Investigating the association between polymorphisms in connective tissue growth factor and susceptibility to colon carcinoma

Ahmad,Abrar; Askari,Shlear; Befekadu,Rahel; Hahn-Strömberg,Victoria

doi:10.3892/mmr.2014.3083

Investigating the association between polymorphisms in connective tissue growth factor and susceptibility to colon carcinoma

Authors:
- Abrar Ahmad
- Shlear Askari
- Rahel Befekadu
- Victoria Hahn-Strömberg
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Affiliations: Department of Clinical Medicine, Örebro University, Örebro 701 81, Sweden, Department of Laboratory Medicine, Section for Transfusion Medicine, Örebro University Hospital, Örebro 701 85, Sweden
Published online on: December 11, 2014 https://doi.org/10.3892/mmr.2014.3083
Pages: 2493-2503
Copyright: © Ahmad et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

There have been numerous studies on the gene expression of connective tissue growth factor (CTGF) in colorectal cancer, however very few have investigated polymorphisms in this gene. The present study aimed to determine whether single nucleotide polymorphisms (SNPs) in the CTGF gene are associated with a higher susceptibility to colon cancer and/or an invasive tumor growth pattern. The CTGF gene was genotyped for seven SNPs (rs6918698, rs1931002, rs9493150, rs12526196, rs12527705, rs9399005 and rs12527379) by pyrosequencing. Formalin‑fixed paraffin‑embedded tissue samples (n=112) from patients diagnosed with colon carcinoma, and an equal number of blood samples from healthy controls, were selected for genomic DNA extraction. The complexity index was measured using images of tumor samples (n=64) stained for cytokeratin‑8. The images were analyzed and correlated with the identified CTGF SNPs and clinicopathological parameters of the patients, including age, gender, tumor penetration, lymph node metastasis, systemic metastasis, differentiation and localization of tumor. It was demonstrated that the frequency of the SNP rs6918698 GG genotype was significantly associated (P=0.05) with an increased risk of colon cancer, as compared with the GC and CC genotypes. The other six SNPs (rs1931002, rs9493150, rs12526196, rs12527705, rs9399005 and rs12527379) exhibited no significant difference in the genotype and allele frequencies between patients diagnosed with colon carcinoma and the normal healthy population. A trend was observed between genotype variation at rs6918698 and the complexity index (P=0.052). The complexity index and genotypes for any of the studied SNPs were not significantly correlated with clinical or pathological parameters of the patients. These results indicate that the rs6918698 GG genotype is associated with an increased risk of developing colon carcinoma, and genetic variations at the rs6918698 are associated with the growth pattern of the tumor. The present results may facilitate the identification of potential biomarkers of the disease in addition to drug targets.

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1	Brigstock DR: The connective tissue growth factor/cysteine-rich 61/nephroblastoma overexpressed. Endocr Rev. 20:189–206. 1999.PubMed/NCBI
2	Dhar A and Ray A: The CCN family proteins in carcinogenesis. Exp Oncol. 32:2–9. 2010.PubMed/NCBI
3	Shimo T, Nakanishi T, Nishida T, et al: Connective tissue growth factor induces the proliferation, migration, and tube formation of vascular endothelial cells in vitro, and angiogenesis in vivo. J Biochem. 126:137–145. 1999. View Article : Google Scholar : PubMed/NCBI
4	Jacobson A and Cunningham JL: Connective tissue growth factor in tumor pathogenesis. Fibrogenesis Tissue Repair. 5(Suppl 1): S82012. View Article : Google Scholar : PubMed/NCBI
5	Chen YQ, Sloan-Lancaster J, Berg DT, et al: Differential mechanisms of plasminogen activator inhibitor-1 gene activation by transforming growth factor-beta and tumor necrosis factor-alpha in endothelial cells. Thromb Haemost. 86:1563–1572. 2001.
