Novel Mutations of the PARP-1 Gene Associated with Colorectal Cancer in the Saudi Population

Background: colorectal cancer (CRC) is the third most common type of cancers and the fourth leading causeof death worldwide. In Saudi Arabia, CRC accounts for 8.5% of all tumors; it ranks first among all cancersin males and third among females. The aim of this study was to link between different PARP-1 mutations andrisk of CRC in Saudi population and to determine common variants of PARP-1 in Saudi CRC patients andnormal individuals. Materials and Methods: DNA samples were isolated from fifty CRC patients and from acomparable number of control subjects then sequenced to detect different variations present in exons 3, 17, and21 of the PARP-1 gene. Results and Conclusions: When comparing the genotype and allele frequencies of alldetected SNPs in CRC patients with those in controls, we found none were significantly different for all variantseven the most common SNP in PARP-1 gene (Val762Ala). However, two novel alterations in exon 21 were foundto be associated with increased risk of CRC. The variants identified as (1) Lys933Asn [p-value 0.0318] and (2)Lys945Asn [p-value 0.0257]. Our results suggest that PARP-1 Lys933Asn and Lys945Asn alterations could beassociated with increased risk of CRC in the Saudi population.     

Mitogenic Properties of Insulin-Like Growth Factors I and II, Insulin-like Growth Factor Binding Protein-3 and Epidermal Growth Factor on Human Breast Stromal Cells in Primary Culture

Insulin-like growth factors I and II (IGF-I and IGF-II) are growth factors implicated in both normal mammary gland development and breast cancer. We have previously reported on the effects of components of the IGF system on breast epithelial cells. Since data suggests that stromal-epithelial interactions play a crucial role in breast cancer, we have now investigated the mitogenic properties of IGF-I, IGF-II, insulin-like growth factor binding protein-3 (IGFBP-3) and epidermal growth factor (EGF) on human breast stromal cells in primary culture. We show that, under serum-free conditions, stromal cells are stimulated to grow in response to IGF-I and IGF-II in a dose-dependent manner. IGF-I and EGF, a potent stimulator of human breast epithelial cell growth in primary culture and also associated with breast cancer, appear to stimulate stromal cell growth in a synergistic manner. IGFBP-3 does not inhibit the stimulation of growth by IGF-I, or IGF-I plus EGF. However, IGFBP-3 does inhibit the stimulation of growth by IGF-II. In contrast to our previous results with human breast epithelial cells, IGFBP-3 does not have an IGF-independent inhibitory effect on stromal cell growth. This study is the first to address the effects of IGF-I, IGF-II and IGFBP-3 alone and in combination with EGF on human breast stromal cell growth in primary culture. Characterizing the role of the IGF system in both normal breast epithelial cells and stromal cells will aid in our understanding of the mechanisms behind the role of the IGF system in breast cancer.     

Lack of Influence of the SMAD7 Gene rs2337107 Polymorphism on Risk of Colorectal Cancer in an Iranian Population

SMAD7 has been identified as a functional candidate gene for colorectal cancer (CRC). SMAD7 protein isa known antagonist of the transforming growth factor beta (TGF-b) signaling pathway which is involved intumorigenesis. Polymorphisms in SMAD7 may thus alter cancer risk. The aim of this study was to investigatethe influence of a SMAD7 gene polymorphism (rs2337107) on risk of CRC and clinicopathological featuresin an Iranian population. In total, 210 subjects including 105 patients with colorectal cancer and 105 healthycontrols were recruited in our study. All samples were genotyped by TaqMan assay via an ABI 7500 Real TimePCR System (Applied Biosystems) with DNA from peripheral blood. The polymorphism was statisticallyanalyzed to investigate the relationship with the risk of colorectal cancer and clinicopathological properties.Logistic regression analysis revealed that there was no significant association between rs2337107and the risk ofcolorectal cancer. In addition, no significant association between genotypes and clinicopathological features wasobserved (p value>0.05). Although there was not any association between genotypes and disorder, CT was themost common genotype in this population. This genotype prevalence was also higher in the patients with wellgrade (54.9%) and colon (72.0%) tumors. Our results provide the first evidence that this polymorphism is not apotential contributor to the risk of colorectal cancer and clinicopathological features in an Iranian population,and suggests the need of a large-scale case-control study to validate our results.     

