Risk Factor For Colon Cancer Research Articles

Glutathione peroxidase-2 and selenium decreased inflammation and tumors in a mouse model of inflammation-associated carcinogenesis whereas sulforaphane effects differed with selenium supply

Chronic inflammation and selenium deficiency are considered as risk factors for colon cancer. The protective effect of selenium might be mediated by specific selenoproteins, such as glutathione peroxidases (GPx). GPx-1 and -2 double knockout, but not single knockout mice, spontaneously develop ileocolitis and intestinal cancer. Since GPx2 is induced by the chemopreventive sulforaphane (SFN) via the nuclear factor E2-related factor 2 (Nrf2)/Keap1 system, the susceptibility of GPx2-KO and wild-type (WT) mice to azoxymethane and dextran sulfate sodium (AOM/DSS)-induced colon carcinogenesis was tested under different selenium states and SFN applications. WT and GPx2-KO mice were grown on a selenium-poor, -adequate or -supranutritional diet. SFN application started either 1 week before (SFN4) or along with (SFN3) a single AOM application followed by DSS treatment for 1 week. Mice were assessed 3 weeks after AOM for colitis and Nrf2 target gene expression and after 12 weeks for tumorigenesis. NAD(P)H:quinone oxidoreductases, thioredoxin reductases and glutathione-S-transferases were upregulated in the ileum and/or colon by SFN, as was GPx2 in WT mice. Inflammation scores were more severe in GPx2-KO mice and highest in selenium-poor groups. Inflammation was enhanced by SFN4 in both genotypes under selenium restriction but decreased in selenium adequacy. Total tumor numbers were higher in GPx2-KO mice but diminished by increasing selenium in both genotypes. SFN3 reduced inflammation and tumor multiplicity in both Se-adequate genotypes. Tumor size was smaller in Se-poor GPx2-KO mice. It is concluded that GPx2, although supporting tumor growth, inhibits inflammation-mediated tumorigenesis, but the protective effect of selenium does not strictly depend on GPx2 expression. Similarly, SFN requires selenium but not GPx2 for being protective.

Effects of S -adenosylmethionine and methylthioadenosine on inflammation-induced colon cancer in mice

Chronic inflammation is an underlying risk factor for colon cancer. Tumor necrosis factor alpha (TNF-α) plays a critical role in the development of inflammation-induced colon cancer in a mouse model. S-adenosylmethionine (SAMe) and its metabolite methylthioadenosine (MTA) can inhibit lipopolysaccharide-induced TNF-α expression in macrophages. The aim of this work was to examine whether SAMe and MTA are effective in preventing inflammation-induced colon cancer and if so identify signaling pathways affected. Balb/c mice were treated with azoxymethane (AOM) and dextran sulfate sodium to induce colon cancer. Two days after AOM treatment, mice were divided into three groups: vehicle control, SAMe or MTA. Tumor load, histology, immunohistochemistry, gene and protein expression were determined. SAMe and MTA treatment reduced tumor load by ∼40%. Both treatments raised SAMe and MTA levels but MTA also raised S-adenosylhomocysteine levels. MTA treatment prevented the induction of many genes known to play pathogenetic roles in this model except for TNF-α and inducible nitric oxide synthase (iNOS). SAMe also had no effect on TNF-α or iNOS and was less inhibitory than MTA on the other genes. In vivo, both treatments induced apoptosis but inhibited proliferation, β-catenin, nuclear factor kappa B activation and interleukin (IL) 6 signaling. Effect of SAMe and MTA on IL-6 signaling was examined using Colo 205 colon cancer cells. In these cells, SAMe and MTA inhibited IL-6-induced IL-10 expression. MTA also inhibited IL-10 transcription and signal transducer and activator of transcription 3 activation. In conclusion, SAMe and MTA reduced inflammation-induced colon cancer and inhibited several pathways important in colon carcinogenesis.