6	Robinson PM, Smith TS, Patel D, et al: Proteolytic processing of connective tissue growth factor in normal ocular tissues and during corneal wound healing. Invest Ophthalmol Vis Sci. 53:8093–8103. 2012. View Article : Google Scholar : PubMed/NCBI
7	Brigstock DR: Regulation of angiogenesis and endothelial cell function by connective tissue growth factor (CTGF) and cysteine-rich 61 (CYR61). Angiogenesis. 5:153–165. 2002. View Article : Google Scholar
8	Moussad EE and Brigstock DR: Connective tissue growth factor: what’s in a name? Mol Genet Metab. 71:276–292. 2000. View Article : Google Scholar : PubMed/NCBI
9	Granel B, Argiro L, Hachulla E, et al: Association between a CTGF gene polymorphism and systemic sclerosis in a French population. J Rheumatol. 37:351–358. 2010. View Article : Google Scholar
10	Wang X, Wan F, Pan J, et al: Tumor size: a non-neglectable independent prognostic factor for gastric cancer. J Surg Oncol. 97:236–240. 2008. View Article : Google Scholar
11	Wang B, Carter RE, Jaffa MA, et al; DCCT/EDIC Study Group. Genetic variant in the promoter of connective tissue growth factor gene confers susceptibility to nephropathy in type 1 diabetes. J Med Genet. 47:391–397. 2010. View Article : Google Scholar : PubMed/NCBI
12	Dessein A, Chevillard C, Arnaud V, et al: Variants of CTGF are associated with hepatic fibrosis in Chinese, Sudanese, and Brazilians infected with schistosomes. J Exp Med. 206:2321–2328. 2009. View Article : Google Scholar : PubMed/NCBI
13	Koliopanos A, Friess H, di Mola FF, et al: Connective tissue growth factor gene expression alters tumor progression in esophageal cancer. World J Surg. 26:420–427. 2002. View Article : Google Scholar : PubMed/NCBI
14	Zhou ZQ, Cao WH, Xie JJ, et al: Expression and prognostic significance of THBS1, Cyr61 and CTGF in esophageal squamous cell carcinoma. BMC Cancer. 9:2912009. View Article : Google Scholar : PubMed/NCBI
15	Liu L, Li Z, Feng G, You W and Li J: Expression of connective tissue growth factor is in agreement with the expression of VEGF, VEGF-C, -D and associated with shorter survival in gastric cancer. Pathol Int. 57:712–718. 2007. View Article : Google Scholar : PubMed/NCBI
16	Chen PP, Li WJ, Wang Y, et al: Expression of Cyr61, CTGF, and WISP-1 correlates with clinical features of lung cancer. PLoS One. 2:e5342007. View Article : Google Scholar : PubMed/NCBI
17	Chien W, O’Kelly J, Lu D, et al: Expression of connective tissue growth factor (CTGF/CCN2) in breast cancer cells is associated with increased migration and angiogenesis. Int J Oncol. 38:1741–1747. 2011.PubMed/NCBI
18	Zhen Y, Ye Y, Yu X, et al: Reduced CTGF expression promotes cell growth, migration, and invasion in nasopharyngeal carcinoma. PLoS One. 8:e649762013. View Article : Google Scholar : PubMed/NCBI
19	Ladwa R, Pringle H, Kumar R and West K: Expression of CTGF and Cyr61 in colorectal cancer. J Clin Pathol. 64:58–64. 2011. View Article : Google Scholar
20	Lin BR, Chang CC, Chen RJ, et al: Connective tissue growth factor acts as a therapeutic agent and predictor for peritoneal carcinomatosis of colorectal cancer. Clin Cancer Res. 17:3077–3088. 2011. View Article : Google Scholar : PubMed/NCBI
21	Bidwell J, Keen L, Gallagher G, et al: Cytokine gene polymorphism in human disease: on-line databases. Genes Immun. 1:3–19. 1999. View Article : Google Scholar
