Polymorphisms of a Disintegrin and Metalloproteinase with Thrombospondin Motifs 5 and Aflatoxin B1-Related Hepatocellular Carcinoma.

BACKGROUND: Altered expression of a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) is observed in hepatocellular carcinoma. The genetic polymorphisms of this gene in aflatoxin B1 (AFB1)-related hepatocellular carcinoma have not yet been elucidated. METHODS: We conducted a hospital-based case-control study, including 1,706 hepatocellular carcinoma cases and 2,270 controls without any liver diseases or tumors, to assess the association between 74 polymorphisms in ADAMTS5 and AFB1-related hepatocellular carcinoma risk and prognosis. Genotype, mRNA levels, and TP53 gene mutation (TP53M) related to AFB1 exposure were tested using TaqMan-PCR or sequencing technique. ADAMTS5 protein level and microvessel density were analyzed by IHC. RESULTS: Among these 74 polymorphisms, only rs2830581 affected hepatocellular carcinoma risk. Compared with the homozygote of rs2830581 G alleles (rs2830581-GG), the genotypes of rs2830581 A alleles (rs2830581-GA or -AA) increased hepatocellular carcinoma risk (OR: 1.85 and 4.40; 95% CI: 1.57-2.19 and 3.43-5.64, respectively). Significant interactive effects between risk genotypes and AFB1 exposure status were also observed in the joint effects analysis. Furthermore, the rs2830581 polymorphism modified the tumor recurrence-free survival and overall survival of patients. This polymorphism not only affected pathologic features of hepatocellular carcinoma such as tumor dedifferentiation and microvessel density, but also modified ADAMTS5 expression and the effects of transarterial chemoembolization treatment on hepatocellular carcinoma. CONCLUSIONS: These results suggest ADAMTS5 polymorphisms may be risk and prognostic biomarkers of AFB1-related hepatocellular carcinoma, and rs2830581 is a potential candidate. IMPACT: Our findings support the hypothesis that ADAMTS5 rs2830581 polymorphism modifies AFB1-related hepatocellular carcinoma risk and prognosis.

[Matrine enhances the anticancer effect of cisplatin against hepatocellular carcinoma xenografts in nude mice by influencing expression of survivin/caspase-3].

OBJECTIVE: To investigate the effect and molecular mechanism of cisplatin (DDP) combined with Matrine (Ma;plant alkaloid) against hepatocellular carcinoma using a nude mouse model with xenografted human tumors. METHODS: Twenty-four 6-week old male BALB/c nude mice were subcutaneously injected with HepG2 cells into the axilla, and randomly divided into four groups:control (NS) group,Ma treatment group,DDP treatment group and DDP+Ma combination treatment group. All treatments were delivered via intraperitoneal injection.Changes in whole body weights and tumor volume were assessed by before and after treatment measurements and plotting of growth curves. After 14 days of drug intervention, the mice were sacrificed for collection of tumor tissue and assessment of the tumor inhibition rates for each treatment. Affects on expression of survivin and caspase-3 were assessed by immunohistochemistry. ANOVA test and t-test were performed for the statistical analyses. RESULTS: The tumor inhibition rates for the various treatments were:37.5%,Ma alone;75.0% DDP alone;83.3%,DDP+Ma group DDP combined. The DDP+Ma-induced inhibition was significantly greater than that achieved wit Ma or DDP alone (both P less than 0.05). The average weight of the DDP+Ma group (21.5 g) was lower than that of the NS group (28.5 g) and the Ma group (26.67 g),but higher than that of the DDP group (17.33 g).In addition, the DDP+Ma group also showed more robust general health,as indicated by activity,participation in life routines and appetite,than the DDP group. The rate of positive staining for survivin expression in tumor tissues was significantly lower in the DDP+Ma group (19.58%+/-4.52%) than in the NS group (83.26%+/-15.56%), the Ma group (62.50%+/-8.09%), and the DDP group (38.67%+/-8.26%) (all P less than 0.05).In contrast, the rate of positive staining for Bax expression was significantly higher in the DDP+Ma group (78.26%+/-6.09%) than in the NS group (21.15%+/-3.68%), the Ma group (35.13%+/-10.57%), and the DDP group (65.88%+/-4.81%) (all P less than 0.05). CONCLUSION: Treatment with Ma alone or DDP alone is sufficient to inhibit the growth ofxenografted human hepatocellular carcinoma cells in nude mice. The DDP+Ma combination treatment,however,shows greater inhibitory effect,suggesting that Ma may enhance DDP's anticancer properties. The improved health status of mice treated with DDP+Ma suggests that Ma may reduce DDP toxicity. The mechanism underlying these beneficial treatment effects may involve modulation of survivin/caspase-3 expression and subsequent apoptosis.

XRCC7 rs#7003908 Polymorphism and Helicobacter pylori Infection-Related Gastric Antrum Adenocarcinoma.

The X-ray repair cross-complementing group 7 (XRCC7) plays a key role in DNA repair that protects against genetic instability and carcinogenesis. To determine whether XRCC7 rs#7003908 polymorphism (XRCC7P) is associated with Helicobacter pylori (H. pylori) infection-related gastric antrum adenocarcinoma (GAA) risk, we conducted a hospital-based case-control study, including 642 patients with pathologically confirmed GAA and 927 individually matched controls without any evidence of tumours or precancerous lesions, among Guangxi population. Increased risks of GAA were observed for individuals with cagA positive (odds ratio (OR) 6.38; 95% confidence interval (CI) 5.03-8.09). We also found that these individuals with the genotypes of XRCC7 rs#7003908 G alleles (XRCC7-TG or -GG) featured increasing risk of GAA (ORs 2.80 and 5.13, resp.), compared with the homozygote of XRCC7 rs#7003908 T alleles (XRCC7-TT). GAA risk, moreover, did appear to differ more significantly among individuals featuring cagA-positive status, whose adjusted ORs (95% CIs) were 15.74 (10.89-22.77) for XRCC7-TG and 38.49 (22.82-64.93) for XRCC7-GG, respectively. Additionally, this polymorphism multiplicatively interacted with XRCC3 codon 241 polymorphism with respect to HCC risk (ORinteraction = 1.49). These results suggest that XRCC7P may be associated with the risk of Guangxiese GAA related to cagA.