Ji-Hai Yu

Ligation of TLR2 by Versican: A Link Between Inflammation and Metastasis

Versican, a large extracellular matrix proteoglycan, accumulates both in tumor stroma and cancer cells. It participates in cell adhesion, migration, and angiogenesis, all features of invasion and metastasis. However, the mechanism(s) whereby versican promotes cancer invasion and metastasis is not yet fully understood. A recent study has documented that versican can activate tumor-infiltrating myeloid cells through toll-like receptor (TLR) 2 and its co-receptors TLR6 and CD14 and elicit the production of proinflammatory cytokines including TNF-alpha that enhance tumor metastasis. As both resident fibroblasts and endothelial cells (ECs) also express functional TLR2 and its co-receptors, we hypothesized that, in addition to myeloid cells, versican may trigger the activation of both fibroblasts and ECs. Of interest, TLR2-mediated activation of EC and fibroblast has been observed to increase the secretion of interleukin-8, a proinflammatory CXC chemokine that potentiates neutrophil infiltration and angiogenesis, as well as metastatic growth. Ligation of TLR2 by versican appears to be directly involved in the activation of multiple types of cells in tumor stroma and the induction of inflammatory cytokine secretion, providing a link between inflammation and cancer metastasis. Accordingly, antagonists of versican and TLR2 restrain the activation of tumor stromal cells, which may offer a novel approach to cancer therapy by targeting tumor microenvironment.

Expression and Correlation of Hypoxia-inducible Factor-1α, Vascular Endothelial Growth Factor and Microvessel Density in Experimental Rat Hepatocarcinogenesis

An experimental rat hepatocellular carcinoma (HCC) model was established using diethylnitrosamine and N-nitrosomorpholine to induce carcinogenesis in Sprague-Dawley rats. During hepatocarcinogenesis, seven rats were sacrificed at 0, 4, 8, 12 and 16 weeks and 10 rats were sacrificed at 20 weeks. The levels of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) protein and mRNA were examined by immunohistochemistry, Western blot and semi-quantitative reverse transcriptase-polymerase chain reaction at different stages in the rat HCC model. Twenty weeks after induction of hepatocarcinogenesis, the expression of HIF-1α and VEGF protein and mRNA significantly increased compared with week 0. Microvessel density (MVD) increased considerably once liver cancer developed. There was a significant positive correlation between MVD and both HIF-1α and VEGF, and between HIF-1α and VEGF levels. These results suggest that HIF-1α and VEGF play important roles in tumour occurrence and development during rat hepatocarcinogenesis, possibly through promoting tumour angiogenesis.

Combined Inhibitory Effects of Celecoxib and Fluvastatin on the Growth of Human Hepatocellular Carcinoma Xenografts in Nude Mice

This study was designed to investigate the in vivo growth inhibitory effects of celecoxib, a cyclo-oxygenase-2 inhibitor, and fluvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, on the hepatocellular carcinoma (HCC) cell line, BEL-7402. Athymic nude mice implanted with BEL-7402 cells were given celecoxib and fluvastatin, either alone or in combination, and the effect of treatment on tumour growth was evaluated after 6 weeks. The combination of celecoxib and fluvastatin enhanced inhibition of tumour growth, induction of apoptosis, inhibition of tumour cell proliferation, and inhibition of tumour angiogenesis compared with either treatment alone. The combination of celecoxib and fluvastatin also increased levels of the cyclin-dependent kinase inhibitor p21Waf1/Cip1, decreased levels of p-Akt, myeloid cell leukaemia-1 (Mcl-1) and survivin protein, but had no effect on Akt protein levels in tumours. These results suggest that celecoxib combined with fluvastatin would be more efficacious for the treatment of HCC than either treatment alone and this combination of therapy warrants further research.

Kindlin-2: A novel prognostic biomarker for patients with hepatocellular carcinoma

The association of aberrant expression of Kindlin-2 with tumor progression has been reported in recent years. The purpose of this study was to investigate the expression of Kindlin-2 in hepatocellular carcinoma (HCC), and to evaluate its clinical and prognostic significance. The mRNA and protein levels of Kindlin-2 in HCC and adjacent non-cancerous tissues were examined by real-time PCR and western blotting. The relationships between Kindlin-2 expression, clinicopathological features and postoperative survival of HCC patients were also evaluated. Kindlin-2 expression was higher in HCC tissues as compared to adjacent non-cancerous tissues at both mRNA and protein levels (P<0.05, respectively). Positive expression of Kindlin-2 was significantly correlated with larger tumor size (P=0.034), capsular invasion (P=0.009), microvascular invasion (P=0.028) and poor prognosis of HCC patients (P<0.001). Moreover, multivariate survival analysis identified Kindlin-2 as an independent prognostic factor for overall and disease-free survival of HCC patients (P=0.018 and 0.001, respectively). Taken together, our findings suggested that Kindlin-2 was highly expressed in HCC tissues and was closely related to clinical progression. Therefore, Kindlin-2 protein could be a potential biomarker for predicting poor prognosis of HCC patients after surgery.

Association between CTLA-4 exon-1 +49A>G polymorphism and primary biliary cirrhosis risk: a meta-analysis.

