142

PARP1

poly (ADP-ribose) polymerase 1;PARP1;poly (ADP-ribose) polymerase 1

ADP-ribosyltransferase (NAD+; poly (ADP-ribose) polymerase)|ADP-ribosyltransferase NAD(+)|ADP-ribosyltransferase diphtheria toxin-like 1|NAD(+) ADP-ribosyltransferase 1|poly (ADP-ribose) polymerase family, member 1|poly [ADP-ribose] polymerase 1|poly(ADP-

1q41-q42

protein-coding

p38gamma MAPK, one of the four members of p38 mitogen-activated protein kinases (MAPKs), has previously been shown to harbor oncogenic functions. However, the biologic function of p38gamma MAPK in breast cancer has not been well defined. In this study, we have shown that p38gamma MAPK is overexpressed in highly metastatic human and mouse breast cancer cell lines and p38gamma MAPK expression is preferentially associated with basal-like and metastatic phenotypes of breast tumor samples. Ectopic expression of p38gamma MAPK did not lead to an increase in oncogenic properties in vitro in most tested mammary epithelial cells. However, knockdown of p38gamma MAPK expression resulted in a dramatic decrease in cell proliferation, colony formation, cell migration, invasion in vitro and significant retardation of tumorigenesis, and long-distance metastasis to the lungs in vivo. Moreover, knockdown of p38gamma MAPK triggered the activation of AKT signaling. Inhibition of this feedback loop with various PI3K/AKT signaling inhibitors facilitated the effect of targeting p38gamma MAPK. We further found that overexpression of p38gamma MAPK did not promote cell resistance to chemotherapeutic agents doxorubicin and paclitaxel but significantly increased cell resistance to PJ-34, a DNA damage agent poly (ADP-ribose)-polymerase-1 (PARP) inhibitor in vitro and in vivo. Finally, we identified that p38gamma MAPK overexpression led to marked cell cycle arrest in G(2)/M phase. Our study for the first time clearly demonstrates that p38gamma MAPK is a promising target for the design of targeted therapies for basal-like breast cancer with metastatic characteristics and for overcoming potential resistance against the PARP inhibitor.

Poly (ADP-ribose) polymerase 1 (PARP1), which plays a critical role in the base excision DNA repair mechanism, and matrix metallopeptidase 2 (MMP2), a member of the matrix metalloprotease family, are involved in tumor formation and metastasis, respectively. In the present study, the possible association of single nucleotide polymorphisms (SNPs) and gene-gene interaction between PARP1 and MMP2 with the increased incidence of gastric cancer (GC) development and lymph node metastasis (LNM) was investigated in a Korean population. Samples were obtained from 326 patients with chronic gastritis and 153 patients with GC and genotyped using the GoldenGate(R) method. The PARP1 rs1136410 genotype showed a significant association with the frequency of LNM of GC (odds ratio [OR] = 2.19, p = 0.02), LNM stage (p = 0.035), and tumor invasion (p = 0.035). The allele frequency of MMP2 rs243865 was not associated with the development of GC or with the development of LNM of GC. Epistasis between the PARP1 SNP and the MMP2 SNP was associated with the development of LNM of GC. The combination of the MMP2 rs243865 CC genotype and the PARP1 rs1136410 CC or CC+CT genotypes showed a high risk of LNM of GC (OR = 2.47, p = 0.01; OR = 2.28, p = 0.01, respectively). In summary, PARP1 is associated with the risk of LNM of GC and the stage of LNM and tumor invasion. Epistasis between PARP1 rs1136410 and MMP2 rs243865 increased the risk of LNM of GC.

PURPOSE: DNA BER pathway is related with carcinogenesis. We hypothesized that functional polymorphisms of three BER genes, XRCC1, apurinic/apyrimidinic endonuclease (APE1), and ADPRT, confer risks for DTC and its progression. EXPERIMENTAL DESIGN: Five common nonsynonymous single nucleotide polymorphisms (Arg194Trp, Arg280His, and Arg399Gln for XRCC1; Asp148Glu for APE1; and Val762Ala for ADPRT) were genotyped in Chinese DTC cases and controls. RESULTS: The XRCC1-194Trp/Trp genotype showed a significantly increased risk for DTC (odds ratio, 1.85; 95% confidence interval, 1.11-3.07; P = 0.018). Subset analysis based on regional LN metastasis showed that the genetic effect came primarily from the subjects with LN metastasis (odds ratio, 4.54; 95% confidence interval, 2.11-9.79; P = 0.0001), but no significant association for subjects without LN metastasis. The other four single nucleotide polymorphisms did not show significant results. Haplotype analysis of XRCC1 polymorphisms yielded a significant result (P = 0.004), especially in the subjects with LN metastasis (P = 0.0002). Moreover, we found that XRCC1-194Trp and ADPRT-762Ala variants collectively contributed to an increased risk of the disease and LN metastasis, with the combined variant homozygotes exhibiting the highest 3.18-fold risk for DTC (P = 0.046) and 9.25-fold risk for DTC with LN metastasis (P = 0.004). CONCLUSIONS: The XRCC1 polymorphisms, especially the 194Trp allele, may have an effect on DTC development and progression. This variant can interact with ADPRT-762Ala variant to further substantially increase susceptibility to the disease and regional LN metastasis. Identifying these risk genetic markers could provide more insight into the DTC pathogenesis and may also provide information to develop better prevention and therapeutic strategies.