Continuing Medical Education: November 2011

Is Diabetes Mellitus an Independent Risk Factor for Colon Cancer and Rectal Cancer? The American College of Gastroenterology is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The American College of Gastroenterology designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Consumption of a Resistant Protein, Sericin, Elevates Fecal Immunoglobulin A, Mucins, and Cecal Organic Acids in Rats Fed a High-Fat Diet

AbstractWe previously reported that consumption of a resistant protein, sericin, reduces colon tumorigenesis, constipation, and serum TG in rodents. The present study was conducted to elucidate the effects of dietary sericin on the intestinal luminal environment in rats fed a high-fat (HF) diet. Rats were fed 300 or 50 g/kg of beef tallow with or without 40 g/kg sericin, a protein purified from cocoons of Bombix mori, for 3 wk. Intestinal luminal variables, including IgA (index of intestinal immune function), mucins (index of barrier function), organic acids, microflora, and secondary bile acids, were measured. Dietary sericin markedly elevated fecal IgA in the HF diet group (3-fold, P < 0.05) but not in the low-fat (LF) diet group. Fecal mucin levels were elevated by sericin intake in the HF diet group (P < 0.05). Cecal organic acids, including acetate, propionate, n-butyrate, and succinate, were significantly lower in the HF diet group compared with the LF diet group. Dietary sericin significantly elevated cecal acetate and n-butyrate in the HF diet group but not in the LF diet group. Compared with the LF diet, the HF diet significantly increased serum TG in the untreated group but not in those fed sericin. The HF diet increased lower density lipoprotein (VLDL + IDL + LDL) cholesterol and it was reduced by sericin intake (P < 0.05). There was an inverse correlation between serum TG and cecal acetate (Spearman rank correlation coefficient = -0.63; P < 0.001). The profile of microflora in cecal digesta and fecal secondary bile acids (a risk factor for colon cancer) did not differ between the HF diet and HF diet with sericin groups. These results suggest a novel and favorable effect of sericin on colon health by modulating intestinal immune and barrier functions and fermentation in rats fed a HF diet.

Colon cancer in rapidly developing countries: review of the lifestyle, dietary, consanguinity and hereditary risk factors

Colon cancer rates are rising dramatically in once low incidence nations. These nations are undergoing rapid economic development and are known as “nations in transition” (NIT). This review identifies some of the most common etiological risk factors of colon cancer in these nations and evaluates the existing epidemiological evidence. The main risk factors which were found to be prevalent in NIT include: lifestyle factors such as physical inactivity, obesity and abdominal adiposity, alcohol consumption and cigarette smoking; dietary factors such as fatty food and red meat consumption. Protective factors included white meat and fiber consumption. Several studies found to have significantly higher rates of colon cancer among the young population (&lt;40 years old). There appears to be a quantitative and qualitative increase in risk to relatives of patients diagnosed at a young age compared with those diagnosed later in life, at least part of which is likely to be the result of a hereditary susceptibility. Close relatives of patients with colon cancer are at an increased risk of developing a colon cancer. Close relatives of early onset cases warrant more intensive endoscopic screening and at an earlier age than relatives of patients diagnosed at older ages. Furthermore, these suggest the existence of genetic predispositions in these nations which need to be investigated further and have implications for screening programs. In conclusion, public health awareness campaigns promoting prevention of modifiable risk factors and screening initiatives with guidelines suited to the age-specific incidence rates of NIT are needed very urgently.

Colon cancer in rapidly developing countries: review of the lifestyle, dietary, consanguinity and hereditary risk factors

Colon cancer rates are rising dramatically in once low incidence nations. These nations are undergoing rapid economic development and are known as “nations in transition” (NIT). This review identifies some of the most common etiological risk factors of colon cancer in these nations and evaluates the existing epidemiological evidence. The main risk factors which were found to be prevalent in NIT include: lifestyle factors such as physical inactivity, obesity and abdominal adiposity, alcohol consumption and cigarette smoking; dietary factors such as fatty food and red meat consumption. Protective factors included white meat and fiber consumption. Several studies found to have significantly higher rates of colon cancer among the young population (&amp;lt;40 years old). There appears to be a quantitative and qualitative increase in risk to relatives of patients diagnosed at a young age compared with those diagnosed later in life, at least part of which is likely to be the result of a hereditary susceptibility. Close relatives of patients with colon cancer are at an increased risk of developing a colon cancer. Close relatives of early onset cases warrant more intensive endoscopic screening and at an earlier age than relatives of patients diagnosed at older ages. Furthermore, these suggest the existence of genetic predispositions in these nations which need to be investigated further and have implications for screening programs. In conclusion, public health awareness campaigns promoting prevention of modifiable risk factors and screening initiatives with guidelines suited to the age-specific incidence rates of NIT are needed very urgently.

