Binkui Li

Identification of MACC1 as a novel prognostic marker in hepatocellular carcinoma

BackgroundMetastasis-associated in colon cancer-1 (MACC1) is a newly identified gene that plays a role in colon cancer metastasis through upregulation of c-MET proto-oncogene (c-MET). However, the value of MACC1 as a potential biomarker for hepatocellular carcinoma (HCC) remains unknown.MethodsMACC1 mRNA expression in 128 HCC tissues was examined by quantitative polymerase chain reaction. To show the potential correlation of MACC1 and c-MET, c-MET was also analysed.ResultsMACC1 was more highly expressed in HCC than in non-HCC tissues (P = 0.009). High MACC1 expression was significantly increased in cases with high alpha fetoprotein (AFP) (P = 0.025). A positive correlation was found between MACC1 and c-MET mRNAs (r = 0.235, P = 0.009). Both univariate and multivariate analyses revealed that MACC1 expression was associated with overall survival (OS) and disease-free survival (DFS). Moreover, stratified analysis showed that tumour-node-metastasis (TNM) stage I patients with high MACC1 levels had shorter OS and DFS than those with low MACC1.ConclusionsMACC1 may identify low- and high-risk individuals with HCC and be a valuable indicator for stratifying the prognosis of TNM stage I patients. MACC1 may serve as a novel biomarker for HCC.

CHK1 targets spleen tyrosine kinase (L) for proteolysis in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies resistant to current chemotherapies or radiotherapies, which makes it urgent to identify new therapeutic targets for HCC. In this study, we found that checkpoint kinase 1 (CHK1) was frequently overexpressed and correlated with poor clinical outcome in patients with HCC. We further showed that the CHK1 inhibitor GÖ6976 was capable of sensitizing HCC cells to cisplatin, indicating that CHK1 may have oncogenic function in HCC. We found that CHK1 phosphorylated the tumor suppressor spleen tyrosine kinase (L) (SYK[L]) and identified the phosphorylation site at Ser295. Furthermore, CHK1 phosphorylation of SYK(L) promoted its subsequent proteasomal degradation. Expression of a nonphosphorylated mutant of SYK(L) was more efficient at suppressing proliferation, colony formation, mobility, and tumor growth in HCC lines. Importantly, a strong inverse correlation between the expression levels of CHK1 and SYK(L) was observed in patients with HCC. Collectively, our data demonstrate that SYK(L) is a substrate of CHK1 in tumor cells and suggest that targeting the CHK1/SYK(L) pathway may be a promising strategy for treating HCC.

Role of Sox2 and Oct4 in predicting survival of hepatocellular carcinoma patients after hepatectomy

OBJECTIVES The present study was aimed to explore the prognostic strength of Sox2 and Oct4A in hepatocellular carcinoma (HCC). DESIGN AND METHODS We investigated the expression of Sox2 and Oct4A in five hepatoma cell lines, one immortalized normal liver cell line, HCC tissues with matched nontumorous liver tissues and normal liver tissues by reverse transcription-polymerase chain reaction. RESULTS Sox2 and Oct4A mRNA were overexpressed in hepatoma cell lines and tumor tissues. Sox2 or Oct4A positive expression was significantly associated with an aggressive phenotype. Both univariate and multivariate analyses revealed that Sox2 or Oct4A was an independent prognostic factor for HCC. When using subgroup analysis, the patients with a co-expression of Sox2/Oct4A had the poorest prognosis. Further analysis demonstrated that Sox2 alone or Sox2/Oct4A could stratify outcome in HCC patients with early stage. CONCLUSIONS Sox2 and Oct4A can be novel predictors of poor prognosis for patients undergoing resection of HCC.

Expression of variant isoforms of the tyrosine kinase syk determines the prognosis of hepatocellular carcinoma

