XRCC2 Promotes Colorectal Cancer Cell Growth, Regulates Cell Cycle Progression, and Apoptosis

AbstractX-ray repair complementing defective repair in Chinese hamster cells 2 (XRCC2) and poly(ADP-ribose) polymerase 1 (PARP1) both play important roles in homologous recombination DNA repair. According to the theory of synthetic lethality, XRCC2-deficient cells are more sensitive to PARP1 inhibitors compared to XRCC2-expressing cells. We investigated XRCC2 expression and function in colorectal cancer (CRC), and the characteristics of sensitivity to PARP1 inhibitor in CRC cells with different XRCC2 levels.We enrolled 153 patients with CRC who had undergone surgery in this study. XRCC2 expression was assessed using immunohistochemistry. Stable CRC SW480 cell lines with low or high XRCC2 expression were constructed. Following treatment with the PARP1 inhibitor olaparib, the viability of cells with different XRCC2 levels was determined; cell cycle distribution and apoptosis were analyzed using flow cytometry. B-cell lymphoma-2 (Bcl-2) protein expression was measured by Western blotting.The positive rates of XRCC2 in primary CRC tissue were significantly higher than that in the matched adjacent noncancerous tissue, and XRCC2 expression status in primary CRC was related to tumor site, Dukes’ stage, and tumor-nodes-metastasis (TNM) stage. XRCC2 overexpression inhibited CRC cell apoptosis and promoted proliferation by enriching cells in the G0/G1 phase. Moreover, olaparib suppressed proliferation, and olaparib sensitivity in CRC cells with high XRCC2 expression was greater.High XRCC2 expression promotes CRC cell proliferation and enriches cells in the G0/G1 phase but inhibits apoptosis. High XRCC2 expression cells are more sensitive to olaparib, which inhibits their viability.

[1]  J. Błasiak,et al.  Polymorphisms in RAD51, XRCC2 and XRCC3 genes of the homologous recombination repair in colorectal cancer—a case control study , 2010, Molecular Biology Reports.

[2]  A. Ashworth,et al.  Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. , 2009, The New England journal of medicine.

[3]  Shyun-Yeu Liu,et al.  Combinational polymorphisms of four DNA repair genes XRCC1, XRCC2, XRCC3, and XRCC4 and their association with oral cancer in Taiwan. , 2007, Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology.

[4]  Michael Peyton,et al.  Synthetic lethal screen identification of chemosensitizer loci in cancer cells , 2007, Nature.

[5]  N. Camp,et al.  A role for XRCC2 gene polymorphisms in breast cancer risk and survival , 2011, Journal of Medical Genetics.

[6]  Libing Song,et al.  Astrocyte Elevated Gene-1 is a Novel Prognostic Marker for Breast Cancer Progression and Overall Patient Survival , 2008, Clinical Cancer Research.

[7]  Alan Ashworth,et al.  Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy , 2005, Nature.

[8]  N. Camp,et al.  Genetic Variants in XRCC2: New Insights Into Colorectal Cancer Tumorigenesis , 2009, Cancer Epidemiology, Biomarkers & Prevention.

[9]  J. Hoeijmakers.  DNA damage, aging, and cancer. , 2009, The New England journal of medicine.

[10]  A. Ashworth,et al.  Synthetic lethality of PARP inhibition in cancers lacking BRCA1 and BRCA2 mutations , 2011, Cell cycle.

[11]  Thomas Helleday,et al.  Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase , 2005, Nature.

[12]  L. Thompson,et al.  Assignment of the XRCC2 human DNA repair gene to chromosome 7q36 by complementation analysis. , 1995, Genomics.

[13]  C. Mathers,et al.  Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008 , 2010, International journal of cancer.

[14]  S. Bouffler,et al.  Xrcc2 Modulates Spontaneous and Radiation-Induced Tumorigenesis in Apcmin/+ Mice , 2010, Molecular Cancer Research.

[15]  J. Lamerdin,et al.  XRCC2 and XRCC3, new human Rad51-family members, promote chromosome stability and protect against DNA cross-links and other damages. , 1998, Molecular cell.

[16]  A. Jemal,et al.  Global Patterns of Cancer Incidence and Mortality Rates and Trends , 2010, Cancer Epidemiology, Biomarkers & Prevention.

[17]  N. Curtin,et al.  Identification of potent nontoxic poly(ADP-Ribose) polymerase-1 inhibitors: chemopotentiation and pharmacological studies. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[18]  B. Smolarz,et al.  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 , 2012, The journal of obstetrics and gynaecology research.

[19]  S. Gruber,et al.  MRE11 deficiency increases sensitivity to poly(ADP-ribose) polymerase inhibition in microsatellite unstable colorectal cancers. , 2011, Cancer research.

[20]  Ni Li,et al.  [Analysis and prediction of colorectal cancer incidence trend in China]. , 2012, Zhonghua yu fang yi xue za zhi [Chinese journal of preventive medicine].

[21]  F. Fan,et al.  shRNA-Mediated XRCC2 Gene Knockdown Efficiently Sensitizes Colon Tumor Cells to X-ray Irradiation in Vitro and in Vivo , 2014, International journal of molecular sciences.

[22]  M. O’Connor,et al.  Targeted cancer therapies based on the inhibition of DNA strand break repair , 2007, Oncogene.

[23]  L. Tsui,et al.  Localization to chromosome 7q36.1 of the human XRCC2 gene, determining sensitivity to DNA-damaging agents. , 1995, Human molecular genetics.

[24]  L. Tentori,et al.  MSH3 expression does not influence the sensitivity of colon cancer HCT116 cell line to oxaliplatin and poly(ADP-ribose) polymerase (PARP) inhibitor as monotherapy or in combination , 2013, Cancer Chemotherapy and Pharmacology.