The association of a genetic variant in CDKN2A/B gene and the risk of colorectal cancer

Colorectal cancer is among the most aggressive tumors, and its development involves an interplay between various genetic and environmental familial risk factors. Several genetic polymorphisms have been reported to be associated with colorectal cancer in recent studies. In this current study, we aimed to evaluate the possible relationship between a CDKN2A/B, single nucleotide polymorphisms (SNP) (rs10811661), with the risk of colorectal cancer. A total of 541 individuals with, or without cancer were recruited. DNA was extracted, and genotyped using a Taq-Man based real‐time PCR method. The rs10811661 SNP was associated with an increased risk of colorectal cancer (additive model: OR=3.46, CI= 1.79-6.69, p<0.0001 and recessive model: 5.72, CI= 3.12-10.49, p<0.0001). The distribution of minor alleles in the total population for homozygote allele was 9.2 %, while this was 20.1 % for heterozygotes. In summary, our findings indicate that the rs10811661 polymorphism of the CDKN2A/B gene was strongly related to the occurrence of colorectal cancer suggesting its potential role as a prognostic biomarker for the management of colorectal cancer

The potential prognostic and therapeutic application of tissue and circulating microRNAs in cervical cancer

Cervical cancer (CC) is a common malignancy in women and a major cause of cancer- related mortality globally. Some novel biomarkers may enable the early diagnosis and monitoring of CC. MicroRNAs are small noncoding RNAs that control gene translation at a post transcriptional level. Hence the deregulation of these molecules can cause many diseases. There appears to be an association between aberrant miRNA expression and CC, but the molecular mechanisms involved in the development of CC remain unknown. The upregulation of some circulating miRNAs, e.g. miRNA-20a, miRNA-203, miRNA-21, miRNA-205, miRNA-218, and miR-485-5, as well as tissue specific-miRNAs, e.g. miR-7, miR-10a, miR-17-5p, miR-135b, miR-149 and miR-203 has been found in patients with CC. There is also growing evidence for the importance of miRNAs in the development of drug-resistance. This review therefore highlights recently published preclinical and clinical investigation performed on tissue-specific and circulating miRNAs, as potential biomarkers for the detection of patients at early stages of CC, in the prediction of prognosis, and monitoring of their response to therapy. Key word: cervical cancer, CIN, MiRNA, circulating biomarker, tissue-specific biomarker, HP

Crocin synergistically enhances the anti-proliferative activity of 5-FU through Wnt/PI3K pathway in a mouse model of colitis-associated colorectal cancer

Colorectal-cancer (CRC) is the third most common cause of cancer-related-death, and hence there is a need for the identification of novel-agents to improve the efficacy of existing-therapies. There is growing evidence for the anti-tumor-activity of crocin, although its activity and molecular-mechanisms in CRC remains to be elucidated. Here we explored the therapeutic-application of crocin or its combination with 5-Flurouracil in a mouse-model of colitis-associated colon-cancer. The anti-proliferative-activity of crocin was assessed in 2- and 3-dimensional cell-culture-models. The migratory-behaviors were determined, while the expression-levels of several-genes were assessed by qRT-PCR/Western-blotting. We examined the anti-inflammatory properties of crocin by pathological-evaluation and disease-activity-index as well as oxidative/ antioxidant markers: malondialdehyde (MDA) and total-thiols (T-SH) levels and superoxide-dismutase (SOD) and catalase (CAT) activity. Crocin suppressed cell-growth and the invasive-behavior of CRC-cells through modulation of the Wnt-pathway and E-cadherin. Moreover, administration of crocin alone, or in combination with 5-FU dramatically reduced the tumor-number and tumor-size in both distal/mid-colon followed by reduction in disease-activity-index. Crocin also suppressed the colonic-inflammation induced by Dextran-sulfate-sodium and notably recovered the increased-levels of MDA, decreased Thiol-levels and activity of CAT-levels. Crocin was able to ameliorate the severe-inflammation with mucosal-ulcers and high grade-dysplastic-crypts as detected by inflammation-score, Crypt-loss, pathological-changes and histology-scores. We demonstrated an antitumor-activity of crocin in CRC and its potential role in improvement of inflammation with mucosal ulcers and high grade dysplastic crypts, supporting the desireability of further investigations on the therapeutic potential of this approach in CRC

A genetic variant in proline and serine rich coiled-coil 1 gene is associated with the risk of cardiovascular disease