The spleen tyrosine kinase (SYK) has been reported as a novel biomarker for human hepatocellular carcinoma, but the functional contributions of its two isoforms SYK(L) and SYK(S) are undefined. In this study, we investigated their biologic functions and possible prognostic values in hepatocellular carcinoma. SYK(L) was downregulated in 38% of human specimens of hepatocellular carcinoma examined, whereas SYK(S) was detectable in 40% of these specimens but not in normal liver tissue samples without cirrhosis. SYK(S) expression correlated with pathologic parameters characteristic of tumor metastasis, including multiple tumors (P = 0.003) and vascular invasion (P = 0.001). Further, SYK(S) was specifically associated with epithelial-mesenchymal transition (EMT) in hepatocellular carcinoma specimens. Functional studies showed that SYK(S) promoted tumor growth, suppressed apoptosis, and induced EMT through the extracellular signal-regulated kinase pathway, countering the opposite effects of SYK(L). Patients with SYK(L(+)/S(-)) tumors exhibited longer overall survival and time to recurrence than those with SYK(L(-)/S(-)) or SYK(L(+)/S(+)) tumors (P < 0.001). Taken together, our findings showed that SYK(S) enhances invasion, whereas SYK(L) inhibits metastasis in hepatocellular carcinoma. We suggest that SYK(L) downregulation or SYK(S) elevation are strong predictors of poor survival in patients with hepatocellular carcinoma, indicative of a need for aggressive therapeutic intervention.

Efficacy and safety of thermal ablation in patients with liver metastases

Objective Thermal ablation is safe and effective for the treatment of hepatocellular carcinoma. However, it remains problematic with respect to liver metastases. Here, we aimed to evaluate the efficacy and safety of thermal ablation in patients with liver metastases. Methods Eighty-nine patients with 132 liver metastases measuring 0.8–5.0 cm were treated with microwave ablation (MWA) or radiofrequency ablation (RFA). The primary lesions were colorectal cancer in 38 cases and others in 51, respectively. Local tumor control, complications, and long-term survival were analyzed. Results Complete ablation was achieved in 117 of 132 (88.6%) nodules. Seventeen of the 117 (14.5%) successfully treated nodules developed local recurrence. In a univariate analysis, a significant trend toward a lower local recurrence rate with MWA was observed (8.6% for MWA vs. 20.3% for RFA, P=0.072). Multivariate analysis showed that number of cycles of chemotherapy was the significant prognostic factor for overall recurrence (P=0.015), whereas disease-free interval was the significant prognostic factor for distant recurrence (P=0.030). Ablation modality showed potential prognostic significance for local recurrence (P=0.053). Major complications occurred in 1.1% of patients. No procedure-related mortalities were observed. The 1, 2, 3, and 5-year overall survival rates after the initial ablation were 84.9, 59.6, 48.8, and 36.3%, respectively. Conclusion Thermal ablation is a safe and effective treatment for patients with liver metastases. MWA has the potential to result in less local recurrence than RFA.

CpG Methylation Signature Predicts Recurrence in Early-Stage Hepatocellular Carcinoma: Results From a Multicenter Study

Purpose Early-stage hepatocellular carcinoma (E-HCC) is being diagnosed increasingly, and in one half of diagnosed patients, recurrence will develop. Thus, it is urgent to identify recurrence-related markers. We investigated the effectiveness of CpG methylation in predicting recurrence for patients with E-HCCs. Patients and Methods In total, 576 patients with E-HCC from four independent centers were sorted by three phases. In the discovery phase, 66 tumor samples were analyzed using the Illumina Methylation 450k Beadchip. Two algorithms, Least Absolute Shrinkage and Selector Operation and Support Vector Machine-Recursive Feature Elimination, were used to select significant CpGs. In the training phase, penalized Cox regression was used to further narrow CpGs into 140 samples. In the validation phase, candidate CpGs were validated using an internal cohort (n = 141) and two external cohorts (n = 191 and n =104). Results After combining the 46 CpGs selected by the Least Absolute Shrinkage and Selector Operation and the Support Vector Machine-Recursive Feature Elimination algorithms, three CpGs corresponding to SCAN domain containing 3, Src homology 3-domain growth factor receptor-bound 2-like interacting protein 1, and peptidase inhibitor 3 were highlighted as candidate predictors in the training phase. On the basis of the three CpGs, a methylation signature for E-HCC (MSEH) was developed to classify patients into high- and low-risk recurrence groups in the training cohort ( P < .001). The performance of MSEH was validated in the internal cohort ( P < .001) and in the two external cohorts ( P < .001; P = .002). Furthermore, a nomogram comprising MSEH, tumor differentiation, cirrhosis, hepatitis B virus surface antigen, and antivirus therapy was generated to predict the 5-year recurrence-free survival in the training cohort, and it performed well in the three validation cohorts (concordance index: 0.725, 0.697, and 0.693, respectively). Conclusion MSEH, a three-CpG-based signature, is useful in predicting recurrence for patients with E-HCC.

