Cytochrome P450 1A1 gene polymorphisms and digestive tract cancer susceptibility: a meta-analysis.

Cytochrome P450 1A1 (CYP1A1) is a phase I enzyme that regulates the metabolism of environmental carcinogens and alter the susceptibility to various cancers. Many studies have investigated the association between the CYP1A1 MspI and Ile462Val polymorphisms and digestive tract cancer (DTC) risk in different groups of populations, but their results were inconsistent. The PubMed and Embase Database were searched for case-control studies published up to 30th September, 2015. Data were extracted and pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to assess the relationship. Totally, 39 case-control studies (9094 cases and 12,487 controls) were included. The G allele in Ile/Val polymorphism was significantly associated with elevated DTC risk with per-allele OR of 1.24 (95% CI = 1.09-1.41, P = 0.001). Similar results were also detected under the other genetic models. Evidence was only found to support an association between MspI polymorphism and DTC in the subgroups of caucasian and mixed individuals, but not in the whole population (the dominant model: OR = 1.19, 95% CI = 0.94-1.91, P = 0.146). In conclusion, our results suggest that the CYP1A1 polymorphisms are potential risk factors for DTC. And large sample size and well-designed studies with detailed clinical information are needed to more precisely evaluate our founding.

Association of genetic variants in lncRNA H19 with risk of colorectal cancer in a Chinese population.

OBJECTIVE: The long non-coding RNA (lncRNA) gene, H19, has been involving in multiple biological functions, which also plays a vital role in colorectal cancer carcinogenesis. However, the association between genetic variants in H19 and colorectal cancer susceptibility has not been reported. In this study, we aim to explore whether H19 polymorphisms are related to the susceptibility of colorectal cancer. METHODS: We conducted a case-control study to evaluate the association between four selected single nucleotide polymorphisms (SNPs) (rs2839698, rs3024270, rs217727, and rs2735971) in H19 and the risk of colorectal cancer in a Chinese population. RESULTS: We found that individuals with rs2839698 A allele had a significantly increased risk of colorectal cancer, compared to those carrying G allele [odds ratio (OR) = 1.20, 95% confidence interval (CI) = 1.05-1.36 in additive model]. Further stratified analyses revealed that colon tumor site, well differentiated grade and Duke's stage of C/D were significantly associated with colorectal cancer risk (P < 0.05). Additionally, bioinformatic analysis showed that rs2839698 may change the crucial folding structures and alter the target microRNAs of H19. CONCLUSIONS: Our results provided the evidence that rs2839698 in H19 was associated with elevated risk of colorectal cancer, which may be a potential biomarker for predicting colorectal cancer susceptibility.

Association between cytosolic serine hydroxymethyltransferase (SHMT1) gene polymorphism and cancer risk: a meta-analysis.

BACKGROUND: The serine hydroxymethyltransferase (SHMT1) is the key enzyme in the folate metabolic pathway to provide one-carbon unit that plays an important role in biosynthesis. Abnormal biosynthesis involved in DNA synthesis and methylation can lead to activation of oncogenes and inactivation of tumor suppressor genes. And the abnormal biosynthesis is closely related to a variety of common tumors' occurrence and development. A SNP in SHMT1 C1420T may effect the procession of biosynthesis and finally influence cancer occurrence. METHODS: Comprehensive searches were performed on PubMed and EMBASE database. We used odds ratio (OR) and 95% confidence interval (95% CI) to assess the strength of associations between SHMT1 C1420T polymorphism and cancer risk. Q-test, I(2), and funnel plot were used to assess the heterogeneity and publication bias. RESULTS: Totally, 19 studies containing 9799 cases and 11,841 controls were performed in this meta-analysis. The results showed that there was no association between SHMT1 C1420T polymorphism and cancer risk. But in the subgroup analysis, the significant associations were found in colorectal cancer and Asian population. Publication bias was not observed in the analysis. CONCLUSIONS: Our results indicate that the SHMT1 C1420T polymorphism do not have a significant association with the risk of cancer overall. Otherwise, SHMT1 C1420T polymorphism may have a protective effect on colorectal cancer and Asian population.

Hypoxia-inducible factor-1α polymorphisms and risk of cancer metastasis: a meta-analysis.

