Effect Of Ape1 T2197g (asp148glu) Polymorphism On Ape1, Xrcc1, Parp1 And Ogg1 Expression In Patients With Colorectal Cancer

It has been hypothesized that genetic variation in base excision repair (BER) might modify colorectal adenoma risk. Thus, we evaluated the influence of APE1 T2197G (Asp148Glu) polymorphism on APE1, XRCC1, PARP1 and OGG1 expression in normal and tumor samples from patients with colorectal cancer. The results indicate a downregulation of OGG1 and an upregulation of XRCC1 expression in tumor tissue. Regarding the anatomical location of APE1, OGG1 and PARP-1, a decrease in gene expression was observed among patients with cancer in the rectum. In patients with or without some degree of tumor invasion, a significant downregulation in OGG1 was observed in tumor tissue. Interestingly, when taking into account the tumor stage, patients with more advanced grades (III and IV) showed a significant repression for APE1, OGG1 and PARP-1. XRCC1 expression levels were significantly enhanced in tumor samples and were correlated with all clinical and histopathological data. Concerning the polymorphism T2197G, GG genotype carriers exhibited a significantly reduced expression of genes of the BER repair system (APE1, XRCC1 and PARP1). In summary, our data show that patients with colorectal cancer present expression changes in several BER genes, suggesting a role for APE1, XRCC1, PARP1 and OGG1 and APE1 polymorphism in colorectal carcinogenesis.15101733317343Jemal, A., Bray, F., Center, M.M., Ferlay, J., Ward, E., Forman, D., Global cancer statistics (2011) CA Cancer J. Clin, 61, pp. 69-90Cummings, O.W., Pathology of the adenoma-carcinoma sequence: From aberrant crypt focus to invasive carcinoma (2000) Semin. Gastrointest. Dis, 11, pp. 229-237Fearon, E.R., Vogelstein, B., A genetic model for colorectal tumorigenesis (1990) Cell, 61, pp. 759-767Shin, A., Lee, K.M., Ahn, B., Park, C.G., Noh, S.K., Park, D.Y., Ahn, S.H., Kang, D., Genotype-phenotype relationship between DNA repair gene genetic polymorphisms and DNA repair capacity (2008) Asian Pac. J. Cancer Prev, 9, pp. 501-505Peterson, C.L., Cote, J., Cellular machineries for chromosomal DNA repair (2004) Genes Dev, 18, pp. 602-616Jagannathan, I., Cole, H.A., Hayes, J.J., Base excision repair in nucleosome substrates (2006) Chromosome Res, 14, pp. 27-37Potter, J.D., Colorectal cancer: Molecules and populations (1999) J. Natl. Cancer Inst, 91, pp. 916-932Slyskova, J., Korenkova, V., Collins, A.R., Prochazka, P., Vodickova, L., Svec, J., Lipska, L., Liska, V., Functional, genetic, and epigenetic aspects of base and nucleotide excision repair in colorectal carcinomas (2012) Clin. Cancer Res, 18, pp. 5878-5887Schreiber, V., Dantzer, F., Ame, J.C., de Murcia, G., Poly(ADP-ribose): Novel functions for an old molecule (2006) Nat. Rev. Mol. Cell Biol, 7, pp. 517-528Grube, K., Burkle, A., Poly(ADP-ribose) polymerase activity in mononuclear leukocytes of 13 mammalian species correlates with species-specific life span (1992) Proc. Natl. Acad. Sci. USA, 89, pp. 11759-11763Nosho, K., Yamamoto, H., Mikami, M., Taniguchi, H., Takahashi, T., Adachi, Y., Imamura, A., Shinomura, Y., Overexpression of poly(ADP-ribose) polymerase-1 (PARP-1) in the early stage of colorectal carcinogenesis (2006) Eur. J. Cancer, 42, pp. 2374-2381Solier, S., Zhang, Y.W., Ballestrero, A., Pommier, Y., Zoppoli, G., DNA damage response pathways and cell cycle checkpoints in colorectal cancer: Current concepts and future perspectives for targeted treatment (2012) Curr. Cancer Drug Targets, 12, pp. 356-371Whitehouse, C.J., Taylor, R.M., Thistlethwaite, A., Zhang, H., Karimi-Busheri, F., Lasko, D.D., Weinfeld, M., Caldecott, K.W., XRCC1 stimulates human polynucleotide kinase activity at damaged DNA termini and accelerates DNA single-strand break repair (2001) Cell, 104, pp. 107-117Yu, J., Mallon, M.A., Zhang, W., Freimuth, R.R., Marsh, S., Watson, M.A., Goodfellow, P.J., McLeod, H.L., DNA repair pathway profiling and microsatellite instability in colorectal cancer (2006) Clin. Cancer Res, 12, pp. 5104-5111Cheng, K.C., Cahill, D.S., Kasai, H., Nishimura, S., Loeb, L.A., 8-hydroxyguanine, an abundant form of oxidative DNA damage, causes G-T and A-C substitutions (1992) J. Biol. Chem, 267, pp. 166-172Paz-Elizur, T., Sevilya, Z., Leitner-Dagan, Y., Elinger, D., Roisman, L.C., Livneh, Z., DNA repair of oxidative DNA damage in human carcinogenesis: Potential application for cancer risk assessment and prevention (2008) Cancer Lett, 266, pp. 60-72Xanthoudakis, S., Miao, G., Wang, F., Pan, Y.C., Curran, T., Redox activation of fos-jun DNA binding activity is mediated by a DNA repair enzyme (1992) EMBO J, 11, pp. 3323-3335Moreno, V., Gemignani, F., Landi, S., Gioia-Patricola, L., Chabrier, A., Blanco, I., Gonzalez, S., Canzian, F., Polymorphisms in genes of nucleotide and base excision repair: Risk and prognosis of colorectal cancer (2006) Clin. Cancer Res, 12, pp. 2101-2108Pardini, B., Naccarati, A., Novotny, J., Smerhovsky, Z., Vodickova, L., Polakova, V., Hanova, M., Kumar, R., DNA repair genetic polymorphisms and risk of colorectal cancer in the czech republic (2008) Mutat. Res, 638, pp. 146-153Kasahara, M., Osawa, K., Yoshida, K., Miyaishi, A., Osawa, Y., Inoue, N., Tsutou, A., Yamamoto, M., Association of mutyh gln324his and apex1 asp148glu with colorectal cancer and smoking in a japanese population (2008) J. Exp. Clin. Cancer Res, 27, p. 49Fisseler-Eckhoff, A., New TNM classification of malignant lung tumors 2009 from a pathology perspective (2009) Pathologe, 30, pp. 193-199Debunne, H., Ceelen, W., Mucinous differentiation in colorectal cancer: Molecular, histological and clinical aspects (2013) Acta Chir. Belg, 113, pp. 385-390Barresi, V., Bonetti, L.R., Ieni, A., Branca, G., Baron, L., Tuccari, G., Histologic grading based on counting poorly differentiated clusters in preoperative biopsy predicts nodal involvement and ptnm stage in colorectal cancer patients (2014) Hum. Pathol, 45, pp. 268-275Xi, T., Jones, I.M., Mohrenweiser, H.W., Many amino acid substitution variants identified in DNA repair genes during human population screenings are predicted to impact protein function (2004) Genomics, 83, pp. 970-979Jelonek, K., Gdowicz-Klosok, A., Pietrowska, M., Borkowska, M., Korfanty, J., Rzeszowska-Wolny, J., Widlak, P., Association between single-nucleotide polymorphisms of selected genes involved in the response to DNA damage and risk of colon, head and neck, and breast cancers in a polish population (2010) J. Appl. Genet, 51, pp. 343-352Li, Y., Li, S., Wu, Z., Hu, F., Zhu, L., Zhao, X., Cui, B., Wang, F., Polymorphisms in genes of APE1, PARP1, and XRCC1: Risk and prognosis of colorectal cancer in a northeast chinese population (2013) Med. Oncol, 30, p. 505Canbay, E., Cakmakoglu, B., Zeybek, U., Sozen, S., Cacina, C., Gulluoglu, M., Balik, E., Bugra, D., Association of ape1 and hogg1 polymorphisms with colorectal cancer risk in a turkish population (2011) Curr. Med. Res. Opin, 27, pp. 1295-1302Silva-Fernandes, I.J., da Silva, T.A., Agnez-Lima, L.F., Ferreira, M.V., Rabenhorst, S.H., Helicobacter pylori genotype and polymorphisms in DNA repair enzymes: Where do they correlate in gastric cancer? (2012) J. Surg. Oncol, 106, pp. 448-455Zhou, W., Liu, G., Miller, D.P., Thurston, S.W., Xu, L.L., Wain, J.C., Lynch, T.J., Christiani, D.C., Gene-environment interaction for the ERCC2 polymorphisms and cumulative cigarette smoking exposure in lung cancer (2002) Cancer Res, 62, pp. 1377-1381Sturgis, E.M., Castillo, E.J., Li, L., Zheng, R., Eicher, S.A., Clayman, G.L., Strom, S.S., Wei, Q., Polymorphisms of DNA repair gene XRCC1 