An Engineered Arginase FC Protein Inhibits Tumor Growth In Vitro

Arginine is a semiessential amino acid required for the growth of melanoma and hepatocellular carcinoma, and the enzymatic removal of arginine by pegylated arginine deiminase (ADI) or arginase is being tested clinically. Here, we report a genetically engineered arginase FC fusion protein exhibiting a prolonged half-life and enhanced efficacy. The use of this enzyme to treat different tumor lines both inhibited cell proliferation and impaired cellular migration in vitro and in vivo. Our data reinforce the hypothesis that nutritional depletion is a key strategy for cancer treatment

An Engineered Arginase FC Protein Inhibits Tumor Growth In Vitro and In Vivo

Arginine is a semiessential amino acid required for the growth of melanoma and hepatocellular carcinoma, and the enzymatic removal of arginine by pegylated arginine deiminase (ADI) or arginase is being tested clinically. Here, we report a genetically engineered arginase FC fusion protein exhibiting a prolonged half-life and enhanced efficacy. The use of this enzyme to treat different tumor lines both inhibited cell proliferation and impaired cellular migration in vitro and in vivo. Our data reinforce the hypothesis that nutritional depletion is a key strategy for cancer treatment

Value of Liver Regeneration in Predicting Short-Term Prognosis for Patients with Hepatitis B-Related Acute-on-Chronic Liver Failure

Background and Aims. The value of hepatocyte regeneration in predicting the outcomes of hepatitis B-related acute-on-chronic liver failure (HBV-ACLF) is not fully assessed. The present study was aimed at establishing a novel scoring system to predict patients’ outcomes within 3 months by applying serological indicators of hepatic regeneration and liver injury. Methods. Patients with chronic hepatitis B who had a rapid deterioration were investigated. Patients were observed for 90 days, and the endpoint of follow-up was death or liver transplantation. Serum parameters were estimated on the diagnosis of acute-on-chronic liver failure (ACLF). Cox proportional hazard regression was used to identify independent prognostic factors and create a novel prognostic scoring system, and a receiver operating characteristic (ROC) curve was used to analyze the performance of the model. Results. A total of 308 patients with HBV-ACLF were incorporated and divided into the training cohort (n=206) and testing cohort (n=102) randomly. Creatine (Cre), age, total bilirubin (TBil), alpha-fetoprotein (AFP), and international normalized ratio (INR) were found to be independent prognostic factors. According to the results of Cox regression analysis, a new prognostic model (we named it the TACIA score) was calculated. The areas under ROC (AUROC) for the new model were 0.861 and 0.763 in the training and testing cohorts, respectively, and patients with lower TACIA scores (<4.34) would survive longer (P<0.001). Conclusions. A pertinent prognostic scoring system for patients with HBV-ACLF was established in our study, and the novel model could predict patients’ short-term survival effectively

Nuclear expression of Twist promotes lymphatic metastasis in esophageal squamous cell carcinoma

China Postdoctoral Science Foundation [20090461447]; National Natural Science Foundation of China [81172288]Twist-1 protein (also called Twist) has been suggested to be involved in tumor epithelial-mesenchymal transition (EMT) related progression, however, the mechanism by which Twist promotes lymph node metastasis is not fully understood. In the present study, we found that nuclear Twist expression is clearly correlated with lymph node (LN) metastasis as determined by immunohistochemistry (IHC). A highly invasive EC109 cell subline, EC109-P, was established by repeated in vitro transwell isolations for the cell model. Immunofluorescence (IF) assay demonstrated that nuclear Twist expression was markedly higher in the highly invasive EC109-P cell line when compared with EC109 and EC9706 cells. Based on our cell model, the function and mechanism by which Twist regulates LN metastasis in ESCC was investigated. The results showed that the overexpression of Twist could significantly increase the invasion and VEGF-C expression of EC9706 cells, whereas the knockdown of Twist expression results in the opposite effects. This finding was further strengthened by the results of the analysis of co-expression of Twist and VEGF-C by IHC in ESCC clinical samples. In summary, our study indicates that nuclear Twist plays an important role in ESCC lymphatic metastasis by increasing the expression of VEGF-C. The combination of Twist and VEGF-C detection could be a reliable prediction of LN metastasis in ESCC

SDR9C7 promotes lymph node metastases in patients with esophageal squamous cell carcinoma.