BACKGROUND: HIF-1α is a major regulator in tumor progression and metastasis which responds to hypoxia. Many studies have demonstrated that hypoxia-inducible factor1-α (HIF-1α) polymorphisms are significantly associated with cancer metastasis, but the results are inconsistent. We conducted a comprehensive meta-analysis to estimate the associations between HIF-1α C1772 T polymorphism and cancer metastasis. METHODS: Comprehensive searches were conducted on PubMed and EMBASE database. Fifteen studies were included in the meta-analysis. We used the OR and 95%CI to assess the associations between HIF-1α C1772T polymorphism and cancer metastasis. Heterogeneity and publication bias were also assessed by Q test, I (2), and funnel plot. RESULTS: Totally, fifteen studies including 1239 cases with metastasis-positive (M+) and 2711 cases with metastasis-negative (M-) were performed in this meta-analysis. The results showed that HIF-1a C1772T polymorphism was associated with the increased risk of cancer metastasis (T allele vs. C allele, OR  = 1.36, 95% CI  = 1.12-1.64; TT+ TC vs. CC, OR  = 1.39, 95% CI  = 1.13-1.71; TT vs. TC+ CC, OR  = 1.93, 95% CI  = 0.86-4.36). In the subgroup analyses, the significant associations remained significant among Asians, Caucasians and other cancers in the dominant model. Publication bias was not observed in the analysis. CONCLUSIONS: Our results indicate that the HIF-1αC1772T polymorphism T allele may increase the risk of cancer metastasis, which might be a potential risk factor of cancer progress.

IL-12 p35 silenced dendritic cells modulate immune responses by blocking IL-12 signaling through JAK-STAT pathway in T lymphocytes.

Dendritic cells (DC) constitute a complex system of uniquely specialized antigen-presenting cells (APC) that play crucial roles in the initiation and regulation of immune responses. Recent studies have demonstrated that DC silenced by siRNA IL-12 p35 showed tolerogenic capacity in vitro. However, their mechanism of action is not fully understood. In this study, IL-12p35 siRNA was chemically synthesized and transfected into DCs. A coculture of T cells and DCs was performed. After 30 min coculture, T cells were harvested and analyzed. We showed that the IL-12 p35 silenced DCs decreased IL-12-induced T cell responses through blocking tyrosine phosphorylation of JAK2, TYK2, STAT3, and STAT4 proteins in T cells. These results demonstrate IL-12 p35 silenced DCs modulate immune responses by blocking IL-12 signaling through JAK-STAT pathway in T cells.

[Efficacy of antitumour colon cancer cell vaccine modified by Escherichia coli cytosine deaminase gene].

OBJECTIVES: To evaluate the efficacy of antitumour colon cancer cell vaccine modified by escherichia coli cytosine deaminase (EC-CD). METHODS: Mouse colon cancer cell vaccine CT26/CD was established by gene modification using retrovirus plasmid pLCDSN. Its tumorigenicity and effect on liver metastasis model established with wild-type colon cancer were evaluated. RESULTS: CT26/CD was established successfully and proliferated in medium containing 0.6 g/L G418 stably. EC-CD gene expression on these mutant cells was confirmed by RT-PCR. These mutant cells were more sensitive to 5-fluorocytosine (5-FC) compared with the wild-type ones (P=0.000), and presented excellent bystander effect. CT26/CD had the same tumorigenicity as its parental cells (P=0.892). CT26/CD, combined with the prodrug 5-FC, could inhibit tumor progress and live metastasis, and prolonged the survival of the liver metastasis model animals (P=0.000). CONCLUSION: The colon cancer cell vaccine modified by EC-CD presented anti-tumor effect in vivo, when treated with the prodrug.

Tamoxifen can reverse multidrug resistance of colorectal carcinoma in vivo.

AIM: To investigate the effect of tamoxifen (TAM) on multidrug resistance (MDR) of colorectal carcinoma in vivo and its relationship with estrogen receptor (ER). METHODS: Multidrug resistance was determined by means of semi-quantitative retro-transcription polymerase chain reaction (RT-PCR) to test mdr1 gene mRNA and ER expression was studied by immunohistochemistry. Tumor tissues from three cases of human colon carcinoma, which had mdr1(+)/ER(+), mdr1(+)/ER(-), mdr1(-) expressions, were planted subcutaneously in the neck of nude mice to establish three xenograft models. These models were subdivided into four subgroups randomly: Doxorubicin (DOX)-treated group, TAM-treated group, DOX and TAM group and control group. The dimensions of these xenografts were measured after each course of treatment and the xenografts were removed at the end of the experiments for measurements of weight and the variation of mdr1 mRNA level with RT-PCR. In each course, TAM (15 mg/(kg/d)) was administrated orally per day in the first seven days and DOX (3.6 mg/kg) was injected peritoneally on the first day. Data was evaluated by q and t tests. RESULTS: In the animal models with mdr1(-) tumor, the weights and volumes of the planted tumor in DOX group ((39.1+/-2.29) mg, (31.44+/-1.61) mm(3)) and TAM and DOX group ((38.72+/-2.56) mg, (31.31+/-1.74) mm(3)), which were lesser than that of control group ((45.48+/-3.92) mg, (36.42+/-2.77)mm(3), P = 0.037, P = 0.016 respectively) significantly. In the animal models with mdr1(+)/ER(+) tumor, the weights and volumes of planted tumor were not affected by DOX or TAM treatment; however, in TAM and DOX group ((425.5+/-28.58) mg, (340.35+/-22.28) mm(3)), they were significantly less than that of control group ((634.23+/-119.41) mg, (507.45+/-93.34) mm(3), P = 0.022, P = 0.045 respectively), which are similar to that in the models with mdr1(+)/ER(-) tumor. No significant changes were found in the expressive level of mdr1 mRNA following these treatments. CONCLUSION: The expression of mdr1 gene corresponds to the sensitivity of colon cancer to anti-tumor drugs in vivo. TAM can reverse the MDR of colorectal carcinoma in nude mice, which is independent of the expression of ER; however, no change was observed in the expressive level of mdr1 mRNA.

