Zhiyun Zheng

Prognostic Role of C-Reactive Protein in Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis

Background: C-reactive protein (CRP) which used to be a prototypical inflammatory cytokine has been identified involving in the progression of tumor-promoting inflammation. Several studies have indicated that CRP is a predictor for hepatocellular carcinoma (HCC), but the results are controversial. Methods: We conducted a systematic review of ten studies (1885 patients) to examine the association of high serum CRP expression with overall survival (OS) and recurrence-free survival (RFS) in HCC patients by meta-analysis. Moreover, the correlation between high serum CRP and tumor clinicopathological parameters was also assessed. Hazard ratio (HR) or odds ratio (OR) with its 95% confidence interval (CI) was used as the effect size estimate. Results: Our pooled results showed that high expression level of serum CRP (≥10 mg/L) was associated with poor OS (HR: 2.15, 95% CI: 1.76-2.63) and RFS (HR: 2.66, 95% CI: 1.54-4.58) in HCC. Serum CRP overexpression (≥10 mg/L) was also significantly associated with the presence of tumor vascular invasion (OR: 3.05, 95% CI: 1.79-5.23), multiple tumor (OR: 2.36, 95% CI: 1.36-4.10), larger tumor size (OR: 3.41, 95% CI: 1.04-11.18), and advanced TNM stage (OR: 3.23, 95% CI: 2.29-4.57). In addition, serum CRP overexpression (≥10 mg/L) tended to be correlated with poor differentiation (OR: 1.58, 95% CI: 0.74-3.39), though not significantly. Conclusion: The present systematic review and meta-analysis demonstrate that high serum level of CRP (≥10 mg/L) denotes a poor prognosis of patients with HCC.

MicroRNA-452 promotes stem-like cells of hepatocellular carcinoma by inhibiting Sox7 involving Wnt/β-catenin signaling pathway

The decrease of microRNA-452 (miR-452) in gliomas promoted stem-like features and tumorigenesis. However, the role of miR-452, especially in regulating cancer stem cells (CSCs) in hepatocellular carcinoma (HCC) remains ambiguous. We enriched stem-like HCC cells by serial passages of hepatospheres with chemotherapeutic agents. Stem-like characteristics including the capabilities of chemo-resistance, stemness-related gene expression profiling, self-renewal, tumorigenicity and metastasis formation were detected. MiR-452 was markedly increased in the chemo-resistant hepatospheres and human HCC tissues. and the overexpression of miR-452 in HCC patients predicted poor overall survival. MiR-452 significantly promoted stem-like characteristics in vitro and in vivo. Further, Sox7 was identified as the direct target of miR-452, which could physically bind with β-catenin and TCF4 in the nucleus and then inhibit the activity of Wnt/β-catenin signaling pathway. Finally, the combined chemotherapy of doxorubicin and all-trans retinoic acid (ATRA) showed dramatically efficiency in suppressing HCC metastasis. These data suggested that miR-452 promoted stem-like traits of HCC, which might be a potential therapeutic target for HCC. The combination of doxorubicin and ATRA might be a promising therapy in HCC management.

Single Nucleotide Polymorphisms in the Metastasis-associated in Colon Cancer-1 Gene Predict the Recurrence of Hepatocellular Carcinoma after Transplantation