The Insulin-Like Growth Factor Pathway in Lung Cancer

The insulin-like growth factor (IGF) pathway is involved in the normal control of fetal development, tissue growth, and metabolism. Two distinct ligands (insulin-like growth factor-1 [IGF-1] and IGF-2) plus insulin, and two receptors (insulin-like growth factor receptor-1 [IGF-1R] and the insulin receptor) capable of both homo- and heteropolymerization mediate the actions of this pathway. Cellular functions of IGF-regulated signaling are influenced by the expression of a variety of receptor docking proteins, including four different insulin receptor substrate proteins. Downstream signaling is primarily through the phosphatidylinositol-3 kinase-Akt pathway and the mitogen-activated protein kinase pathway, resulting in increased cell proliferation and apoptosis inhibition. Ligand-driven activation is influenced by upstream endocrine factors (particularly for IGF-1), imprinting (for IGF-2), by multiple circulating and tissue-based IGF-binding proteins/proteases, and by the expression of the IGF-2 clearance receptor (IGF-2R). Deregulation of IGF signaling has been described in several cancer types, including both small cell and non-small cell lung cancer. A number of IGF receptor inhibitors, including monoclonal antibodies and small molecule inhibitors are currently undergoing testing in clinical trials as both monotherapy, and in combination with chemotherapy, or with other targeted agents. Preliminary results from a randomized phase II trial of an anti-IGF-1R monoclonal antibody in combination with carboplatin/paclitaxel already suggest a potential efficacy benefit from targeting this pathway in the first line advanced non-small cell lung cancer setting.     

Genetic Variations in the HIF1A Gene Modulate Response to Adjuvant Chemotherapy after Surgery in Patients with Colorectal Cancer

Background: Hypoxia-inducible factor 1α (HIF-1α) plays an important role in regulating cell survivaland angiogenesis, which are critical for tumor growth and metastasis. Genetic variations of HIF1A have beenshown to influence the susceptibility to many kinds of human tumors. Increased expression of HIF-1α has alsobeen demonstrated to be involved in tumor progression. However, the prognostic value of single nucleotidepolymorphisms (SNPs) inthe HIF1A gene remains to be determined in most cancer types, including colorectalcancer (CRC). In this study, we sought to investigate the predictive role of HIF1A SNPs in prognosis of CRCpatients and efficacy of chemotherapy. Materials and Methods: We genotyped two functional SNPs in HIF1Agene using the Sequenom iPLEX genotyping system and then assessed their associations with clinicopathologicalparameters and clinical outcomes of 697 CRC patients receiving radical surgery using Cox logistic regressionmodel and Kaplan Meier curves. Results: Generally, no significant association was found between these 2 SNPsand clinical outcomes of CRC. In stratified analysis of subgroup without adjuvant chemotherapy, patientscarrying CT/TT genotypes of rs2057482 exhibited a borderline significant association with better overallsurvival when compared with those carrying CC genotype [Hazard ratio (HR), 0.47; 95% confidence interval(95% CI): 0.29-0.76; P < 0.01]. Moreover, significant protective effects on CRC outcomes conferred by adjuvantchemotherapy were exclusively observed in patients carrying CC genotype of rs2057482 and in those carryingAC/CC genotype of rs2301113. Conclusions: Genetic variations in HIF1A gene may modulate the efficacy ofadjuvant chemotherapy after surgery in CRC patients.     