Is Diabetes Mellitus an Independent Risk Factor for Colon Cancer and Rectal Cancer?

Diabetes mellitus (DM) has been associated with an increased risk of colorectal cancer (CRC). The American College of Gastroenterology Guidelines for Colorectal Cancer Screening 2008 recommend that clinicians be aware of an increased CRC risk in patients with smoking and obesity, but do not highlight the increase in CRC risk in patients with DM. To provide an updated quantitative assessment of the association of DM with colon cancer (CC) and rectal cancer (RC), we conducted a meta-analysis of case-control and cohort studies. We also evaluated whether the association varied by sex, and assessed potential confounders including obesity, smoking, and exercise. We identified studies by searching the EMBASE and MEDLINE databases (from inception through 31 December 2009) and by searching bibliographies of relevant articles. Summary relative risks (RRs) with 95% confidence intervals (CIs) were calculated with fixed- and random-effects models. Several subgroup analyses were performed to explore potential study heterogeneity and bias. DM was associated with an increased risk of CC (summary RR 1.38, 95% CI 1.26-1.51; n=14 studies) and RC (summary RR 1.20, 95% CI 1.09-1.31; n=12 studies). The association remained when we limited the meta-analysis to studies that either controlled for smoking and obesity, or for smoking, obesity, and physical exercise. DM was associated with an increased risk of CC for both men (summary RR 1.43, 95% CI 1.30-1.57; n=11 studies) and women (summary RR 1.35, 95% CI 1.14-1.53; n=10 studies). For RC, there was a significant association between DM and cancer risk for men (summary RR 1.22, 95% CI 1.07-1.40; n=8 studies), but not for women (summary RR 1.09, 95% CI=0.99-1.19; n=8 studies). These data suggest that DM is an independent risk factor for colon and rectal cancer. Although these findings are based on observational epidemiological studies that have inherent limitations due to diagnostic bias and confounding, subgroup analyses confirmed the consistency of our findings across study type and population. This information can inform risk models and specialty society CRC screening guidelines.

Role of intestinal microbiota in colon cancer prevention

Environmental and hereditary factors, together with lifestyle, are important factors in colon cancer development. Considering the increasing incidence of this disease, especially in the developed western world, the last decade has seen much attention directed towards understanding possible prevention strategies. Efforts to study the intestinal microbiota and its interaction with the host have underlined that disbiosis in colonic bacterial composition is a risk factor for colon cancer. Modulation of the composition of intestinal microbiota through the use of probiotic, prebiotic and synbiotic products could therefore represent a strategy for prevention of cancer development. The mechanisms underlying the probiotic-prebiotic anticarcinogenic effect involve a combination of events: e.g. binding of mutagens, suppression of bacteria that convert pro-carcinogens into carcinogens, immune system stimulation, and a reduction in the level of certain intestinal bacterial enzymes that promote carcinogen formation.