Background: The newly identified metastasis-associated in colon cancer-1 (MACC1) gene is involved in angiogenesis, epithelial-to-mesenchymal transition (EMT), invasiveness, and metastasis in a variety of malignancies. Overexpression of MACC1 gene is a prognostic marker for poor outcome of hepatocellular carcinoma (HCC) patients. However, the association between genetic polymorphisms of MACC1 gene and poor outcome in HCC has been not been performed. We therefore investigated the correlation of MACC1 single nucleotide polymorphisms (SNPs) with tumor recurrence and overall survival in HCC patients undergoing liver transplantation (LT). Methods: The study included 187 HCC patients treated with LT. Five polymorphisms in the MACC1 gene (rs1990172, rs3735615, rs4721888, rs2241056, rs975263) were genotyped in 183 cases of tumorous tissue sample and 117 cases of adjacent normal tissue sample using SNaP-Shot assays. The association of SNPs with tumor recurrence and overall survival was then analyzed by additive, dominant, recessive, and overdominant models in a cohort of 156 HCC patients. Results: In terms of tumor recurrence, heterozygous of SNP rs1990172 and SNP rs975263 showed a significant high risk of relapse using univariate and multivariate analysis (overdominant, HR(95%CI)=2.27 [1.41-3.66], P=0.001; HR(95%CI)=2.16 [1.37-3.39], P=0.001). But the difference between heterozygous of these two SNPs and overall survival did not reach a significance in all models. The other three investigated SNPs were not significantly associated with tumor recurrence and overall survival (P>0.05). In addition, we found no significant difference in genotype frequencies between HCC and controls. Conclusions: Our data suggest that SNP rs1990172 and SNP rs975263 in the MACC1 gene may be potential genetic markers for HCC recurrence in LT patients.

Role of overexpression of MACC1 and/or FAK in predicting prognosis of hepatocellular carcinoma after liver transplantation

Background: Metastasis-associated in colon cancer-1 (MACC1) acts as a promoter of tumor metastasis; however, the predictive value of MACC1 for hepatocellular carcinoma (HCC) after liver transplantation (LT) remains unclear. Methods: We examined the expression of MACC1 and its target genes MET and FAK by quantitative PCR in 160 patients with HCC that was undergone LT. Results: The patients with MACC1high or FAKhigh in HCCs showed a significantly shorter overall survival and higher cumulative recurrence rates after liver transplantation (LT), compared with MACC1low or FAKlow group. Multivariate analysis indicated that MACC1 alone or combination of MACC1/FAK was an independent prognostic factor for overall survival and cumulative recurrence. Conclusions: MACC1 or combination of MACC1/FAK could serve as a novel biomarker in predicting the prognosis of HCC after LT.

High neutrophil-lymphocyte ratio indicates poor prognosis for acute-on-chronic liver failure after liver transplantation

AIM To investigate the significance of pre-transplant neutrophil-lymphocyte ratio (NLR) in determining the prognosis of liver transplant (LT) recipients with acute-on-chronic liver failure (ACLF). METHODS Data were collected from the liver transplantation data bank. The NLR values and other conventional inflammatory markers were evaluated for their ability to predict the prognosis of 153 patients with ACLF after LT. The NLR cut-off value was based on a receiver operating characteristic curve analysis. A Kaplan-Meier curve analysis and univariate and multivariate Cox regression models were used to define the independent risk factors for poor outcomes. RESULTS The optimal NLR cut-off value was 4.6. Out of 153 patients, 83 (54.2%) had an NLR ≥ 4.6. The 1-, 3-, and 5-year overall survival rates were 94.3%, 92.5% and 92.5%, respectively, in the normal NLR group and 74.7%, 71.8% and 69.8%, respectively, in patients with high NLRs (P < 0.001). Furthermore, there was a significant difference in infectious complications after LT between the high and normal NLR groups. There were no significant differences for other complications. In the multivariate Cox regression model, a high NLR was defined as a significant predictor of poor outcomes for LT. CONCLUSION A high NLR is a convenient and available predictor for prognosis of LT patients and can potentially optimize the current criteria for LT in ACLF.

Absolute lymphocyte count recovery at 1 month after transplantation predicts favorable outcomes of patients with hepatocellular carcinoma.

Absolute lymphocyte count (ALC) and the recovery of ALC after treatment have been identified as a prognostic biomarker for several malignancies. In this study, we aimed to investigate the prognostic role of peritransplant ALC and ALC recovery after liver transplantation (LT) in hepatocellular carcinoma (HCC) patients.