Lack of any Prognostic Role of Insulin-Like Growth Factor-1 Receptor in Non-Small Cell Lung Cancer

Background: The purpose of this study is to determine whether the IGF1R expression has a prognostic role innon-small cell lung cancer. Materials and Methods: Forty-seven patients histopathologically diagnosed with smallcell lung cancer upon bronchoscopic biopsy or resection materials were included in the study. IGF1R expressionwas examined via immunohistochemical methods. In samples, >10% staining were assessed as positive and ≤10%as negative. Information about demographic datas and treatments was obtained by retrospective searches ofpatient files. Results: IGF1R expression was determined as positive in 38 (80.9%) and as negative in 9 (19.1%)patients. There was no significant relation between IGF1R expression and histological sub-type, local invasion,lymph node and metastasis status (p=0.842, p=0.437, 0.064, 0.447, respectively). There was also no correlationwith IGF1R expression and survival (p=0.141). Conclusions: There are conflicting results between IGF1R andits prognostic effects in the various studies. It has been claimed in some studies it is not related to prognosis asin our study, and in some studies it has been claimed that it is a good prognostic factor whereas in some studiesit has been claimed as being a factor for worse prognosis. We think that IGF1R expression in non-small cell lungcarcinoma patients deserves further analysis, because of its potential prognostic and predictive roles.     

Cytochrome P450 1A1, 2E1 and GSTM1 Gene Polymorphisms and Susceptibility to Colorectal Cancer in the Saudi Population

Background: The Saudi population has experienced a sharp increase in colorectal and gastric cancer incidenceswithin the last few years. The relationship between gene polymorphisms of xenobiotic metabolizing enzymesand colorectal cancer (CRC) incidence has not previously investigated among the Saudi population. The aimof the present study was to investigate contributions of CYP1A1, CYP2E1, and GSTM1 gene polymorphisms.Materials and Methods: Blood samples were collected from CRC patients and healthy controls and genotypeswere determined by polymerase chain reaction restriction fragment length polymorphism and sequencing.Results and Conclusions: CYP2E1*6 was not significantly associated with CRC development (odd ratio=1.29;confidence interval 0.68-2.45). A remarkable and statistically significant association was observed amongpatients with CYP1Awt/*2A (odd ratio=3.65; 95% confidence interval 1.39-9.57). The GSTM1*0/*0 genotypewas found in 2% of CRC patients under investigation. The levels of CYP1A1, CYP2E1 and GSTM1 mRNAgene expression were found to be 4, 4.2 and 4.8 fold, respectively, by quantitative real time PCR. The results ofthe present case-control study show that the studied Saudi population resembles Caucasians with respect to theconsidered polymorphisms. Investigation of genetic risk factors and susceptibility gene polymorphisms in ourSaudi population should be helpful for better understanding of CRC etiology.     

Circulating insulin-like growth factor axis and the risk of pancreatic cancer in four prospective cohorts

Insulin-like growth factor (IGF)-I induces growth in pancreatic cancer cells and blockade of the IGF-I receptor has antitumour activity. The association of plasma IGF-I and IGF binding protein-3 (IGFBP-3) with pancreatic cancer risk has been investigated in two small studies, with conflicting results. We conducted a nested case-control study within four large, prospective cohorts to investigate whether prediagnostic plasma levels of IGF-I, IGF-II, and IGFBP-3 were associated with pancreatic cancer risk. Plasma levels in 212 cases and 635 matched controls were compared by conditional logistic regression, with adjustment for other known pancreatic cancer risk factors. No association was observed between plasma levels of IGF-I, IGF-II, or IGFBP-3 and incident diagnosis of pancreatic cancer. Relative risks for the highest vs the lowest quartile of IGF-I, IGF-II, and IGFBP-3 were 0.94 (95% confidence interval (CI), 0.60-1.48), 0.96 (95% CI, 0.61-1.52), and 1.21 (95% CI, 0.75-1.92), respectively. The relative risk for the molar ratio of IGF-I and IGFBP-3, a surrogate measure for free IGF-I, was 0.84 (95% CI, 0.54-1.31). Additionally, no association was noted in stratified analyses or when requiring longer follow-up. In four prospective cohorts, we found no association between the risk of pancreatic cancer and prediagnostic plasma levels of IGF-I, IGF-II, or IGFBP-3.     