The study on the relationship between XRCC1 gene polymorphisms and the susceptibility of colorectal cancer

Objective To investigate the correlation between three gene locus polymorphisms of X-ray repair cross-complementary protein 1 (XRCC1) exon (Arg194Trp, Arg280His and Arg399Gln) and the risk of colorectal cancer (CRC). Methods A case-control study was performed in 250 CRC patients (case group, 128 colon cancer patients and 122 rectal cancer patients) and 213 healthy individuals (control group). The three gene locus polymorphism of XRCC1 was tested by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) method. The genotype distribution and allele frequency of each locus was analyzed with SPSS 10.0 software. Results There was no significant difference in allele frequency of XRCC1 at 194 and 399 loci (P > 0.05). However, the 280 Arg/His allele frequency of XRCC1 was higher in case group than that in control group (OR=1.66,95%CI:1.01~2.73,P=0.047). The 280Arg/His allele frequency was higher in rectal cancer group than that in control group (OR =1.82,95%CI:1.02~3.27). The frequency of 280His allele (Arg280His and His280His) was higher in case group than that in control group (OR=1.85,95%CI:1.06~3.22). However, it was a relative low risk factor of colon cancer and there was no significant difference between colon cancer group and control group (OR=1.85, 95%CI:1.06~3.22). Conclusions There was no correlation between XRCC1 Arg194Trp and Arg399Gln polymorpohisms and the risk of CRC. However, 280Arg/His genotype may increase the risk of CRC, and 280His allele is a risk factor of rectal cancer. Key words: Colorectal neoplasms; Polymorphism, genetic; DNA repairnzynes; Alleles; Genetic predisposition to disease

Effects of genetic variations in the Adiponectin pathway genes on the risk of colorectal cancer in the Chinese population

BackgroundDecreased expression of adiponectin (ADIPOQ) is associated with an increased risk for developing colorectal cancer (CRC) in humans. This study was designed to determine whether polymorphisms present in the ADIPOQ and its type 1 receptor (ADIPOR1) could affect the risk of CRC.MethodsWe measured five polymorphisms in the ADIPOQ and two polymorphisms in ADIPOR1, and analyzed their associations with CRC risk in 420 CRC patients and 555 age- and gender-matched healthy individuals.ResultsMultivariate logistic regression analyses revealed that the CRC risks (adjusted odds ratio and 95% confidence interval) associated with the ADIPOR1 genotypes were 0.53 (95% CI, 0.35-0.81) for rs12733285C/T, 0.59 (95% CI, 0.45-0.78) for rs1342387A/G, and 0.59 (95% CI, 0.39-0.89) for rs1342387A/A, respectively. Furthermore, the risks were more significant in carriers of the allele A of rs1342387A/G (adjusted OR, 0.59; 95% CI, 0.46-0.77) than noncarriers (G/G). In a further subgroup analysis, we observed that rs266729G/C was associated with an increased risk for colon cancer (adjusted OR, 1.50; 95% CI, 1.05-2.14) but not for rectal cancer (adjusted OR, 0.88; 95% CI, 0.63-1.22), and that carriers of the G allele had an increased risk for developing colon cancer (adjusted OR, 1.45; 95% CI, 1.03-2.05).ConclusionsWe conclude that the rs12733285C/T genotype and the carriage of the A allele of rs1342387 (A/G or A/A) in ADIPOR1 are the protective factors for CRC, while that rs266729G/C and G allele of ADIPOQ are the risk factors for colon cancer after excluding rectal cancer cases.

Obesity‐induced metabolic stresses in breast and colon cancer

Epidemiological studies have suggested that excess body weight gain may be a major risk factor for colon and breast cancer. A positive energy balance creates metabolic stresses, including the excess production of reactive oxygen species (ROS), hyperinsulinemia, the elevated adipokine secretion, and increased gut permeability. Obesity is a risk factor for breast cancer in postmenopausal women, and overweight women are more likely to have poor outcomes. The higher circulating concentration of insulin-like growth factor 1 (IGF-1) in overweight and obese women is thought to be an important mediator to promote cell proliferation and survival via the activation of phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK)/p38 signaling pathways. In an animal model of colon carcinogenesis, overweight mice fed a high-fat diet exhibited a greater number of colon tumors than lean animals. The increased abdominal fat was associated with higher concentrations of leptin, insulin, and IGF-1, which possibly mediate tumor growth. These data suggest that the metabolic burden created by excess adiposity accelerates uncontrolled cell growth and survival, thereby increasing the risk of developing breast and colon cancer.

