Jian-Yin Lin

Thrombospondin 1 (THBS1) plays an important role in angiogenesis and tumor progression. The aim of the present study was to investigate the effects of single‑nucleotide polymorphisms (rs1478605 and rs3743125) in the untranslated regions of the THBS1 gene on the development and progression of gastric cancer. In the case‑control study, 275 gastric cancer patients and 275 cancer‑free controls were successfully genotyped using polymerase chain reaction‑restriction fragment length polymorphism. The data demonstrated that THBS1 rs1478605 genotypic distributions significantly differed between the patient and control groups (P=0.005). Carriers of the CC genotype exhibited a decreased risk of developing gastric cancer compared to the carriers of the CT and TT genotypes [adjusted odd ratio (OR), 0.56; 95% confidence interval (CI), 0.39‑0.79; P=0.001]. The CC genotype of rs1478605 was negatively associated with gastric cancer lymph node metastasis (OR, 0.41; 95% CI, 0.23‑0.71; P=0.001) and was associated with a reduced risk of lymph node metastasis in male patients (OR, 0.27; 95% CI, 0.14‑0.52; P<0.001). The THBS1 CT haplotype was associated with a reduced risk of developing gastric cancer (OR, 0.56; 95% CI, 0.33‑0.93; P=0.02). By contrast, no association was observed between THBS1 rs3743125 and the development and progression of gastric cancer. These results suggest that THBS1 rs1478605 represents a potential molecular marker for gastric cancer.

Previous studies have shown that transfection of the snake venom cystatin (sv-cystatin) gene can inhibit the invasion and metastasis of tumor cells. The aim of this study was to investigate the pharmaceutical applications of sv-cystatin in melanoma gene therapy. We constructed a recombinant adenovirus carrying sv-cystatin (Ad/sv-cystatin) and a control virus (Ad/null). Matrigel assays were used to assess melanoma cell migration and invasiveness in vitro. The antimelanoma effects of Ad/sv-cystatin were assessed in a syngeneic mouse model with an experimental lung colonization assay. Ad/sv-cystatin significantly inhibited the invasion and growth of B16F10 cells in vitro compared with control and Ad/null. Ad/sv-cystatin significantly inhibited experimental lung colonization in C57BL/6 mice as compared with that in control (PPP-treated mice (Pin vitro and in vivo. Our findings provide support for the further examination of the pharmaceutical applications of Ad/sv-cystatin.

Thrombospondin-1 plays an important role in cancer development and progression. This study investigated if a correlation exists between single-nucleotide polymorphisms (SNPs) in the Thrombospondin-1 gene (THBS1) and gastric cancer. We conducted a case–control study on a randomly recruited population of 283 patients and 283 healthy individuals from the city of Fuzhou in Southeast China. Individuals were genotyped for four SNPs (rs1478604 A>G, rs2228261 C>T, rs2292305 T>C, and rs3743125 C>T) in THBS1 using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. THBS1 genotypic distributions between the case and control groups were tested for correlations with cancer development. Comparisons between the case and control groups showed no significant differences in the genotypic distributions of rs1478604 A>G, rs2228261 C>T, and rs3743125 C>T. However, we found a statistically significant association between homozygous CC of THBS1 rs2292305 T>C and development of highly differentiated carcinoma (HDC). The rs1478604 A>G variant was found to be associated with invasion and lymph node metastasis in gastric cancer. After logistic regression and stratification analysis, rs1478604 A>G was more strongly associated with lymph node metastasis in HDC gastric cancer. The power to detect an effect for rs1478604 A>G in HDC was 90%. These findings indicate that the THBS1 rs1478604 A>G variant is linked with differential risks for gastric cancer nodal metastasis. These results support further investigation of THBS1 as a potential therapeutic target in gastric cancer.

Snake venom metalloproteinase inhibitor BJ46a is from the serum of the venomous snake Bothrops jararaca. It has been proven to possess the capacity to inhibit matrix metalloproteinases (MMPs), likely based on its structural similarity to MMPs. This report describes the successful expression, purification, and characterization of the recombinant protein BJ46a in Pichia pastoris. Purified recombinant protein BJ46a was found to inhibit MMPs. Structural modeling was completed and should provide the foundation for further functional research. To our knowledge, this is the first report on the large scale expression of BJ46a, and it provides promise as a method for generation of BJ46a and investigation of its potential use as a new drug for treatment of antitumor invasion and metastasis.

