Hepatocellular carcinoma and macrophage interaction induced tumor immunosuppressionvia Treg requires TLR4 signaling

AIM: To investigated the interaction between toll-like receptor 4 (TLR4)-activated hepatoma cells and macrophages in the induction of tumor-immune suppression mediated by CD4+CD25high family of transcription factor P3 (FOXP3) regulatory T cells (Tregs). METHODS: The proportion of FOXP3+ Tregs was identified in peripheral blood and tumor tissues of 60 hepatocellular carcinoma (HCC) patients. TLR4 expression was examined in tumor tissues and cell lines. The correlation was examined between FOXP3+ Tregs in peripheral blood and TLR4 expression of HCC tissues. Following activation of TLR4 in H22 murine hepatoma cells pre-incubated with lipopolysaccharide (LPS) and co-cultured with macrophage cell line RAW246.7, the synthesis of cytokines tumor necrosis factor-α, CCL22, and interleukin (IL)-10 by the two cell lines was detected and analyzed. RESULTS: FOXP3+ Tregs were enriched in tumor sites, and circulating FOXP3+ Tregs were increased in HCC patients in correlation with multiple tumor foci and up-regulated TLR4 expression in HCC tissues. Semi-quantitative analysis indicated that TLR4 was over-expressed in HCC compared with the matched normal tissues. Cell cultivation experiments indicated that the mRNAs of IL-10 and CCL22 were significantly up-regulated in the RAW246.7 cell line when co-cultured with LPS preincubated H22 cells. CONCLUSION: In hepatoma cell lines, TLR4 may indirectly facilitate the recruitment of Tregs to the tumor site and promote intrahepatic metastasis through its interaction with macrophages.

MiR-183-5p-PNPT1 Axis Enhances Cisplatin-induced Apoptosis in Bladder Cancer Cells

Objective:It has been reported that intrinsic apoptosis is associated with the progression of bladder cancer(BC).Recent evidence suggests that polyribonucleotide nucleotidyltransferase 1(PNPT1)is a pivotal mediator involved in RNA decay and cell apoptosis.However,the regulation and roles of PNPT1 in bladder cancer remain largely unclear.Methods:The upstream miRNA regulators were predicted by in silico analysis.The expression levels of PNPT1 were evaluated by real-time PCR,Western blotting,and immunohistochemistry(IHC),while miR-183-5p levels were evaluated by qPCR in BC cell lines and tissues.In vitro and in vivo assays were performed to investigate the function of miR-183-5p and PNPT1 in apoptotic RNA decay and the tumorigenic capability of bladder cancer cells.Results:PNPT1 expression was decreased in BC tissues and cell lines.Overexpression of PNPT1 significantly promoted cisplatin-induced intrinsic apoptosis of BC cells,whereas depletion of PNPT1 potently alleviated these effects.Moreover,oncogenic miR183-5p directly targeted the 3′UTR of PNPT1 and reversed the tumor suppressive role of PNPT1.Intriguingly,miR-183-5p modulated not only PNPT1 but also Bcl2 modifying factor(BMF)to inhibit the mitochondrial outer membrane permeabilization(MOMP)in BC cells.Conclusion:Our results provide new insight into the mechanisms underlying intrinsic apoptosis in BC,suggesting that the miR-183-5p-PNPT1 regulatory axis regulates the apoptosis of BC cells and might represent a potential therapeutic avenue for the treatment of BC.

Serum carbohydrate antigen (CA) 19-9 as a prognostic factorin cholangiocarcinoma: A meta-analysis

This study was performed to determine the prognostic role of preoperative serum carbohydrate antigen(CA)19-9 levels in the survival of patients with cholangiocarcinoma.Articles published up to June 1st,2010 that evaluated preoperative CA19-9 levels and the prognosis of cholangiocarcinoma were collected for meta-analysis.The required information for calculating indivi-dual relative risk(RR)was extracted from the studies,and a combined overall RR was estimated.Nine eligible studies were included.One study dealt with extra-hepatic cholangiocarcinoma,while the other eight studies analyzed intra-hepatic cholangiocarcinoma.The mean methodolo-gical quality score was 74.1%,ranging from 65.5%to 82.5%.The overall RR for the nine studies was 1.28(95%confidence interval=1.10–1.46),and the Z-score for overall effect was 13.83(P<0.001).The association between serum CA19-9 level and lymph node involvement was also assessed.The combined RR was 1.471(95%confidence interval=0.411–5.264)and Z-score for overall effect was 0.59(P=0.553).CA19-9 levels were associated significantly with the prognosis of patients with cholan-giocarcinoma.This meta-analysis shows that elevation of preoperative CA19-9 levels is correlated with a poor prognosis of patients with cholangiocarcinoma.However,larger scale and randomized studies are needed to draw a more substantive conclusion.