in squamous cell carcinoma of the head and neck (1999) Carcinogenesis, 20, pp. 2125-2129Hadi, M.Z., Coleman, M.A., Fidelis, K., Mohrenweiser, H.W., Wilson, D.M., III, Functional characterization of ape1 variants identified in the human population (2000) Nucleic Acids Res, 28, pp. 3871-3879Yu, H., Zhao, H., Wang, L.E., Liu, Z., Li, D., Wei, Q., Correlation between base-excision repair gene polymorphisms and levels of in vitro bpde-induced DNA adducts in cultured peripheral blood lymphocytes (2012) PLoS One, 7Obtulowicz, T., Swoboda, M., Speina, E., Gackowski, D., Rozalski, R., Siomek, A., Janik, J., Jawien, A., Oxidative stress and 8-oxoguanine repair are enhanced in colon adenoma and carcinoma patients (2010) Mutagenesis, 25, pp. 463-471Saebo, M., Skjelbred, C.F., Nexo, B.A., Wallin, H., Hansteen, I.L., Vogel, U., Kure, E.H., Increased mrna expression levels of ERCC1, OGG1 and rai in colorectal adenomas and carcinomas (2006) BMC Cancer, 6, p. 208Sulzyc-Bielicka, V., Domagala, P., Hybiak, J., Majewicz-Broda, A., Safranow, K., Domagala, W., Colorectal cancers differ in respect of PARP-1 protein expression (2012) Pol. J. Pathol, 63, pp. 87-92Tudek, B., Speina, E., Oxidatively damaged DNA and its repair in colon carcinogenesis (2012) Mutat. Res, 736, pp. 82-92Murakami, T., Fujimoto, M., Ohtsuki, M., Nakagawa, H., Expression profiling of cancer-related genes in human keratinocytes following non-lethal ultraviolet b irradiation (2001) J. Dermatol. Sci, 27, pp. 121-12

Effect Of Mlh1 −93g>a On Gene Expression In Patients With Colorectal Cancer

The DNA repair machinery plays a key role in maintaining genomic stability by preventing the emergence of mutations. Furthermore, the −93G>A polymorphism in the MLH1 gene has been associated with an increased risk of developing colorectal cancer. Therefore, the aim of this study was to examine the expression pattern and effect of this polymorphism in normal and tumour samples from patients with colorectal cancer. The MLH1 −93G>A (rs1800734) polymorphism was detected by PCR–RFLP in 49 cases of colorectal cancer. MLH1 expression was investigated using real-time quantitative PCR. The results indicate a significant decrease in MLH1 expression in tumour samples compared to their normal counterparts. The MLH1 gene was also significantly repressed in samples from patients who had some degree of tumour invasion into other organs. Similarly, those patients who were in a more advanced tumour stage (TNM III and IV) exhibited a significant reduction in MLH1 gene expression. Finally, the mutant genotype AA of MLH1 was associated with a significant decrease in the expression of this gene. This finding suggests that this polymorphism could increase the risk of developing colorectal cancer by a defective mismatch repair system, particularly through the loss of MLH1 expression in an allele-specific manner.31915Jemal, A., Bray, F., Center, M.M., Ferlay, J., Ward, E., Forman, D., Global cancer statistics (2011) CA Cancer J Clin, 61 (2), pp. 69-90. , PID: 21296855Bacani, J., Zwingerman, R., Di Nicola, N., Spencer, S., Wegrynowski, T., Mitchell, K., Tumor microsatellite instability in early onset gastric cancer (2005) J Mol Diagn, 7 (4), pp. 465-477. , PID: 16237216, COI: 1:CAS:528:DC%2BD2MXhtFGqsbvPKolodner, R.D., Marsischky, G.T., Eukaryotic DNA mismatch repair (1999) Curr Opin Genet Dev, 9 (1), pp. 89-96. , PID: 10072354, COI: 1:CAS:528:DyaK1MXhsFSntLY%3DLipkin, S.M., Wang, V., Jacoby, R., Banerjee-Basu, S., Baxevanis, A.D., Lynch, H.T., MLH3: a DNA mismatch repair gene associated with mammalian microsatellite instability (2000) Nat Genet, 24 (1), pp. 27-35. , PID: 10615123, COI: 1:CAS:528:DC%2BD3cXks1emsw%3D%3DThibodeau, S.N., Bren, G., Schaid, D., Microsatellite instability in cancer of the proximal colon (1993) Science, 260 (5109), pp. 