22	Pivovarova O, Fisher E, Dudziak K, et al: A polymorphism within the connective tissue growth factor (CTGF) gene has no effect on non-invasive markers of beta-cell area and risk of type 2 diabetes. Dis Markers. 31:241–246. 2011. View Article : Google Scholar : PubMed/NCBI
23	Poli F, Boschiero L, Giannoni F, et al: Tumour necrosis factor-alpha gene polymorphism: implications in kidney transplantation. Cytokine. 12:1778–1783. 2000. View Article : Google Scholar : PubMed/NCBI
24	Awad MR, El-Gamel A, Hasleton P, et al: Genotypic variation in the transforming growth factor-beta1 gene: association with transforming growth factor-beta1 production, fibrotic lung disease, and graft fibrosis after lung transplantation. Transplantation. 66:1014–1020. 1998. View Article : Google Scholar : PubMed/NCBI
25	Bylund JR, Gayheart D, Fleming T, et al: Association of tumor size, location, R.E.N.A.L., PADUA and centrality index score with perioperative outcomes and postoperative renal function. J Urol. 188:1684–1689. 2012. View Article : Google Scholar : PubMed/NCBI
26	Compton CC: Colorectal carcinoma: diagnostic, prognostic, and molecular features. Mod Pathol. 16:376–388. 2003. View Article : Google Scholar : PubMed/NCBI
27	Jung CK, Kang YG, Bae JS, et al: Unique patterns of tumor growth related with the risk of lymph node metastasis in papillary thyroid carcinoma. Mod Pathol. 23:1201–1208. 2010. View Article : Google Scholar : PubMed/NCBI
28	Jass JR: The pathological classification of colorectal cancer. Ann Acad Med Singapore. 16:469–473. 1987.PubMed/NCBI
29	Jass JR, Atkin WS, Cuzick J, et al: The grading of rectal cancer: historical perspectives and a multivariate analysis of 447 cases. Histopathology. 41:59–81. 2002.PubMed/NCBI
30	Franzén LE, Hahn-Strömberg V, Edvardsson H and Bodin L: Characterization of colon carcinoma growth pattern by computerized morphometry: definition of a complexity index. Int J Mol Med. 22:465–472. 2008.PubMed/NCBI
31	Ohene-Abuakwa Y and Pignatelli M: Adhesion molecules as diagnostic tools in tumor pathology. Int J Surg Pathol. 8:191–200. 2000. View Article : Google Scholar
32	Lee HK, Bier A, Cazacu S, et al: MicroRNA-145 is downregulated in glial tumors and regulates glioma cell migration by targeting connective tissue growth factor. PLoS One. 8:e546522013. View Article : Google Scholar : PubMed/NCBI
33	Mannan A and Hahn-Strömberg V: K-ras mutations are correlated to lymph node metastasis and tumor stage, but not to the growth pattern of colon carcinoma. APMIS. 120:459–468. 2012. View Article : Google Scholar : PubMed/NCBI
34	Hahn-Strömberg V, Edvardsson H, Bodin L and Franzén L: Tumor volume of colon carcinoma is related to the invasive pattern but not to the expression of cell adhesion proteins. APMIS. 117:205–211. 2009. View Article : Google Scholar : PubMed/NCBI
35	Gao YB, Xiang ZL, Zhou LY, et al: Enhanced production of CTGF and IL-11 from highly metastatic hepatoma cells under hypoxic conditions: an implication of hepatocellular carcinoma metastasis to bone. J Cancer Res Clin Oncol. 139:669–679. 2013. View Article : Google Scholar : PubMed/NCBI
36	Xie H, Zhao Y, Caramuta S, Larsson C and Lui WO: miR-205 expression promotes cell proliferation and migration of human cervical cancer cells. PLoS One. 7:e469902012. View Article : Google Scholar : PubMed/NCBI
37	Heinzle C, Gsur A, Hunjadi M, et al: Differential effects of polymorphic alleles of FGF receptor 4 on colon cancer growth and metastasis. Cancer Res. 72:5767–5777. 2012. View Article : Google Scholar : PubMed/NCBI