VEGF的SNP状态预测贝伐株单抗治疗转移性结直肠癌的长期疗效

目的 检测转移性结直肠癌患者外周血血管内皮生长因子(VEGF)单核苷酸多态性(SNP),探讨VEGF的SNP与患者预后的关系.方法 60例转移性结直肠癌患者的外周血样本,均接受过标准的化疗,其中20例加用了贝伐珠单抗,应用MassARRAY方法,成功进行9个VEGF的SNP的检测,包括-2578C＞A、-460T＞C、-1455T＞C、-1154G＞A、-634G＞C、-398G＞A、-497T＞C、-2455 ＞-T、-936C＞T.结果 60例转移性结直肠癌患者,联合靶向治疗组的总生存期优于单用化疗组(P=0.01),VEGF各SNP变异率与NDBI数据库相似,-1455T＞C变异率极低,无临床价值;-2578C＞A和-460C＞T变异具有较高一致性;入组患者中SNP-497TT纯合子患者总生存期劣于其他患者(P=0.02);应用贝伐株单抗患者,SNP-497 3种基因型总生存期均有明显差异(P=0.01),SNP-398AA纯合变异者总生存期优于其他患者(P=0.02)SNP-2455 CC纯合子者总生存期优于其他患者(P=0.01).结论 在转移性结直肠癌,外周血VEGF的SNP状态与贝伐珠单抗以及化疗的长期疗效可能相关,需要进一步增加病例,加强这方面的研究.     

Associations between Single Nucleotide Polymorphisms of COX-2 and MMP-2 Genes and Colorectal Cancer Susceptibility in the Saudi Population

Background: It has been reported that COX-2 expression is associated with MMP-2 expression in thyroid and breast cancers, suggesting that MMPs are linked to COX-2-mediated carcinogenesis. Several polymorphisms within the MMP2 promoter region have been reported in cases with oncogenesis and tumor progression, especially in colorectal carcinogenesis. Materials and Methods: This research evaluated risk of association of the SNPs, including genes for COX-2 (A/G transition at +202) and MMP-2 (C/T transition at-1306), with colorectal cancer in 125 patients and 125 healthy controls. Results and Conclusions: Our data confirmed that MMP2 C-1306 T mutations were significantly more common in colon cancer patients than in our control Saudi population; p=0.0121. On the other hand in our study, there was no significant association between genotype distribution of the COX2 polymorphism and colorectal cancer; p=0.847. An elevated frequency of the mutated genotype inthe control group as compared to the patients subjects indeed suggested that this polymorphism could decrease risk in the Saudi population. Our study confirmed that the polymorphisms that could affect the expressions of MMP-2 and COX-2 the colon cancer patients were significantly higher than that in the COX-2 negative group. The frequency of individuals with MMP2 polymorphisms in colon cancer patients was higher than individuals with combination of COX2 and MMP2 polymorphisms. Our study confirmed that individuals who carried the polymorphisms that could affect the expressions of COX2 are more susceptible to colon cancer. MMP2 regulatory polymorphisms could be considered as protective; further studies need to confirm the results with more samples and healthy subjects.     