Drinking, Smoking Confirmed as Colon Cancer Risk Factors

Drinking, Smoking Confirmed as Colon Cancer Risk Factors

Sedenatry Occupation, Its Validity and Risk for Colon Cancer

Although sedentary occupation has become more common, it is still uncertain how much physical activity spent at work contributes to total energy expenditure (TEE) and health outcomes. PURPOSE: The primary objective of this study is to examine the relationship between posture at work and TEE by the DLW method as a gold standard. The secondary objective is to investigate the relationship between posture at work and cancer incidence. METHODS: 1) Study participants were 226 Japanese men and women aged 20 to 83 years. TEE and TEE per unit weight (TEE/BW) were estimated over one or two weeks depending on the two half-lives of the isotopes using the DLW method. The posture at work, which is a component of our physical activity questionnaire (JALPAQ), was surveyed for every participant before DLW dosing. 2) We asked similar questions about physical activity of 7,796 urban male workers aged 35-59 who participated in periodic health check-up between 1988 and 1990. Subjects were followed till the end of December, 1994, and a total of 123 cancers (and 36 colon cancers) were identified during the period by Osaka Cancer Registry. Cox proportional hazards models were used to estimate age-adjusted relative risks (RR) and 95% confidence intervals (CI). RESULTS: The posture at work was most closely related with TEE/BW, and there was the dose-response relationship between the posture and TEE/BW. The relation of the posture at work with all-cause cancer appeared to be U-shaped. Compared to those who were almost sitting, those who were standing more frequently had a significantly lower risk (RR = 0.46, CI = 0.22-0.98). There seemed to be dose-response relationships between the posture and colon cancer. Compared to those who were almost sitting, RRs (CI) for those who were sitting more frequently, sitting for half of work time, standing more frequently, and almost standing were 0.50(0.20-1.28), 0.59(0.24-1.44), 0.45(0.13-1.54), and 0.27(0.09-0.83), respectively. CONCLUSIONS: These data suggest that the posture at work is a simple and useful question item to estimate a TEE, and the sedentary lifestyle may be one of strong risk factors for colon cancer among Japanese male workers.

Risk Factors for Distal Colon and Rectal Cancer Following a Negative Screening Sigmoidoscopy

Risk Factors for Distal Colon and Rectal Cancer Following a Negative Screening Sigmoidoscopy

Abstract 5113: Discovery and application of a biomarker cassette to inflammatory bowel disease

Abstract Inflammatory bowel disease (IBD) results from intermittent and severe activation of the mucosal immune system in the gastrointestinal tract to promote a chronic state of inflammation. Crohn's disease (CD) and ulcerative colitis (UC) are the two major forms of IBD. Infiltration of gut tissue by lymphocytes, neutrophils, and macrophages results in prolonged exposure to chemical agents such as pro-inflammatory cytokines and reactive oxygen/nitrogen species. Chronic exposure to these inflammation products leads to mis-regulated cell signaling, altered protein expression, and chemical damage to lipids, protein, and nucleic acids. IBD is a significant risk factor for colon cancer. IBD exhibits phases of active disease (active inflammation) and remission, which complicate therapeutic intervention. Clinical biomarkers currently in use are not predictive of the transition from remission to active disease. Our laboratory has conducted an unbiased, four-pronged approach to IBD biomarker identification in human serum utilizing proteomic discovery of acute phase proteins, cytokine profiling, quantification of oxidative tyrosine modifications (chlorotyrosine (Cl-Tyr), bromotyrosine (Br-Tyr), and nitrotyrosine (NO-Tyr)–markers of neutrophil activity), and measurement of carbonylated proteins. One hundred and ten human serum samples were analyzed. This network of data was analyzed by orthogonormalized partial least squares (OPLS) analysis to identify covariance in the data set. Variable importance in projection (VIP) scores were determined to identify which variables were most predictive of clinically diagnosed disease score (VIP &amp;gt;1). Using data available from the cytokine and oxidative tyrosine analysis, the data set was stratified to clinically diagnosed active and inactive disease, with the intent of identifying serum markers that were predictive of this transition. Several variables for UC and CD demonstrated strong covariance with disease score. The top VIP scores identified for UC were: Interleukin-8 (IL-8), granulocyte-colony stimulating factor (G-CSF), IL-6, and Cl-Tyr. The top VIP scores identified for CD were: Cl-Tyr, macrophage inflammatory protein-1β (MIP-1β), inflammatory chemokine-10 (IP-10), IL-6, and IL-1 receptor antagonist (IL-1ra). A Total Score was generated for each UC and CD serum sample by normalizing the raw data to a base-10 spread, scaling by the VIP factor, and summing the total. Based on the Total Score the calculated specificity and sensitivity for identifying active UC was 81.8% and 84.2%, respectively, while the specificity and sensitivity for identifying active CD was 87.5% and 75%, respectively. We anticipate that the addition of acute phase and cabonylated protein analysis will improve the Total Score assessment. Results from this study strongly suggest that a cassette of in vivo serum markers may be predictive of the transition from remission to active disease in IBD. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5113. doi:10.1158/1538-7445.AM2011-5113

