levels. The 8-year overall survival and disease-free survival rates in OPN+ and/or CD44+ patients were 28.2% and 25.6%, respectively, which were significantly lower than those of OPN−CD44− patients (52.1% and 51.6%, respectively). Conclusions. OPN combined with CD44 is a promising independent predictor of tumor recurrence and survival in hepatocellular carcinoma patients.
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 α-fetoprotein, tumor-node-metastasis stage, and vascular invasion. The 7-year OS and disease-free 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; P < 0.001). 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.
Abstract Hepatocellular carcinoma (HCC) is closely associated with abnormal DNA methylation. In this study, we analyzed 450K methylation chip data from 377 HCC samples and 50 adjacent normal samples in the TCGA database. We screened 47,099 differentially methylated sites using Cox regression as well as SVM‐RFE and FW‐SVM algorithms, and constructed a model using three risk categories to predict the overall survival based on 134 methylation sites. The model showed a 10‐fold cross‐validation score of 0.95 and satisfactory predictive power, and correctly classified 26 of 33 samples in testing set obtained by stratified sampling from high, intermediate and low risk groups.
Liver-intestine cadherin (LI-cadherin; CDH-17) is a new member of the cadherin superfamily with distinct structural and functional features. The study was designed to investigate the role of LI-cadherin in tumor invasion and prognosis of human hepatitis B virus (HBV)-positive hepatocellular carcinoma (HCC).LI-cadherin expression in HBV-positive hepatocellular carcinoma cell lines with low- and high-invasive potentials was evaluated by Western-blot, immunofluorescence, and real-time polymerase chain reaction (PCR) analyses. The role of LI-cadherin in tumor invasion was also evaluated in vitro by a small-interfering ribonucleic acid (siRNA)-mediated approach. The prognostic significance of LI-cadherin was validated in a cohort of HBV-positive HCC patients by immunohistochemistry and Western-blot.Significant high levels of LI-cadherin mRNA and protein were found in the high-invasive HCCLM3 as compared with those in low-invasive PLC/PRF/5 and Hep3B cell line. Cell migration, adhesion to extracellular matrix, and matrigel invasion were significantly reduced after LI-cadherin knockdown in HCCLM3 cells. Immunohistochemical analysis of 255 HBV-positive HCC cases showed that overexpression of LI-cadherin was well correlated with microvascular invasion, which was confirmed by Western-blot in 32 tumor tissues, and its overexpression was strongly associated with shorter overall survival as well as higher incidence of tumor recurrence.LI-cadherin is predictive of microvascular invasion and poor prognosis of HBV-positive HCC, and would be a potential useful intervention target for HCC.
The loss of 5-hydroxymethylcytosine (5-hmC) has been identified as an epigenetic hallmark in several malignancies. However, its role in intrahepatic cholangiocarcinoma (ICC) is still unknown. Our study aims to investigate the level of 5-hmC in diagnosis and prognosis prediction of ICC. The 5-hmC levels were detected using dot blot, tissue microarray technique and immunohistochemical method, and the correlation between 5-hmC level and ICC clinicopathological parameters was analysed. Compared with matched liver tissues, most of ICC tissues presented with the loss of 5-hmC. Furthermore, the subgroups of cirrhotic and poor differentiation tissues showed the lowest level of 5-hmC. We found that 5-hmC level in non-elevated ICC patients was significantly related to lymph node metastasis and TNM stage and not related to vessel invasion, sex, age, HBV, cirrhosis or degree of differentiation. ICC patients with high TNM stage (stages III and IV) and lymph node metastases had significantly lower 5-hmC level than those with low TNM stage (stages I and II) and no lymph node metastases. Further analysis showed that low 5-hmC level is significantly correlated with worse overall survival (OS) and disease-free survival (DFS). Importantly, multivariate analysis indicated that 5-hmC level, tumour diameter, lymphatic metastasis and tumour differentiation could be used as independent prognostic factors for ICC. The loss of 5-hmC is implicated in the progression of ICC. Our results can contribute to the diagnostic ability and postoperative surveillance of ICC patients.
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