Vascular Endothelial Growth Factor (VEGF) Gene Polymorphisms and Breast Cancer Risk in a Chinese Population

Vascular endothelial growth factor (VEGF) is a potent regulator of angiogenesis and thereby involved in thedevelopment and progression of solid tumours. Associations between three VEGF gene polymorphisms (-634G/C, +936 C/T, and +1612 G/A) and breast cancer risk have been extensively studied, but the currently availableresults are inconclusive. Our aim was to investigate associations between three VEGF gene polymorphisms andbreast cancer risk in Chinese Han patients. We performed a hospital-based case-control study including 680female incident breast cancer patients and 680 female age-matched healthy control subjects. Polymerase chainreaction restriction fragment length polymorphism (PCR-RFLP) analysis was performed to detect the threeVEGF gene polymorphisms. We observed that women carriers of +936 TT genotypes [odds ratio (OR) =0.46,95% confidence interval (CI) = 0.28, 0.76; P=0.002] or 936 T-allele (OR=0.81, 95% CI= 0.68, 0.98; P=0.03) hada protective effect concerning the disease. Our study suggested that the +1612G/A polymorphism was unlikelyto be associated with breast cancer risk. The -634CC genotype was significantly associated with high tumoraggressiveness [large tumor size (OR=2.63, 95% CI=1.15, 6.02; P=0.02) and high histologic grade (OR=1.47,95% CI= 1.06, 2.03; P=0.02)]. The genotypes were not related with other tumor characteristics such as regionalor distant metastasis, stage at diagnosis, or estrogen or progesterone receptor status. Our study revealed thatthe VEGF -634 G/C and +936 C/T gene polymorphisms may be associated with breast cancer in Chinese Hanpatients.     

Promoter -202 A/C polymorphism of insulin-like growth factor binding protein-3 gene and non-small cell lung cancer risk

Insulin-like growth factor binding protein-3 (IGFBP-3) inhibits the mitogenic and antiapoptotic activity of insulin-like growth factor (IGF) by blocking the binding of IGF to its receptor. However, under certain circumstances, IGFBP-3 can enhance the activity of IGF by protecting IGF from degradation. More than half of the interindividual variations in IGFBP-3 levels are known to be genetically determined by the polymorphism at -202 locus of IGFBP-3 gene. Therefore, we attempted to ascertain whether the A-202C polymorphic variation of IGFBP-3 gene constitutes a risk factor for non-small cell lung cancer (NSCLC). Our study included 209 NSCLC patients and 209 age-, gender- and smoking status-matched control subjects. The frequencies of each polymorphic variation in the control population were as follows: AA = 95 (45.5%), AC = 91 (43.5%) and CC = 23 (11.0%). In the NSCLC subjects, the genotypic frequencies were as follows: AA = 131 (62.7%), AC = 73 (34.9%) and CC = 5 (2.4%). We detected statistically significant differences in the genotypic distribution between the NSCLC and the control subjects (p < 0.05, Pearson's chi-square test). The NSCLC risk correlated significantly with AA genotype. Using CC genotype as a reference, the odds ratio for the subjects with AC genotype was 2.45 (95% CI = 1.17-5.40) and that for the ones with AA genotype was 4.58 (95% CI = 2.17-10.30). These results indicate that the dysregulation of IGF axis should now be considered as another important risk factor for NSCLC and a potential target for novel antineoplastic therapies and/or preventative strategies in high-risk groups.     

Intronic Polymorphisms of the SMAD7 Gene in Association with Colorectal Cancer

Based on genome-wide association studies (GWAS) a linkage between several variants such as single nucleotidepolymorphisms (SNPs) in intron 3 of SMAD7 (mothers against decapentaplegic homolog7) were, rs12953717,rs4464148 and rs4939827 has been noted for susceptibility to colorectal cancer (CRC). In this study we investigatedthe relationship of rs12953717 and rs4464148 with risk of CRC among 487 Iranian individuals based on a casecontrolstudy. Genotyping of SNPs was performed by PCR-RFLP and for confirming the outcomes, 10% ofgenotyping cases were sequenced with RFLP. Comparing the case and control group, we have found significantassociation between the rs4464148 SNP and lower risk of CRC. The AG genotype showed decreased risk withand odds ratio of 0.635 (adjusted OR=0.635, 95% CI: 0.417-0.967, p=0.034). There was no significant differencein the distribution of SMAD7 gene rs12953717 TT genotype between two groups of the population evaluated(adjusted OR=1.604, 95% CI: 0.978-2.633, p=0.061). On the other hand, rs12953717 T allele showed a statisticallysignificant association with CRC risk (adjusted OR=1.339, 95% CI: 1.017-1.764, p=0.037). In conclusion, wefound a significant association between CRC risk and the rs4464148 AG genotype. Furthermore, the rs12953717T allele may act as a risk factor. This association may be caused by alternative splicing of pre mRNA. Althoughwe observed a strong association with rs4464148 GG genotype in affected women, we did not detect the sameassociation in CRC male patients.     