BACKGROUND:The major reason for the poor prognosis of esophageal squamous cell carcinoma (ESCC) patients is lymph node (LN) metastases. METHODOLOGY/PRINCIPAL:In the present study, gene expression profiling assay (GEP) was performed to identify the differences in gene expression profiles between primary ESCC tumors that were with LN metastases (N(+)) and those without LN metastases (N(-)). CONCLUSIONS/SIGNIFICANCE:A total of 23 genes were identified as being significantly elevated, and 30 genes were sharply decreased in ESCC tumors that were N(+) compared with N- tumors. Among these genes, two transcripts of the short chain dehydrogenase/reductase family 9C, member 7 (SDR9C7) were observed 7 times more frequently in N(+) compared with N(-) tumors. Immunohistochemical staining showed that SDR9C7 expression closely correlated with metastasis, and would be a prognostic marker for ESCC patients. To investigate the role of SDR9C7 in the ESCC metastasis, repeated transwell assays were adopted to establish highly and non-invasive ESCC sublines, and western blot showed that SDR9C7 expression was markedly higher in highly invasive cells compared with non-invasive ones. Down-regulation of SDR9C7 dramatically inhibited the metastatic abilities in vitro and in vivo, and repressed the expression of MMP11 in highly invasive cells, indicating that SDR9C7 promotes ESCC metastasis partly through regulation of MMP11, and might be a potential prognostic and therapeutic marker for ESCC patients

An Engineered Arginase FC Protein Inhibits Tumor Growth In Vitro and In Vivo

Arginine is a semiessential amino acid required for the growth of melanoma and hepatocellular carcinoma, and the enzymatic removal of arginine by pegylated arginine deiminase (ADI) or arginase is being tested clinically. Here, we report a genetically engineered arginase FC fusion protein exhibiting a prolonged half-life and enhanced efficacy. The use of this enzyme to treat different tumor lines both inhibited cell proliferation and impaired cellular migration in vitro and in vivo. Our data reinforce the hypothesis that nutritional depletion is a key strategy for cancer treatment

Ectopic expression of MiR-125a inhibits the proliferation and metastasis of hepatocellular carcinoma by targeting MMP11 and VEGF.

BACKGROUND: Studies have been shown that miR-125a plays an important role in carcinogenesis, however, the role of miR-125a in hepatocellular carcinoma (HCC) remains elusive. METHODOLOGY/PRINCIPAL: Real time-PCR (qRT-PCR) was performed to test the significance of miR-125a in HCC. Ectopic expression of miR-125a was used to test the influences of miR-125a on proliferation and metastasis of HCC cells in vitro and in vivo. Predicted target genes of miR-125a were determined by dual-luciferase reporting, qRT-PCR, and western blot (WB) analyses. Then immunohistochemical staining (IHC) was used to detect the expression of target genes, and the correlations and prognostic values of miR-125a and its target genes were also investigated. CONCLUSIONS/SIGNIFICANCE: Decreased miR-125a was observed in both HCC tissues and cell lines, and associated with patients' aggressive pathologic features. Up-regulating miR-125a significantly inhibited the malignant phenotypes by repressing the expression of matrix metalloproteinase 11 (MMP11) and vascular endothelial growth factor A (VEGF-A) both in vitro and in vivo. Furthermore, miR-125a expression was inversely correlated with both MMP11 and VEGF-A expression in HCC tissues. Inhibiting miR-125a could increase both MMP11 and VEGF-A expression, and RNA interference targeting MMP11 or VEGF-A mRNA could rescue the loss of miR-125a functions. MiR-125a inhibits the proliferation and metastasis of HCC by targeting MMP11 and VEGF-A. Up-regulation of miR-125a might be a promising approach and a prognostic marker for HCC