Abstract 830: Angiotensin converting enzyme inhibitor and angiotensin receptor blocker suppress obesity-related colonic preneoplastic lesions in male C57BL/KsJ-db/db obese mice

Abstract Obesity and related metabolic abnormalities, including a state of chronic inflammation and oxidative stress, are risk factors for colon cancer. Dysregulation the renin-angiotensin system (RAS) also plays a critical role in obesity-related metabolic disorders and certain types of carcinogenesis. In the present study, we examined the effects of angiotensin converting enzyme (ACE) inhibitor and angiotensin receptor blocker (ARB), both of which target RAS, on the development of azoxymethane (AOM)-initiated colonic premalignant lesions in C57BL/KsJ-db/db (db/db) obese mice. Male db/db mice were given 4 weekly subcutaneous injections of AOM (15 mg/kg body weight) and then they received drinking water containing captopril (ACE inhibitor, 5 mg/kg/day) or telmisartan (ARB, 5 mg/kg/day) for 7 weeks. At sacrifice, administration of captopril and telmisartan significantly reduced the total number of colonic premalignant lesions, aberrant crypt foci and β-catenin accumulated crypts, compared with the control untreated-group. Both agents decreased the expression levels of TNF-α mRNA on the colonic mucosa of experimental mice. The expression levels of TNF-α, COX-2, IL-1β, IL-6, and PAI-1 mRNAs on the visceral fat were also decreased by administration of these agents. In addition, captopril and telmisartan significantly decreased the levels of urinary 8-OHdG, a surrogate marker of oxidative damage to DNA, in the experimental mice. These findings suggest that both ACE inhibitor and ARB suppress obesity-related colon carcinogenesis by attenuating chronic inflammation and reducing oxidative stress. Targeting the dysregulation of RAS might be, therefore, one of the effective strategies for the chemoprevention of obesity-related colon cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 830. doi:10.1158/1538-7445.AM2011-830

Abstract 3178: Identification and validation of markers for colon adenoma and adenocarcinoma