Case-Control Study on the Fibroblast Growth Factor Receptor 2 Gene Polymorphisms Associated with Breast Cancer in Chinese Han Women

Purpose

Genetic variation in fibroblast growth factor receptor 2 (FGFR2) is a newly described risk factor for breast cancer. This study aimed to evaluate the association of four single nucleotide polymorphisms (SNPs) in FGFR2 with breast cancer in Han Chinese women.

Methods

Two hundred three women with breast cancer and 200 breast cancer-free age-matched controls were selected. Four SNPs (rs2981579, rs1219648, rs2420946, and rs2981582) and their haplotypes were analyzed to test for their association with breast cancer susceptibility. The presence of the four FGFR2 SNPs was determined by polymerase chain reaction-restriction fragment length polymorphism analysis.

Results

A statistically significant difference was observed in the frequency of rs2981582 in the FGFR2 gene (p<0.05) between case and control groups. In subjects stratified by menopausal status, rs2981582 TT, rs2420946 AA, and rs1219648 CC were significantly associated with the risk of breast cancer in postmenopausal subjects, but no significant associations between these four SNPs and the risk of breast cancer were identified in premenopausal subjects. Further, there was no significant association between hormone receptor status (estrogen receptor and progesterone receptor) and breast cancer risk. Six common (> 3%) haplotypes were identified. Three of these haplotypes, CGTC (odds ratio [OR], 0.613; 95% confidence interval [CI], 0.457-0.82; p=0.001), TGTC (OR, 6.561; 95% CI, 2.064-20.854; p<0.001), and CATC (OR, 12.645; 95% CI, 1.742-91.799; p=0.001) were significantly associated with breast cancer risk.

Conclusion

Our findings indicated that the SNP rs2981582 and haplotypes CGTC, TGTC, and CATC in FGFR2 may be associated with an increased risk of breast cancer in Han Chinese women.     

Insulin-Like Growth Factors and Their Binding Proteins in Tumors and Ascites of Ovarian Cancer Patients: Association With Response To Neoadjuvant Chemotherapy

Purpose: Tumor cell growth and sensitivity to chemotherapy depend on many factors, among which insulin-like growth factors (IGFs) may play important roles. The aim of the present study was to evaluate the levels of insulin-like growth factors (IGFs) and IGF binding proteins (IGFBPs) in primary tumors and ascites as predictors of response to neoadjuvant chemotherapy in ovarian cancer (OC) patients. Materials and Methods: Tumor tissue samples and ascitic fluid were obtained from 59 patients with advanced OC. The levels of IGF-I, IGF-II, IGFBP-3, IGFBP-4 and PAPP-A were determined using ELISA kits. Taking into account the data on expression of these IGF-related proteins and outcome, logistic regression was performed to identify predictors of response to neoajuvant chemotherapy. Results: Human ovarian tumors expressed IGFs, IGFBP-3, IGFBP-4 and PAPP-A and these proteins were also present in ascites fluid and associated with its volume. IGFs and IGFBPs in ascites and soluble PAPP-A might play a key role in ovarian cancer progression . However, levels of proteins of the IGF system in tumors were not significant predictors of objective clinical response (oCR). Univariate analysis showed that the level of IGF-I in ascites was the only independent predictor for oCR. Conclusion: The level of IGF-I in ascites was shown to be an independent predictor of objective clinical response to chemotherapy for OC patients treated with neoadjuvant chemotherapy and debulking surgery.     