BACKGROUND AND AIMS CTLA-4 exon-1 +49A>G polymorphisms have been reported to influence the risk for primary biliary cirrhosis in many studies; however, the results still remain controversial and ambiguous. The aim of this study was to determine more precise estimations for the relationship between CTLA-4 exon-1 +49A>G polymorphisms and the risk for primary biliary cirrhosis. METHODS Electronic searches for all publications were conducted on associations between this variant and breast cancer in several databases through November 2010. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to estimate the strength of the association. Eight studies were identified including 2151 cases and 2214 controls. RESULTS Overall, there were no significant associations between CTLA +49G>A polymorphism and primary biliary cirrhosis risk (codominant model: GA vs. AA OR=1.190, 95% CI=0.818-1.732; GG vs. AA OR=1.153, 95% CI=0.858-1.550; dominant model: OR=1.181, 95% CI=0.873-1.599; and recessive model: OR=1.148; 95% CI=0.903-1.459). In the subgroup analysis by ethnicity, a significantly increased risk was found for Asians (GG vs. AA OR=1.873; 95% CI=1.202-2.921) and recessive model (OR=1.758; 95% CI = 1.271-2.433). In the stratified analysis by control sources, significant association were observed in population-based studies (GA vs. AA OR=1.432; 95% CI=1.078-1.902). CONCLUSIONS This meta-analysis suggests that the CTLA-4 +49G>A polymorphism may be a risk factor for primary biliary cirrhosis in Asians.

Protective effect of S-adenosylmethionine on hepatic ischemia-reperfusion injury during hepatectomy in HCC patients with chronic HBV infection.

BackgroundAlthough hepatectomy is often performed with the Pringle maneuver, the problem of hepatic ischemia-reperfusion injury (HIRI) can also be serious. Thus, the present study was designed to investigate the protective effect of S-adenosylmethionine (SAMe) on HIRI, especially for patients with hepatocellular carcinoma (HCC) associated with chronic hepatitis B virus (HBV) infection and cirrhosis.MethodsEighty-one HCC patients with chronic HBV infection, undergoing partial hepatectomy with inflow occlusion, were divided into three groups. In the pretreatment group (PR group, n = 26), patients were given SAMe two hours before surgery. In the post-treatment group (PO group, n = 25), patients were given SAMe six hours after surgery. And in the control group (control group, n = 30), patients received partial hepatectomy without any SAMe. All pre-, intra- and postoperative blood samples were collected to measure the plasma levels of transaminases, bilirubin and cytokines. The results were compared among the three groups.ResultsThere were no statistically significant intergroup differences observed in age, gender, hepatic inflow occlusion time and the results of liver function tests. Preoperative administration of SAMe (PR group) significantly reduced the plasma levels of alanine transaminase (ALT), aspartate transferase (AST), total bilirubin (TBIL) and direct bilirubin (DBIL) as compared to the other two groups. In the PO group, TBIL and DBIL were significantly lower than in the control group. Significant differences were also seen in IL-6 and TNF-α between the PR group and the other groups. In all groups, postoperative liver reserve function in the PR group as revealed by ICGR15 (Post ICGR15) was at its best before abdominal closure. Compared to the control group, the risk of complications and the hospital stay after surgery were significantly meliorated in the PR group. Additionally, patients with cirrhosis had a more acute rate of change in ALT and AST than non-cirrhotic patients.ConclusionsTaken together, our preliminary findings suggest that preoperative administration of SAMe is useful and safe for reducing the HIRI in partial hepatectomy, especially for HCC patients whose disease is associated with chronic HBV infection and cirrhosis.

Beneficial effects of S-adenosyl-L-methionine on post-hepatectomy residual liver function: a prospective, randomized, controlled clinical trial.

BACKGROUND/AIMS Hepatectomy is associated with high rates of postoperative liver dysfunction in patients with cirrhosis. Since S-adenosyl-L-methionine (SAMe) can be used to treat liver disease, we performed a prospective clinical trial to investigate whether it could be used after hepatectomy to benefit residual liver function. METHODOLOGY We studied 79 hepatitis-related chronic patients who underwent resection of hepatocellular carcinoma; 39 patients were randomly assigned to receive postoperative intravenous SAMe treatment, and 40 were randomly assigned to a control group. The postoperative SAMe treatment consisted of SAMe 1,000mg given intravenously for seven days. The other treatment was standardized. RESULTS At inclusion into the trial no significant differences were observed between the two groups with respect to gender, age, Child classification, preoperative liver function tests, blood loss, total time of hepatic pedicle occlusion and the extent of liver resection. The overall frequency of postoperative liver insufficiency decreased from 42% in the control group to 31% in the SAMe group, although not statistically significant (p=0.121). When the patients who underwent hepatic pedicle occlusion by Pringle’s maneuver over 15min were analyzed, the frequency of postoperative liver insufficiency (p=0.028), serum total bilirubin levels on days 5 (p=0.025) and 7 (p=0.032) preoperatively, and the maximum value of postoperative serum total bilirubin (p=0.040) were significantly greater in the control than in the SAMe group. CONCLUSIONS The results indicate that the postoperative SAMe therapy can benefit residual liver function of the patients with cirrhosis, especially in those suffering greater ischemia reperfusion injury.