Abstract Colorectal cancer (CRC) is the second leading cause of cancer related deaths in the United States and Europe. The early detection and diagnosis of dysplastic and early neoplastic colonic lesions will improve survival and make possible curative treatments. Currently, this is best done with colonoscopy, which is expensive and requires a cathartic bowel prep that has led to low compliance. The goal of this study is to develop targeted molecular imaging agents for the early detection of colon cancer via targeted and potentially prepless colonography using CT or MRI contrast. Such agents can also be used to improve detection of lesions for removal during traditional colonoscopy. By gene expression profiling of DNA microarray data from patient samples of colon adenoma (n =39), adenocarcinoma (n = 432), inflammatory bowel disease (IBD) (n = 16) and unaffected gastrointestinal (GI) tract tissues (normal colon, n = 178 and other gastrointestinal tissues n = 32), we have identified 6 potential cell-surface targets that are highly expressed in colon adenomas and adenocarcinomas relative to unaffected GI tissues: TLR4, LY6G6D, GRM8, GPR56, SLCO1B3 and CLDN1. None of these markers alone cover 100% of the colon adenoma and adenocarcinoma samples surveyed, although combinations did. Nearly all (99.7%) of the adenoma and adenocarcinoma samples express at least one of the three markers TLR4, LY6G6D and CLDN1. One tumor did not express any of these markers. CSF3R and SLC6A14 are expressed exclusively in IBD, which is a risk factor for colon cancer. DNA microarray expression data for colon tumor cell lines (DIFI, SW-620, SW-480, HT-29, COLO-205, KM12, KM12S, HCT116, and HCT115) were also analyzed, and SW-620 and SW-480 cell lines were identified as expressing TLR4, LY6G6D, GPR56 and CLDN1. COLO-205 cells highly express GRM8 and KM12 cells express SLCO1B3. GPR56 and CLDN1 were broadly expressed amongst all cell lines. Validation of these markers for protein expression in patient tissue samples by immunohistochemistry is underway. Molecular imaging agents against validated targets are being developed for the potentially prepless and non-invasive detection of colon adenomas and adenocarcinomas using molecular colonography. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3178. doi:10.1158/1538-7445.AM2011-3178

Association of MTHFR, MTR, MTRR, RFC1, and DHFR Gene Polymorphisms with Susceptibility to Sporadic Colon Cancer

Altered folate levels may play an important role in colon carcinogenesis. The aim of this study was to investigate the association of polymorphisms in key folate-metabolizing genes with susceptibility to sporadic colon cancer. Six common polymorphisms (two in MTHFR and one each in MTR, MTRR, RFC1, and DHFR genes) were genotyped in 300 healthy subjects and 300 colon cancer patients from Croatia. Obtained results indicate possible protective role of MTRR 66 AA in sporadic colon cancer (OR=0.655; 95% CI=0.441-0.973; p=0.04). Maximum-likelihood analysis of haplotypes revealed a linkage disequilibrium (LD) between the two investigated polymorphisms of the MTHFR gene (C677T and A1298C), both in the control and patient groups (p<0.01 for both). LD was also detected between MTRR A66G and MTHFR A1298C polymorphisms but only in a group of patients (p<0.01). A haplotype of A66G and A1298C polymorphisms, A/A, proved to be protective (OR=0.775; 95% CI=0.603-0.996; p=0.04), whereas haplotype A/G was a risk factor for colon cancer (OR=1.270; 95% CI=1.007-1.602; p=0.04). Contrary to some previous studies, single-locus analyses identified no polymorphisms associated with risk for colon cancer, but demonstrated a possible protective effect of MTRR 66 AA genotype. The detected significant LD between two loci (MTHFR A1298C and MTRR A66G) located on different chromosomes indicates a strong selective force as a mechanism for the maintenance of their linkage. Specific combinations of alleles of these two polymorphisms showed a protective but also a risk effect on colon cancer susceptibility.

Obesity, insulin and chemoresistance in colon cancer.

Obesity, insulin and chemoresistance in colon cancer.

Effect of HFE Variants on Sphingolipid Expression by SH-SY5Y Human Neuroblastoma Cells

C282Y and H63D are two common variants of the hemochromatosis protein HFE. SH-SY5Y human neuroblastoma cells stably transfected to express either wild type HFE (WT-HFE), or the C282Y or H63D allele were analyzed for effect of expression of the mutant proteins on transcription of 14 enzymes involved in sphingolipid metabolism. Cells expressing the C282Y variant showed significant increases (>2-fold) in transcription of five genes and decreases in two compared to that seen for cells expressing WT-HFE, while cells expressing the H63D variant showed an elevation in transcription of one gene and a decrease in two. These changes were seen as alterations in ganglioside composition, cell surface binding by the binding subunit of cholera toxin, expression of sphingosine-kinase-1 and synthesis of sphingosine-1-phosphate. These changes may explain why C282Y-HFE is a risk factor for colon and breast cancer and possibly protective against Alzheimer's disease while H63D-HFE is a risk factor for neurodegenerative diseases.