Loss of Imprinting of Insulin-Like Growth Factor 2 is Associated with Increased Risk of Primary Lung Cancer in the Central China Region

Background: To determine the imprinting status of the IGF2 in Chinese patients with primary lung cancerand to analyze the clinical significance of the loss of imprinting (LOI) of IGF2. Materials and Methods: PCRRFLPand RT-PCR-RFLP were carried out to select heterozygous cases for the ApaI polymorphism within exon9 of the IGF2 gene and further analyze IGF2 LOI in 64 lung cancer patients, respectively. Results: Of 64 lungcancer patients, 31 were heterozygous for IGF2. The positive rates of IGF2 LOI of lung cancer foci, matchedparacancer tissues, and normal lung tissues were 77.4% (24/31), 61.3% (19/31), and 29.0% (9/31), respectively.The LOI differences for IGF2 among the three groups were statistically significant (χ2=15.267, p=0.000), andthe LOI frequency of IGF2 in normal lung tissue was significantly lower than that in lung cancer foci andparacancer tissues (χ2=14.577, p=0.000; χ2=6.513, p=0.011). No statistical difference was observed between thelung tumor group and the matched paracancer group (χ2=1.897, p=0.168). The prevalence of advanced clinicalstages (χ2=2.379; p=0.017) and lymph node metastasis (χ2=5.552; p=0.018) was significantly higher for LOIpositiveparacancer tissues than for LOI-negative paracancer tissues. Conclusions: IGF2 LOI is highly frequentin Chinese primary lung cancer patients, especially those with increased risk of lymph node metastasis andadvanced clinical stages. IGF2 LOI may be an early epigenetic event in human lung carcinogenesis.     

Inhibition of Colorectal Cancer Cell Proliferation by Regulating Platelet-Derived Growth Factor B Signaling with a DNA Aptamer

Background: Overexpression of platelet-derived growth factor-BB (PDGF-BB) is associated with colorectalcarcinogenesis. PDGF-BB plays a role in the autocrine growth stimulation of cancer cells. Aptamers are shortsingle-stranded oligonucleotides that can bind to cellular targets with high affinity and specificity and offer the advantageof non-immunogenicity, non-toxicity and high stability. Thus, they receive interest as potential therapeutic agents.Methods: The endogenous level of PDGF-BB in Caco-2 and SW480, colorectal cancer (CRC) cells, was evaluatedusing ELISA. The effect of the PDGF-BB aptamer on cell proliferation was investigated in two CRC cell lines andCCD841 CoN, normal colon cells. The effective molar ratio between PDGF-BB and PDGF-BB aptamer was furtherexplored. Cell viability in all experiments was analyzed using MTS assay. Western blotting was performed to examinethe alteration of relevant signaling pathways. Results: Caco-2 and SW480 cells endogenously synthesized and secretedPDGF-BB to stimulate their growth. Cells treated with the PDGF-BB aptamer proliferated at a slower rate, but CCD841CoN did not. Pre-incubation of PDGF-BB with the corresponding aptamer at the molar ratio 1:1 could significantlysilence its proliferative effect on CRC cells. Western blot analysis revealed that the phosphorylation level of ERK1/2, akey component in PDGF downstream signaling pathway, was down-regulated by the aptamer, indicating the underlyingmechanism of inhibition of CRC cell proliferation. Conclusions: This study demonstrated that using a DNA aptamerto interfere with the binding of PDGF-BB to its receptor suppressed CRC cell proliferation in part via down-regulationof the Ras/Raf/MEK/ERK signaling pathway. It raised the possibility that the PDGF-BB-specific aptamer could be apromising therapeutic agent for CRC targeted therapy.     