Effect of local CTLA4Ig gene transfection on acute rejection of small bowel allografts in rats.

AIM: To evaluate the local expression of CTLA4Ig gene in small bowels and its effect on preventing acute rejection of the small bowel allografts. METHODS: Groups of Wistar rats underwent heterotopic small bowel transplantation from SD rats. The recipients were randomly divided into experimental group (allografts were transfected with CTLA4Ig gene) and control group (non CTLA4Ig gene transfected). In the experimental group, the donor small bowels were perfused ex vivo with CTLA4Ig cDNA packaged with lipofectin vector via intra-superior mesenteric artery before transplantation, and the CTLA4Ig expression in the small bowel grafts post-transplantation was assessed by immunohistology. On d 3, 7 and 10 post-transplantation, the allografts in each group were harvested for the examination of histology and detection of apoptosis. RESULTS: Small bowel allografts treated with CTLA4Ig cDNA showed abundant CTLA4Ig expression after transplantation. Acute rejection of grade I on d 7 and grade II on d 10 after transplantation was noticed in the control allografts, and a dramatically increased number of apoptotic enterocytes in parallel to the progressive rejection could be recognized. In contrast, the allografts treated with CTLA4Ig cDNA showed nonspecific histological changes and only a few apoptotic enterocytes were found after transplantation. CONCLUSION: Local CTLA4Ig gene transfection of small bowel allograft is feasible, and the local CTLA4Ig expression in the allograft can prevent acute rejection after transplantation.

Specific CEA-producing colorectal carcinoma cell killing with recombinant adenoviral vector containing cytosine deaminase gene.

AIM: To kill CEA positive colorectal carcinoma cells specifically using the E coli cytosine deaminase (CD) suicide gene, a new replication-deficient recombinant adenoviral vector was constructed in which CD gene was controlled under CEA promoter and its in vitro cytotoxic effects were evaluated. METHODS: Shuttle plasmid containing CD gene and regulatory sequence of the CEA gene was constructed and recombined with the right arm of adenovirus genome DNA in 293 cell strain. Dot blotting and PCR were used to identify positive plaques. The purification of adenovirus was performed with ultra-concentration in CsCl step gradients and the titration was measured with plaque formation assay. Cytotoxic effects were assayed with MTT method, The fifty percent inhibition concentration (IC(50)) of 5-FC was calculated using a curve-fitting parameter. The human colorectal carcinoma cell line, which was CEA-producing, and the CEA-nonproducing Hela cell line were applied in cytological tests. An established recombinant adenovirus vector AdCMVCD, in which the CD gene was controlled under CMV promoter, was used as virus control. Quantitative results were expressed as the mean +/- SD of the mean. Statistical analysis was performed using ANOVA test. RESULTS: The desired recombinant adenovirus vector was named AdCEACD. The results of dot blotting and PCR showed that the recombinant adenovirus contained CEA promoter and CD gene. Virus titer was about 5.0 X 10(14)pfu/L(-1) after purification. The CEA-producing Lovo cells were sensitive to 5-FC and had the same cytotoxic effect after infection with AdCEACD and AdCMVCD (The IC(50) values of 5-FC in parent Lovo cells, Lovo cells infected with 100 M.O.I AdCEACD and Lovo cells infected with 10 M.O.I AdCMVCD were >15000, 216.5+/-38.1 and 128.8+/-25.4 micromol.L(-1), P<0.001, respectively), and the cytotoxicity of 5-FC increased accordingly when the m.o.i of adenoviruses were enhanced (The value of IC(50) of 5-FC was reduced to 27.9+/-4.2 micromol.L(-1) in 1000 M.O.I AdCEACD infected Lovo cells and 24.8+/-7.1 micromol.L(-1) in 100 M.O.I AdCMVCD infected Lovo cells, P<0.05, P<0.01, respectively). The CEA-nonproducing Hela cells had no effect after infection with AdCEACD, but Hela cells had the cytotoxic sensitivity to 5-FC after infection with AdCMVCD (The IC(50) of 5-FC in parent Hele cells and Hela cells infected with AdCMVCD at 10 M.O.I was >15000 and 214.5+/-31.3 micromol.L(-1), P<0.001). AdCEACD/5-FC system also had bystander effect, and the viability was about 30 percent when the proportion of transfected cells was only 10 percent. CONCLUSION: The recombinant adenovirus vector AdCEACD has the character of cell type-specific gene delivery. The AdCEACD/5-FC system may become a new, potent and specific approach for the gene therapy of CEA-positive neoplasms, especially colon carcinoma.