XRCC2 rs3218536 polymorphism decreases the sensitivity of colorectal cancer cells to poly(ADP‑ribose) polymerase 1 inhibitor

Xu,Kaiwu; Song,Xinming; Chen,Zhihui; Qin,Changjiang; He,Yulong

doi:10.3892/ol.2014.2236

XRCC2 rs3218536 polymorphism decreases the sensitivity of colorectal cancer cells to poly(ADP‑ribose) polymerase 1 inhibitor

Authors:
- Kaiwu Xu
- Xinming Song
- Zhihui Chen
- Changjiang Qin
- Yulong He
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Affiliations: Department of Gastrointestinal and Pancreatic Surgery, The First Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China
Published online on: June 11, 2014 https://doi.org/10.3892/ol.2014.2236
Pages: 1222-1228

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Abstract

Single nucleotide polymorphisms (SNPs) are associated with the development of certain types of cancer. The present study aimed to investigate the association between X‑ray repair complementing defective repair in Chinese hamster cells 2 (XRCC2) SNPs and colorectal cancer (CRC) cell sensitivity to the poly(ADP‑ribose) polymerase (PARP) 1 inhibitor olaparib (AZD2281). SNaPshot® analysis of XRCC2 SNPs was performed in five CRC cell lines. The AZD2281‑sensitivities of the CRC cells were also analyzed using MTT assays. The effect of AZD2281 on XRCC2 and PARP1 expression was investigated in the five cell lines using quantitative polymerase chain reaction and western blot analyses. Parallel investigations were performed using a cisplatin (DDP) model of DNA damage. The XRCC2 rs3218536 SNP was found to be associated with the LoVo microsatellite instability CRC cell line. The relative rate of growth inhibition was found to be lower in the LoVo cells following treatment with AZD2281 compared with the other four cell lines (P=0.002). Furthermore, the XRCC2 mRNA level in the LoVo cells was observed to be significantly higher than that in the other four cell lines (P<0.05). Similar results were found using the DDP model of DNA damage (P<0.05). The present study indicated that the XRCC2 rs3218536 polymorphism decreases the sensitivity of CRC cells to AZD2281.

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1	Hampel H, Frankel WL, Martin E, et al: Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). N Engl J Med. 352:1851–1860. 2005.
2	Gryfe R, Kim H, Hsieh ET, et al: Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer. N Engl J Med. 342:69–77. 2000.
3	Greenson JK, Bonner JD, Ben-Yzhak O, et al: Phenotype of microsatellite unstable colorectal carcinomas: Well-differentiated and focally mucinous tumors and the absence of dirty necrosis correlate with microsatellite instability. Am J Surg Pathol. 27:563–570. 2003.
4	Greenson JK, Huang SC, Herron C, et al: Pathologic predictors of microsatellite instability in colorectal cancer. Am J Surg Pathol. 33:126–133. 2009.
5	Duval A and Hamelin R: Mutations at coding repeat sequences in mismatch repair-deficient human cancers: toward a new concept of target genes for instability. Cancer Res. 62:2447–2454. 2002.
6	Wang HC, Liu CS, Chiu CF, et al: Significant association of DNA repair gene Ku80 genotypes with breast cancer susceptibility in Taiwan. Anticancer Res. 29:5251–5254. 2009.
7	Jones NJ, Zhao Y, Siciliano MJ and Thompson LH: Assignment of the XRCC2 human DNA repair gene to chromosome 7q36 by complementation analysis. Genomics. 26:619–622. 1995.
8	Thacker J, Tambini CE, Simpson PJ, Tsui LC and Scherer SW: Localization to chromosome 7q36.1 of the human XRCC2 gene, determining sensitivity to DNA-damaging agents. Hum Mol Genet. 4:113–120. 1995.
9	Liu N, Lamerdin JE, Tebbs RS, et al: XRCC2 and XRCC3, new human Rad51-family members, promote chromosome stability and protect against DNA cross-links and other damages. Mol Cell. 1:783–793. 1998.
10	Rafii S, O’Regan P, Xinarianos G, et al: A potential role for the XRCC2 R188H polymorphic site in DNA-damage repair and breast cancer. Hum Mol Genet. 11:1433–1438. 2002.
11	Wang R, Wang W and Zhang JW: Correlation between XRCC2 and XRCC5 single nucleotide polymorphisms and drug-sensitivity of human lung cancer cells. Zhonghua Yi Xue Za Zhi. 88:3059–3062. 2008.(In Chinese).
12	Romanowicz-Makowska H, Smolarz B, Połać I and Sporny S: Single nucleotide polymorphisms of RAD51 G135C, XRCC2 Arg188His and XRCC3 Thr241Met homologous recombination repair genes and the risk of sporadic endometrial cancer in Polish women. J Obstet Gynaecol Res. 38:918–924. 2012.
13	Han J, Hankinson SE, Hunter DJ and De Vivo I: Genetic variations in XRCC2 and XRCC3 are not associated with endometrial cancer risk. Cancer Epidemiol Biomarkers Prev. 13:330–331. 2004.
14	Lin WY, Camp NJ, Cannon-Albright LA, et al: A role for XRCC2 gene polymorphisms in breast cancer risk and survival. J Med Genet. 48:477–484. 2011.
15	Yen CY, Liu SY, Chen CH, et al: Combinational polymorphisms of four DNA repair genes XRCC1, XRCC2, XRCC3, and XRCC4 and their association with oral cancer in Taiwan. J Oral Pathol Med. 37:271–277. 2008.
16	Curtin K, Lin WY, George R, et al: Genetic variants in XRCC2: new insights into colorectal cancer tumorigenesis. Cancer Epidemiol Biomarkers Prev. 18:2476–2484. 2009.
17	Krupa R, Sliwinski T, Wisniewska-Jarosinska M, et al: Polymorphisms in RAD51, XRCC2 and XRCC3 genes of the homologous recombination repair in colorectal cancer - a case control study. Mol Biol Rep. 38:2849–2854. 2011.
18	Hoeijmakers JH: DNA damage, aging, and cancer. N Engl J Med. 361:1475–1485. 2009.
19	Farmer H, McCabe N, Lord CJ, et al: Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 434:917–921. 2005.
20	Whitehurst AW, Bodemann BO, Cardenas J, et al: Synthetic lethal screen identification of chemosensitizer loci in cancer cells. Nature. 446:815–819. 2007.
21	Vilar E, Bartnik CM, Stenzel SL, et al: MRE11 deficiency increases sensitivity to poly(ADP-ribose) polymerase inhibition in microsatellite unstable colorectal cancers. Cancer Res. 71:2632–2642. 2011.
22	O’Connor MJ, Martin NM and Smith GC: Targeted cancer therapies based on the inhibition of DNA strand break repair. Oncogene. 26:7816–7824. 2007.
23	Fong PC, Boss DS, Yap TA, et al: Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 361:123–134. 2009.
24	Calabrese CR, Batey MA, Thomas HD, et al: Identification of potent nontoxic poly(ADP-Ribose) polymerase-1 inhibitors: chemopotentiation and pharmacological studies. Clin Cancer Res. 9:2711–2718. 2003.