Expression and prognostic significance of CIP2A mRNA in hepatocellular carcinoma and nontumoral liver tissues

Objective: This study was undertaken to determine the role of cancerous inhibitor of protein phosphatase 2A (CIP2A) in predicting prognosis of hepatocellular carcinoma (HCC). Methods: CIP2A mRNA level of 136 pairs of tumor and nontumoral liver tissues of HCC patients after hepatectomy were investigated by quantitative real-time reverse transcription polymerase chain reaction. Results: Intratumoral CIP2A mRNA was not associated with patients’ prognosis. However, nontumoral CIP2A mRNA, which was correlated with lack of tumor encapsulation, poor tumor differentiation, intrahepatic metastasis, and high tumor-node-metastasis stage was an independent risk factor for overall survival and recurrence-free survival. Conclusions: Nontumoral CIP2A mRNA expression might serve as a novel biomarker for HCC patients undergoing resection.

The role of clinically significant portal hypertension in hepatic resection for hepatocellular carcinoma patients: a propensity score matching analysis.

BackgroundWhether portal hypertension (PHT) is an appropriate contraindication for hepatic resection (HR) in hepatocellular carcinoma (HCC) patient is still under debate.Aims: Our aim was to assess the impact of clinically significant PHT on postoperative complication and prognosis in HCC patients who undergo HR.MethodsTwo hundred and nine HCC patients who underwent HR as the initial treatment were divided into two groups according to the presence (n = 102) or absence (n = 107) of clinically significant PHT. Propensity score matching (PSM) analysis was used to compare postoperative outcomes and survival.ResultsBefore PSM, PHT patients had higher rates of postoperative complication (43.1% vs. 23.4%; P = 0.002) and liver decompensation (37.3% vs. 17.8%; P = 0.002) with similar rates of recurrence-free survival (RFS; P = 0.369) and overall survival (OS; P = 0.205) compared with that of non-PHT patients. However, repeat analysis following PSM revealed similar rates of postoperative complication (32.2% vs. 39.0%; P = 0.442), liver decompensation (25.4% vs. 32.2%; P = 0.416), RFS (P = 0.481) and OS (P = 0.417; 59 patients in each group). Presence of PHT was not associated with complication by logistic regression analysis, or with overall survival by Cox regression analysis.ConclusionsThe presence of clinically significant PHT had no impact on postoperative complication and prognosis, and should not be regarded as a contraindication for HR in HCC patients.

Clinical features and outcome of multiple primary malignancies involving hepatocellular carcinoma: A long-term follow-up study

BackgroundThe prolonged survival of individuals diagnosed with cancer has led to an increase in the number of secondary primary malignancies. We undertook to perform a definitive study to characterize and predict prognosis of multiple primary malignancies (MPM) involving hepatocellular carcinoma (HCC), due to the scarcity of such reports.MethodsClinicopathological data were analyzed for 68 MPM patients involving HCC, with 35 (target group) underwent curative liver resection. Additional 140 HCC-alone patients with hepatectomy were selected randomly during the same period as the control group.ResultsOf the 68 patients with extrahepatic primary malignancies (EHPM), 22 were diagnosed synchronously with HCC, and 46 metachronously. The most frequent EHPM was nasophargeal carcinoma, followed by colorectal and lung cancer. Univariate analysis demonstrated that synchronous (P = 0.008) and non-radical treatment for EHPM (P < 0.001) were significant risk factors associated with poorer overall survival (OS). While, Cox modeling revealed that the treatment modality for EHPM, but not the synchronous/metachronous determinant, was an independent factor for OS, and that therapeutic option for HCC was an independent factor for HCC-specific OS. Moreover, no HCC-specific overall and recurrence-free survival benefit were observed in the control group when compared with that of the target group (P = 0.607, P = 0.131, respectively).ConclusionsCurative treatment is an independent predictive factor for OS and HCC-specific OS, and should been taken into account both for synchronous and metachronous patients. MPM patients involving HCC should not be excluded from radical resection for HCC.

Resection vs. ablation for alpha-fetoprotein positive hepatocellular carcinoma within the Milan criteria: a propensity score analysis

The lack of histopathological confirmation of hepatocellular carcinoma (HCC) diagnosis for patients receiving ablation may result in misdiagnosis of benign liver nodule as HCC occasionally, contributing to false treatment efficacy. This underestimated issue is one reason why the ablation efficacy remains undetermined compared with hepatic resection. Our aim is to compare the efficacy of ablation and resection for HCC within the Milan criteria after excluding the impact of misdiagnosis.