胰岛素样生长因子-1受体在乳腺癌组织和正常乳腺组织中的表达

目的　探讨胰岛素样生长因子 1受体 (IGF 1R)在乳腺癌组织和正常乳腺组织中的分布和表达。方法　采用免疫组织化学方法 ,对乳腺癌组织和正常的乳腺组织中IGF 1R的表达情况进行检测分析。结果　乳腺癌组织中IGF 1R的阳性表达率均明显较正常乳腺组织高 (P <0 .0 5 )。结论　由此推断 ,IGF 1R在乳腺癌发生发展过程中发挥着重要作用。IGF 1R有可能成为临床乳腺癌诊断和判断预后的一个重要指标。     

Matrix Metalloproteinase-2 (-1306 C>T) Promoter Polymorphism and Risk of Colorectal Cancer in the Saudi Population

Background: Matrix metalloproteinase-2 (MMP-2) is an enzyme with proteolytic activity against matrixproteins, particularly basement membrane constituents. A single nucleotide polymorphism (SNP) at -1306,which disrupts a Sp1-type promoter site (CCACC box), results in strikingly lower promoter activity with theT allele. In the present study, we investigated whether this MMP-2 genetic polymorphism might be associatedwith susceptibility to colorectal cancer (CRC) in the Saudi population. We also analyzed MMP-2 gene expressionlevel sin CRC patients and 4 different cancer cell lines. Materials and Methods: TaqMan allele discriminationassays and DNA sequencing techniques were used to investigate the C-1306T SNP in the MMP-2 gene of Saudicolorectal cancer patients and controls. The MMP-2 gene expression level was also determined in 12 coloncancer tissue samples collected from unrelated patients and histologically normal tissues distant from tumormargins. Results and Conclusions: The MMP-2 C-1306T SNP in the promoter region was associated with CRC inour Saudi population and the MMP-2 gene expression level was found to be 10 times higher in CRC patients.The MMP-2 C-1306T SNP is significantly associated with CRC in the Saudi population and this finding suggestedthat MMP-2 variants might help predict CRC progression risk among Saudis. We propose that analysis of thisgene polymorphism could assist in identification of patient subgroups at risk of a poor disease outcome.     

Polymorphisms in the Thymidylate Synthase Gene and Risk of Colorectal Cancer

To evaluate the relationship between polymorphisms (28 bp repeated sequences in 5’-UTR and 6-bp ins/del in 3’-UTR) in then thymidylate synthetase gene (TS) and risk of colorectal, colon and rectal cancers, weconducted a case-control study with 315 cases of colorectal cancer and 439 population-based controls in Jiangsuprovince, China. TS genotypes were identified using PCR–RFLP (restriction fragment length polymorphism)methods. Odds ratios (ORs) were estimated with an unconditional logistic regression model. We found that thedistributions of 5’-UTR genotypes in TS were significantly different between controls and male colon cases (χ2=8.25, P = 0.016). Compared with 3R/3R genotype, individuals with the 2R allele were at an increased risk ofcolon cancer (age-, BMI-, smoking- and alcohol drinking-adjusted OR=1.98, 95%CI: 1.11-3.53) among men. Inccontrast, the 6-bp ins/del polymorphism at the TS 3’- UTR did not influence risk of the colorectal, colon andrectal cancers. When combined genotypes for both TS 5’-UTR and 3’-UTR polymorphisms were evaluated,individuals with the 5’-UTR 2R allele had a OR of 3.61 (95%CI: 1.38-9.49) for colon cancer among men withthe 3’-UTR –6bp/-6bp genotype. These results show that the polymorphism of the 28 bp repeated sequences inTS 5’-UTR could influence susceptibility to colon cancer and that there was a coordinated effect between TS3’-UTR and 5’-UTR polymorphisms in increasing risk of colon cancer among Chinese men.