Background and Objectives: The roles of thrombospondin‐1 (THBS‐1) in tumor growth and metastasis are complicated and its function as a cancer inhibitor or promoter remains controversial. This clinical study investigated the functional roles of THBS‐1 in gastric carcinoma by examining the expression patterns of THBS‐1 protein and mRNA levels during gastric cancer development.Methods: Eighty‐two gastric carcinomas were included in this study. THBS‐1, α‐smooth muscle actin, and CD34 proteins were localized by immunohistochemical staining, and the levels of THBS‐1 mRNA were quantified by real‐time polymerase chain reaction.Results: THBS‐1 mRNA expression in gastric carcinoma tissues was significantly higher than in adjacent non‐cancerous stomach tissues (P = 0.03). Tumor THBS‐1 mRNA expression level was significantly related to lymph node metastasis (P = 0.031), tumor size (P = 0.021) and patient age (P = 0.005). THBS‐1 protein was mainly located in stromal myofibroblasts, and was undetectable in tumor cells. Myofibroblasts may be mainly derived from stromal fibroblasts in gastric cancer. The abundance of myofibroblasts was positively correlated with tumor growth and nodal metastasis in gastric carcinoma (P = 0.03, P = 0.0008, respectively).Conclusions: This clinical study revealed that overexpression of THBS‐1 in stromal myofibroblasts is associated with tumor growth and nodal metastasis in gastric carcinoma. THBS‐1 may activate latent transforming growth factor‐β1 to stimulate fibroblasts to differentiate into myofibroblasts, though further studies are needed to validate this hypothesis. These results suggest that THBS‐1 and myofibroblasts may serve as novel targets for strategies aimed at protection against and treatment of gastric carcinoma. J. Surg. Oncol. 2012; 106:94–100.

Snake venom cystatin (sv-cystatin) is a member of the cystatin family of cysteine protease inhibitors. To further evaluate the possibility of sv-cystatin in cancer therapy, this study examined the effects of sv-cystatin on the invasion and metastasis of liver cancer cells (MHCC97H) in vitro and in vivo as well as the underlying mechanism. sv-cystatin cDNA was transfected into MHCC97H cells and the anti-invasion and antimetastasis effects of sv-cystatin were determined using migration and matrigel invasion assays and a lung-metastasis mice model. The results suggest that sv-cyst clone (sv-cystatin expression in MHCC97H cells) delayed the invasion and metastasis in vitro and in vivo compared to the parental, mock and si-sv-cyst clone cells (inhibited sv-cystatin expression by siRNA). The decreased activities of cathepsin B, MMP-2 and MMP-9 and EMT change index including higher E-cadherin, lower N-cadherin and decreased Twist activity were observed in the sv-cyst clone, which contributes to the change in invasion and metastasis ability of MHCC97H cells. This study provides evidence that expression of the sv-cystatin gene in MHCC97H cells inhibits tumor cell invasion and metastasis through the reduction of the proteinases activity and Epithelial-Mesenchymal Transition (EMT), which might contribute to the anticancer research of the sv-cystatin protein.

A MYCL1 single nucleotide polymorphism, rs3134613, has been reported to play an important role in many cancers. However, its involvement in gastric cancer is controversial. The aim of the study was to investigate the influence of rs3134613 on the development and progression of gastric cancer in a southeast Chinese population. Genotypes were analyzed by polymerase chain reaction–restriction fragment length polymorphism in 317 gastric cancer patients and 200 cancer-free controls. Data show that the risk of diffuse-type gastric cancer in carriers with the T allele (T/T or G/T genotype) was higher than that in carriers with the G/G genotype (adjusted odds ratio [OR] = 2.601, 95% confidence interval [CI] = 1.431–4.895, p = 0.003). The risk of diffuse-type gastric cancer in T allele carriers was higher than that in G allele carriers (adjusted OR = 1.594, 95% CI = 1.157–2.286, p = 0.009). The risk of poorly differentiated cancer in carriers with the T allele (T/T or G/T genotype) was higher than that in carriers with the G/G genotype (adjusted OR = 1.963, 95% CI = 1.156–3.325, p = 0.015). The results demonstrate that rs3134613 is associated with susceptibility to diffuse-type gastric cancer and with differentiation of gastric cancer. rs3134613 may be used as a potential marker to identify individuals who are at high risk of diffuse-type gastric cancer.

To investigate the influencing factors of nonalcoholic fatty liver disease (NAFLD). A hospital-based case-control study was conducted in patients with NAFLD and controls without NAFLD in a hospital from January to August in 2007. All data were analyzed by SPSS 13.0 software. One-way analysis of variance found that the two groups were significantly different in cigarette smoking, alcohol and tea comsumption, movement index, speed of food intake, frequency of social engagement, kinds of edible oil, marine products, family history of NAFLD, hypertension, higher blood sugar, abnormality of blood fat, higher level of ALT, higher level of AST, hyperuricemia, obesity, decrease of high density lipoprotein (HDL), and increase of low density lipoprotein. By non-conditional logistic stepwise regression analysis, 12 of 18 factors were used to construct a model, ten of which were the risk factors and two were protective factors of NAFLD. Risk factors included obesity (OR=6.35), hypertension(OR=3.82), dyslipidemia (OR=2.95), decrease of HDL (OR=2.85), hyperglycemia (OR=2.82), increase of ALT (OR=2.80), hyperuricemia (OR=2.35), HBsAg positive (OR=1.99), family history of fatty liver (OR=1.79) and frequently intake of marine products (OR=1.58), and protective factors included tea drinking (OR=0.72) and exercise (OR=0.90). There are many influencing factors of NAFLD, and life styles are the key factors. Genetic background may also play some roles in NAFLD.