MicroRNA-34c-3p promotes cell proliferation and invasion in hepatocellular carcinoma by regulation of NCKAP1 expression.

PURPOSE: Our previous miRNA profiling study indicated that microRNA-34c-3p (miR-34c-3p) was overexpressed and associated with survival in HCC. This study is aimed to confirm its clinical significance and explore the function and underlying mechanism of miR-34c-3p in HCC. METHODS: We first evaluated miR-34c-3p expression and its relationship with prognosis in HCC patients. We then established stable HCC cell lines with miR-34c-3p overexpression and knockdown by the lentiviral packaging systems and performed the functional assays in vitro and in vivo, respectively. We next identified the target of miR-34c-3p by using microRNA target databases and dual-luciferase assay. Finally, the correlation between the expression of miR-34c-3p and the target gene was analyzed by immunohistochemistry and qRT-PCR in HCC tissues and hepatoma xenografts. RESULTS: Overexpressed miR-34c-3p was confirmed in HCC tissues and significantly associated with poor survival of HCC patients. miR-34c-3p expression was also recognized as an independent risk factor for DFS and OS in multivariate analysis. Ectopic expression of miR-34c-3p significantly promotes the proliferation, colony formation, invasion and cell cycle regression of HCC cell lines. Knockdown of miR-34c-3p remarkably blocked hepatoma growth in the xenograft model. miRNA target databases and luciferase reporter assay showed that NCKAP1 was a direct target of miR-34c-3p in HCC cells and the high expression of NCKAP1 in HCC tissues is significantly correlated with low expression of miR-34c-3p and associated with a favorable prognosis of HCC patients. CONCLUSION: The current study demonstrates that miR-34c-3p functions as a tumor promoter by targeting NCKAP1 that is associated with prognosis in HCC. miR-34c-3p and NCKAP1 may be new potential molecular targets for HCC therapy.

Transarterial chemoembolization combined with sorafenib for the treatment of hepatocellular carcinoma with hepatic vein tumor thrombus.

OBJECTIVE: To compare the treatment outcomes of sorafenib plus transarterial chemoembolization (TACE) vs TACE alone in patients with hepatocellular carcinoma (HCC) and hepatic vein tumor thrombus (HVTT). METHODS: Twenty patients who were initially diagnosed with HCC and HVTT and received TACE combined with sorafenib during February 2009 to October 2013 were included in the study. To minimize selection bias, these patients were compared with 60 case-matched controls selected from a pool of 81 patients (in a 1:3 ratio) who received TACE alone during the same period. The primary end point was overall survival (OS). The secondary end points were time to progression, disease control rate, and adverse events. RESULTS: After a median follow-up period of 12.5 months (range, 1.03-44.23 months), the OS of the combined group was found to be significantly higher compared with the monotherapy group (14.9 vs 6.1 months, P=0.010). The time to progression was found to be significantly longer in the combined group (4.9 vs 2.4 months, P=0.016). Univariate and multivariate analyses revealed that the treatment allocation was an independent predictor of OS. CONCLUSION: Sorafenib plus TACE was well tolerated and was more effective in treating patients with advanced HCC and HVTT. Future trials with prospective larger samples are required to validate these results.

Optimal surgical strategy for hepatocellular carcinoma with portal vein tumor thrombus: a propensity score analysis.

OBJECTIVES: The optimal surgical resection method for hepatocellular carcinoma (HCC) patients with portal vein tumor thrombus (PVTT) that maximizes both safety and long-term outcome has not yet been determined. The aim of this study was to compare the clinical outcomes following peeling off versus en bloc resection for PVTT. METHODS: From 2005 to 2012, 252 patients with HCC and type I/II PVTT who underwent hepatic resection were divided into two groups according to whether they received en bloc resection (n = 113) or peeling off resection (n = 139). The clinical outcomes were compared before and after propensity score matching. RESULTS: The propensity model matched 113 patients with en bloc resection for further analyses. After matching, overall survival (OS) and disease-free survival (DFS) rates were significantly increased in the en bloc group compared with the peeling off group (p = 0.011 and p = 0.015). A multivariate analysis indicated that en bloc resection independently improved both OS and DFS (HR = 1.471, 95% CI: 1.071-2.018, p = 0.017 and HR = 1.415, 95% CI: 1.068-1.874, P=0.016). The adverse events were not significantly different between the two groups. However, the peeling off group showed a significantly increased recurrence rate of vascular invasion compared with the en bloc group (23.9% vs. 9.7%, p = 0.005). Similar results were also demonstrated prior to the matched analysis. CONCLUSIONS: An en bloc resection is safe and confers a survival advantage compared with a peeling off resection in HCC patients with PVTT; thus, en bloc resection should be recommended as a standard treatment for these patients when possible.

Elevated expression of Cripto-1 correlates with poor prognosis in hepatocellular carcinoma.