Background: Cardiovascular disease is one of the most common causes of morbidity and mortality worldwide. The Proline and Serine Rich Coiled-Coil 1 gene in 1p13.3 locus has been reported to be associated with low density lipoprotein cholesterol (LDL-C) and coronary artery disease (CAD). The objective of this study was to investigate the association between the rs599839 polymorphism of the Proline and Serine Rich Coiled-Coil 1 (PSRC1) gene with CVD outcomes in a population sample recruited as part of the Mashhad-Stroke and Heart-Atherosclerotic-Disorders (MASHAD) cohort. Methods: Five hundred and nine individuals who had an average follow-up period of 10 years were enrolled as part of the MASHAD cohort. DNA was extracted and genotyped using the TaqMan-real-time-PCR based method. Results: The study found individuals with GA/GG genotypes were at a higher risk of CVDs (OR= 4.7; 95% CI, 2.5-8.7; p< 0.001) in comparison to those with AA genotype; however, the result was not significant for GG genotype data. Conclusions: The results suggest that the GA/GG genotypes of the PSRC1gene locus were at increased risk of CVD in a representative population-based cohort, demonstrating further functional analysis to discover the value of emerging marker as a risk stratification biomarker to recognize high risk cases

The association between a variant of the cyclin-dependent kinase inhibitor 2A/B gene and risk of cardiovascular disease

Background Cardiovascular disease (CVD) is the most common cause of morbidity and mortality globally. Despite progress being made in the diagnosis and treatment of CVDs, one third of deaths are due to CVDs. We have investigated the association between the rs1333049 polymorphism of the cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) gene with CVD outcomes in a population sample recruited as part of the Mashhad-Stroke and Heart-Atherosclerotic-Disorders (MASHAD) cohort. Methods and results Five hundred and nine individuals who had a median follow-up period of 10 years were recruited as part of the MASHAD cohort. Anthropometric, and biochemical parameters were assessed followed by genotyping using TaqMan-real-time-PCR based method. Our data showed that carriers of the GG genotype were significantly more likely to develop CVD, compared to those with a CC or CG genotypes (OR: 4.77, 95%CI: 2.62–8.68, p = 0.001). Similar result we also found in second population which were follow up for 10 years. In particular cases who had an event in recessive genetic model (CC vs CG + GG) had a higher risk of developing CVD (OR: 5.57, 95%CI: 2.80–11.06, p = 0.001). Conclusion We have found that carriers of the GG genotype of the CDKN2A/B gene locus were at increased risk of CVD in a representative population-based cohort, indicating further functional analysis to explore the value of emerging marker as a risk stratification biomarker to identify high risk cases

Inhibition of the Wnt/b-catenin pathway using PNU-74654 reduces tumor growth in in vitro and in vivo models of colorectal cancer

Background Colorectal-cancer (CRC) is amongst the most lethal-cancers, mainly due to its metastatic spread and drug chemoresistance. Hence there is a need for new approaches to either increase the efficacy of current therapy or introduce new therapies that have greater efficacy. There is increasing evidence that dysregulation of WNT-signaling-pathway plays an essential role in the development and prognosis of CRC. Here we have investigated the therapeutic potential of targeting the WNT/b-catenin pathway using a novel Wnt/b-catenin inhibitor, PNU-74654, in combination with 5-FU in CRC. Methods The anti-proliferative-effect of PNU-74654 was evaluated in two-/three-dimensional cell models. The activity of agents on cell growth, migration, invasion, cell cycle and apoptosis was evaluated by MTT, wound healing assay, invasion, FACS, and annexin V staining, respectively. The oxidant/antioxidant levels were also assessed by determining the level of MDA, SOD, as well as using the DCFH-DA assay. We used a xenograft model of CRC to investigate PNU-74654 activity alone and in combination with 5-FU follow by histological staining and biochemical and gene expression analyses by RT-PCR and western blot. Results PNU-74654 inhibited cell-growth and synergistically affected the anti-tumor properties of 5-FU via modulation of Cyclin D1 and survivin. This agent inhibited the migration/invasion of colorectal cancer cells via perturbation of E-cadherin. Furthermore, PNU-74654 inhibited the tumor growth, which was more pronounced using the PNU-74654 plus 5-FU combination via induction of reactive oxygen species, down-regulation of SOD and modulation of MCP-1, P53, TNF-α. Conclusions Our finding demonstrated that PNU-74654 can target Wnt-pathway, interfere with cell-proliferation, induced-cell death, reduced-migration and interact with 5-FU, supporting further investigations on this therapeutic-approach for colorectal cancer