816-819. , PID: 8484122, COI: 1:CAS:528:DyaK3sXkt1GlsLs%3DWang, T., Liu, Y., Sima, L., Shi, L., Wang, Z., Ni, C., Association between MLH1 −93G>A polymorphism and risk of colorectal cancer (2012) PLoS One, 7 (11), p. e50449. , PID: 23226285, COI: 1:CAS:528:DC%2BC38XhvVKqtrrMIto, E., Yanagisawa, Y., Iwahashi, Y., Suzuki, Y., Nagasaki, H., Akiyama, Y., A core promoter and a frequent single-nucleotide polymorphism of the mismatch repair gene hMLH1 (1999) Biochem Biophys Res Commun, 256 (3), pp. 488-494. , PID: 10080925, COI: 1:CAS:528:DyaK1MXhvVahtb0%3DCampbell, P.T., Curtin, K., Ulrich, C.M., Samowitz, W.S., Bigler, J., Velicer, C.M., Mismatch repair polymorphisms and risk of colon cancer, tumour microsatellite instability and interactions with lifestyle factors (2009) Gut, 58 (5), pp. 661-667. , PID: 18523027, COI: 1:CAS:528:DC%2BD1MXls1yrurc%3DRaptis, S., Mrkonjic, M., Green, R.C., Pethe, V.V., Monga, N., Chan, Y.M., MLH1 −93G>A promoter polymorphism and the risk of microsatellite-unstable colorectal cancer (2007) J Natl Cancer Inst, 99 (6), pp. 463-474. , PID: 17374836, COI: 1:CAS:528:DC%2BD2sXktl2lt78%3DMartinez-Uruena, N., Macias, L., Perez-Cabornero, L., Infante, M., Lastra, E., Cruz, J.J., Incidence of −93 MLH1 promoter polymorphism in familial and sporadic colorectal cancer (2013) Colorectal Dis, 15 (3), pp. e118-e123. , PID: 23374646, COI: 1:STN:280:DC%2BC3szkvVKqtw%3D%3DWhiffin, N., Broderick, P., Lubbe, S.J., Pittman, A.M., Penegar, S., Chandler, I., MLH1−93G>A is a risk factor for MSI colorectal cancer (2011) Carcinogenesis, 32 (8), pp. 1157-1161. , PID: 21565826, COI: 1:CAS:528:DC%2BC3MXhtVSitLfLAllan, J.M., Shorto, J., Adlard, J., Bury, J., Coggins, R., George, R., MLH1 -93G > A promoter polymorphism and risk of mismatch repair deficient colorectal cancer (2008) Int J Cancer, 123 (10), pp. 2456-2459. , PID: 18712731, COI: 1:CAS:528:DC%2BD1cXhtleiurfEMei, M., Liu, D., Dong, S., Ingvarsson, S., Goodfellow, P.J., Chen, H., The MLH1 −93 promoter variant influences gene expression (2010) Cancer Epidemiol, 34 (1), pp. 93-95. , PID: 20060799, COI: 1:CAS:528:DC%2BC3cXltFGguro%3DBeiner, M.E., Rosen, B., Fyles, A., Harley, I., Pal, T., Siminovitch, K., Endometrial cancer risk is associated with variants of the mismatch repair genes MLH1 and MSH2 (2006) Cancer Epidemiol Biomarkers Prev, 15 (9), pp. 1636-1640. , PID: 16985024, COI: 1:CAS:528:DC%2BD28Xps1yntrc%3DHarley, I., Rosen, B., Risch, H.A., Siminovitch, K., Beiner, M.E., McLaughlin, J., Ovarian cancer risk is associated with a common variant in the promoter sequence of the mismatch repair gene MLH1 (2008) Gynecol Oncol, 109 (3), pp. 384-387. , PID: 18405947, COI: 1:CAS:528:DC%2BD1cXmvVKrsLg%3DPark, S.H., Lee, G.Y., Jeon, H.S., Lee, S.J., Kim, K.M., Jang, S.S., 93G–>A polymorphism of hMLH1 and risk of primary lung cancer (2004) Int J Cancer, 112 (4), pp. 678-682. , PID: 15382050, COI: 1:CAS:528:DC%2BD2cXptlGjtrg%3DMalekzadeh, R., Bishehsari, F., Mahdavinia, M., Ansari, R., Epidemiology and molecular genetics of colorectal cancer in iran: a review (2009) Arch Iran Med, 12 (2), pp. 161-169. , PID: 19249887, COI: 1:CAS:528:DC%2BD1MXhtVyhurzJKarahalil, B., Bohr, V.A., Wilson, D.M., 3rd, Impact of DNA polymorphisms in key DNA base excision repair proteins on cancer risk (2012) Hum Exp Toxicol, 31 (10), pp. 981-1005. , PID: 23023028, COI: 1:CAS:528:DC%2BC2cXhs1OjurzNMichailidi, C., Papavassiliou, A.G., Troungos, C., DNA repair mechanisms in colorectal carcinogenesis (2012) Curr Mol Med, 12 (3), pp. 237-246. , PID: 22082485, COI: 1:CAS:528:DC%2BC38XktFWju7Y%3DLi, X., Yao, X., Wang, Y., Hu, F., Wang, F., Jiang, L., MLH1 promoter methylation frequency in colorectal cancer patients and related clinicopathological and molecular features (2013) PLoS One, 8 (3), p. e59064. , PID: 23555617, COI: 1:CAS:528:DC%2BC3sXmtFWrsr8%3