Reduced expression of DACT2 promotes hepatocellular carcinoma progression: involvement of methylation-mediated gene silencing

BackgroundHepatocellular carcinoma (HCC) is one of the most aggressive malignancies in humans, and its prognosis is generally poor even after surgery. Many advances have been made to understand the pathogenesis of HCC; however, the molecular mechanisms that lead to hepatocarcinogenesis and progression are still not clearly understood.MethodsThe expression of DACT2 in specimens from 30 paired HCCs and an additional 61 HCC patients after liver transplantation was evaluated by quantitative RT-PCR and immunohistochemical analysis. We investigated the methylation status of the DACT2 promoter region. We also analyzed the alterations of the cell cycle, migration and invasion after DACT2 knockdown.ResultsThe expression level of DACT2 was significantly lower in HCC tissues than in non-cancerous tissues. Reduced DACT2 expression was associated with large tumor size. DACT2 transcripts were at low levels in hypermethylated liver cancer cells and were restored by exposure to a demethylating agent. Reduced expression of DACT2 in MHCC97L cells induced G1/S arrest, increased cell proliferation, and promoted cell invasion.ConclusionsOur study suggests that DACT2 is silenced by promoter hypermethylation, and reduced DACT2 can promote liver cancer progression. DACT2 may serve as a novel tumor suppressor gene in HCC.

FAM83D associates with high tumor recurrence after liver transplantation involving expansion of CD44+ carcinoma stem cells

To investigate the potential oncogene promoting recurrence of hepatocellular carcinoma (HCC) following liver transplantation (LT), throughput RNA sequencing was performed in a subgroup of HCC patients. The up-regulated FAM83D in HCC tissues was found and further verified in 150 patients by real-time PCR and immunohistochemistry. FAM83D overexpression significantly correlated with high HCC recurrence rate following LT and poor HCC characteristics such as high AFP, poor differentiation. Of cancer stem cells (CSCs) markers, CD44 expression was effectively suppressed when FAM83D was knocked down by siRNA. Meanwhile, the siRNA transfected cells suppressed formation of sphere and ability of self-renew. In a xenograft tumorigenesis model, FAM83D knockdown apparently inhibited tumor growth and metastasis. Microarray assays revealed that FAM83D promotes CD44 expression via activating the MAPK, TGF-β and Hippo signaling pathways. Furthermore, CD44 knockdown presented reverse effect on above signaling pathways, which suggested that FAM83D was a key activator of loop between CD44 and above signaling pathways. In conclusion, FAM83D promotes HCC recurrence by promoting CD44 expression and CD44+ CSCs malignancy. FAM83D provides a novel therapeutic approach against HCC recurrence after LT.

The predictive value of blood neutrophil-lymphocyte ratio in patients with end-stage liver cirrhosis following ABO-incompatible liver transplantation

Background: The study was designed to assess the role of preoperative neutrophil, lymphocyte, and neutrophil-lymphocyte ratio (NLR) in predicting survival outcomes of ABO-incompatible liver transplantation (LT). Materials and Methods: We retrospectively collected the demographic and clinical characteristics of 71 patients with end-stage liver cirrhosis following ABO-incompatible LT in this study. Kaplan–Meier survival analysis and Cox multiple factors regression analysis were performed to determine the independent risk factors from preoperative blood parameters for poor prognosis. Results: The 1-, 3-, and 5-year overall survival were 94.9%, 80.0%, and 80.0% in the normal NLR group, respectively, and 59.4%, 55,4%, and 55.4% in patients with up-regulated NLR, respectively (P = 0.001). Furthermore, no significant difference was observed on post-LT complications between normal NLR and high-NLR groups. The high NLR was identified as the only independent prognostic risk factor for recipient survival (P = 0.015, 95% confidence interval = 3.573 [1.284–9.943]). Conclusion: The preoperative high NLR could be considered as a convenient and available indicator for selecting ABO-incompatible LT candidates.