38	Zhong R, Liu L, Zou L, et al: Genetic variations in the TGFβ signaling pathway, smoking and risk of colorectal cancer in a Chinese population. Carcinogenesis. 34:936–942. 2013. View Article : Google Scholar : PubMed/NCBI
39	Jang MJ, Jeon YJ, Kim JW, et al: Association of VEGF and KDR single nucleotide polymorphisms with colorectal cancer susceptibility in Koreans. Mol Carcinog. 52(Suppl 1): E60–69. 2013. View Article : Google Scholar
40	Hahn-Strömberg V, Edvardsson H, Bodin L and Franzén L: Disturbed expression of E-cadherin, beta-catenin and tight junction proteins in colon carcinoma is unrelated to growth pattern and genetic polymorphisms. APMIS. 116:253–262. 2008. View Article : Google Scholar : PubMed/NCBI
41	Fonseca C, Lindahl GE, Ponticos M, et al: A polymorphism in the CTGF promoter region associated with systemic sclerosis. N Engl J Med. 357:1210–1220. 2007. View Article : Google Scholar : PubMed/NCBI
42	Greenawalt DM, Sieberts SK, Cornelis MC, et al: Integrating genetic association, genetics of gene expression, and single nucleotide polymorphism set analysis to identify susceptibility Loci for type 2 diabetes mellitus. Am J Epidemiol. 176:423–430. 2012. View Article : Google Scholar : PubMed/NCBI
43	Katakami N, Kume S, Kaneto H, et al: Association of myeloperoxidase G-463A gene polymorphism with diabetic nephropathy. Endocr J. 60:457–471. 2012.
44	Guo H, Bao Z, Li J, et al: Molecular characterization of TGF-β type I receptor gene (Tgfbr1) in Chlamys farreri, and the association of allelic variants with growth traits. PLoS One. 7:e510052012. View Article : Google Scholar
45	Kovalenko E, Tacke F, Gressner OA, et al: Validation of connective tissue growth factor (CTGF/CCN2) and its gene polymorphisms as noninvasive biomarkers for the assessment of liver fibrosis. J Viral Hepat. 16:612–620. 2009. View Article : Google Scholar : PubMed/NCBI
46	Davies SR, Davies ML, Sanders A, et al: Differential expression of the CCN family member WISP-1, WISP-2 and WISP-3 in human colorectal cancer and the prognostic implications. Int J Oncol. 36:1129–1136. 2010.PubMed/NCBI
47	Lin BR, Chang CC, Che TF, et al: Connective tissue growth factor inhibits metastasis and acts as an independent prognostic marker in colorectal cancer. Gastroenterology. 128:9–23. 2005. View Article : Google Scholar : PubMed/NCBI
48	Chang CC, Lin MT, Lin BR, et al: Effect of connective tissue growth factor on hypoxia-inducible factor 1alpha degradation and tumor angiogenesis. J Natl Cancer Inst. 98:984–995. 2006. View Article : Google Scholar : PubMed/NCBI
49	Deng YZ, Chen PP, Wang Y, et al: Connective tissue growth factor is overexpressed in esophageal squamous cell carcinoma and promotes tumorigenicity through beta-catenin-T-cell factor/Lef signaling. J Biol Chem. 282:36571–36581. 2007. View Article : Google Scholar : PubMed/NCBI
50	Victoria HS, Henrik E, Lennart B and Lennart F: Claudin 1 and claudin 7 gene polymorphisms and protein derangement are unrelated to the growth pattern and tumor volume of colon carcinoma. Int J Biomed Sci. 6:96–102. 2010.PubMed/NCBI
51	Margadant C and Sonnenberg A: Integrin-TGF-beta crosstalk in fibrosis, cancer and wound healing. EMBO Rep. 11:97–105. 2010. View Article : Google Scholar : PubMed/NCBI
52	Radisky DC, Kenny PA and Bissell MJ: Fibrosis and cancer: do myofibroblasts come also from epithelial cells via EMT? J Cell Biochem. 101:830–839. 2007. View Article : Google Scholar : PubMed/NCBI