Cripto-1 could promote tumorigenesis in a wide range of carcinomas, yet little is known in hepatocellular carcinoma (HCC). The expression of Cripto-1 and MMP-9 were assessed by immunohistochemistry in 205 HCC specimens. The correlation between Cripto-1 and MMP-9, clinicopathological/prognostic value in HCC was examined. Cripto-1 overexpression was correlated with larger tumor, TNM stage, BCLC stage and tumor recurrence. In multivariate analyses, Cripto-1 was an independent predictor for overall survival (OS) and time to recurrence (TTR). Cripto-1 expression was increased in TNM and BCLC stage-dependent manner. Cripto-1 overexpression was associated with poor prognosis in patients subgroups stratified by tumor size, tumor differentiation, TNM and BCLC stage. In addition, Cripto-1 was positively correlated with MMP-9 among 205 HCC samples. Patients with Cripto-1 upregulation had poor OS and shorter TTR in low and high aggressiveness groups. Furthermore, Cripto-1 had predictive validity for early and late recurrence in HCC patients. Combination of Cripto-1 and serum AFP was correlated with OS and TTR. In conclusion, Cripto-1 overexpression contributes to aggressiveness and poor prognosis of HCC. Cripto-1/AFP expression could be a potential prognostic biomarker for survival in HCC patients.

A prognosis model for patients with hepatocellular carcinoma and portal vein tumor thrombus following hepatic resection.

The present study aimed to identify the risk factors influencing the survival of patients with hepatocellular carcinoma (HCC) affected by portal vein tumor thrombus (PVTT), following hepatic resection, and to establish a prognostic model. Between March 2001 and May 2008, 234 cases of HCC with PVTT that underwent hepatic resection were randomly divided into experimental or validation groups. The association between the clinicopathological factors and disease-free survival (DFS) and overall survival (OS) was analyzed, and the significant factors involved were used to establish a prognostic model, which was then validated. Tumor rupture, number of tumors and macroscopic vascular invasion were observed to be independent risk factors of DFS and OS. In the prognostic model, the DFS and OS of low-, medium- and high-risk patients in the experimental group were observed to be significantly different, compared to those in the validation group. In conclusion, the present study established a prognostic model for patients with HCC affected by PVTT following hepatectomy, and demonstrated that the model may be used to guide the treatment of these patients and predict their prognosis.

Risk factors for early and late intrahepatic recurrence in patients with single hepatocellular carcinoma without macrovascular invasion after curative resection.

BACKGROUND: Prognostic factors of postoperative early and late recurrence in patients with hepatocellular carcinoma (HCC) undergoing curative resection remain to be clarified. The aim of this study was to identify risk factors for postoperative early (≤ 2 year) and late (> 2 year) intrahepatic recurrences in patients with single HCCs without macrovascular invasion. METHODS: A total of 280 patients from December 2004 to December 2007 were retrospectively included in this study. Intrahepatic recurrence was classified into early (≤ 2 year) and late (> 2 year) and the Chi-Square test or Fisher's exact test and multivariate logistic regression analysis were performed to determine significant risk factors. RESULTS: During the follow-up, 124 patients had intrahepatic recurrence, early and late in 82 and 42 patients, respectively. Multivariate logistic regression analysis showed that microvascular invasion (p=0.006, HR: 2.397, 95% CI: 1.290-4.451) was the only independent risk factor for early recurrence, while being female (p = 0.031, HR: 0.326, 95% CI: 0.118-0.901), and having a high degree of cirrhosis (P=0.001, HR: 2.483, 95% CI: 1.417-4.349) were independent risk factors for late recurrence. CONCLUSIONS: Early and late recurrence of HCC is linked to different risk factors in patients with single HCC without macrovascular invasion. This results suggested different emphases of strategies for prevent of recurrence after curative resection, more active intervention including adjuvant therapy, anti-cirrhosis drugs and careful follow-up being necessary for patients with relevant risk factors.

Long-term outcomes after curative resection for patients with macroscopically solitary hepatocellular carcinoma without macrovascular invasion and an analysis of prognostic factors.

The long-term outcome and prognostic factors after curative in patients with single hepatocellular carcinoma (HCC) without macrovascular invasion are still unclear. The objective of this study is to evaluate the effect of curative resection on survival and analyze the prognostic clinicopathologic factors, especially the presence of microvascular invasion (MVI), in these patients. Two hundred and sixty consecutive patients with single HCC without macrovascular invasion who underwent curative resection from December 2004 to December 2007 were retrospectively reviewed in this study. Survival rates were calculated by using the Kaplan-Meier method. Univariate and multivariate analyses of 14 clinicopathologic factors were performed to determine the significant prognostic factors. No patient died within 1 month after the operation. The 1-, 3-, and 5-year overall survival rates after curative resection were 96.54, 83.46, and 74.01%, respectively. Multivariate analysis revealed that only the presence of MVI was an independent negative prognostic factor affecting overall survival. The 1-, 3-, and 5-year disease-free survival rates were 79.62, 62.69, and 56.01%, respectively. The presence of MVI was the only independent unfavorable prognostic factor for disease-free survival. According to our analysis, patients with single HCC without macrovascular invasion after curative resection can be expected to have considerable long-term survival. The presence of MVI was an independent negative prognostic factor for both overall survival and disease-free survival. To improve the prognosis, these patients should be followed up more carefully and might be good candidates for adjuvant therapy.