Abstract
This study aimed to investigate the relationship between polymorphisms in the lipid metabolism-related gene PLA2G16 encoding Group XVI phospholipase A2 and the risk of colorectal cancer (CRC) in the Chinese population. A total of 185 patients with CRC and 313 healthy controls were enrolled. Thirteen single nucleotide polymorphisms (SNPs) of PLA2G16 were genotyped with SNPscan™. Linkage disequilibrium and haplotypes were analysed using Haploview software. Multivariate logistic regression was used to determine the association between the various genotypes and CRC risk. We identified five PLA2G16 SNPs (rs11600655, rs3809072, rs3809073, rs640908 and rs66475048) that were associated with CRC risk after adjusting for age, sex and body mass index. Two haplotypes (CTC and GGA) of rs11600655, rs3809073 and rs3809072, were relevant to CRC risk. The rs11600655 polymorphism was also associated with lymph node metastasis and CRC staging, while rs3809073 and rs3809072 may affect transcriptional regulation of PLA2G16 by altering transcription factor binding. These findings suggest that PLA2G16 polymorphisms—especially CTC and GGA haplotypes—increase CRC susceptibility. Importantly, we showed that the rs11600655 CC, rs640908 CT and rs66475048 GA genotypes are independent risk factors for CRC in the Chinese population.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Azarsina S, Otoukesh B, Taheriazam A, Kaghazian M, Boddouhi B, Yahaghi E, Kaghazian P (2017) Diagnostic investigations of PLA2G16 and CDH11 expression levels as independent prognostic markers of human osteosarcoma. Arch Med Sci 13(6):1347–1351. https://doi.org/10.5114/aoms.2016.59710
Bardou M, Barkun AN, Martel M (2013) Obesity and colorectal cancer. Gut 62(6):933–947. https://doi.org/10.1136/gutjnl-2013-304701
Boyle AP, Hong EL, Hariharan M, Cheng Y, Schaub MA, Kasowski M, Karczewski KJ, Park J, Hitz BC, Weng S, Cherry JM, Snyder M (2012) Annotation of functional variation in personal genomes using RegulomeDB. Genome Res 22(9):1790–1797. https://doi.org/10.1101/gr.137323.112
Castellone MD, Teramoto H, Williams BO, Druey KM, Gutkind JS (2005) Prostaglandin E2 promotes colon cancer cell growth through a Gs-axin-beta-catenin signaling axis. Science 310(5753):1504–1510. https://doi.org/10.1126/science.1116221
Ceddia RP, Lee D, Maulis MF, Carboneau BA, Threadgill DW, Poffenberger G, Milne G, Boyd KL, Powers AC, McGuinness OP, Gannon M, Breyer RM (2016) The PGE2 EP3 receptor regulates diet-induced adiposity in male mice. Endocrinology 157(1):220–232. https://doi.org/10.1210/en.2015-1693
Chen J, Chen Z (2014) The effect of immune microenvironment on the progression and prognosis of colorectal cancer. Med Oncol 31(8):82. https://doi.org/10.1007/s12032-014-0082-9
Coulson JM (2005) Transcriptional regulation: cancer, neurons and the REST. Curr Biol 15(17):R665–R668. https://doi.org/10.1016/j.cub.2005.08.032
Dai Q, Wei HL, Huang J, Zhou TJ, Chai L, Yang ZH (2016) KRAS polymorphisms are associated with survival of CRC in Chinese population. Tumour Biol 37(4):4727–4734. https://doi.org/10.1007/s13277-015-4314-1
Duncan RE, Sarkadi-Nagy E, Jaworski K, Ahmadian M, Sul HS (2008) Identification and functional characterization of adipose-specific phospholipase A2 (AdPLA). J Biol Chem 283(37):25428–25436. https://doi.org/10.1074/jbc.M804146200
Hardwick JP, Eckman K, Lee YK, Abdelmegeed MA, Esterle A, Chilian WM, Chiang JY, Song BJ (2013) Eicosanoids in metabolic syndrome. Adv Pharmacol 66:157–266. https://doi.org/10.1016/B978-0-12-404717-4.00005-6
Hawken SJ, Greenwood CM, Hudson TJ, Kustra R, McLaughlin J, Yang Q, Zanke BW, Little J (2010) The utility and predictive value of combinations of low penetrance genes for screening and risk prediction of colorectal cancer. Hum Genet 128(1):89–101. https://doi.org/10.1007/s00439-010-0828-1
Huang F, Cao J, Liu Q, Zou Y, Li H, Yin T (2013) MAPK/ERK signal pathway involved expression of COX-2 and VEGF by IL-1beta induced in human endometriosis stromal cells in vitro. Int J Clin Exp Pathol 6(10):2129–2136
Husmann K, Sers C, Fietze E, Mincheva A, Lichter P, Schafer R (1998) Transcriptional and translational downregulation of H-REV107, a class II tumour suppressor gene located on human chromosome 11q11-12. Oncogene 17(10):1305–1312. https://doi.org/10.1038/sj.onc.1202060
Jaworski K, Ahmadian M, Duncan RE, Sarkadi-Nagy E, Varady KA, Hellerstein MK, Lee H, Samuel VT, Shulman GI, Kim K, de Val S, Kang C, Sul HS (2009) AdPLA ablation increases lipolysis and prevents obesity induced by high-fat feeding or leptin deficiency. Nat Med 15(2):159–168. https://doi.org/10.1038/nm.1904
Kaklamani VG, Wisinski KB, Sadim M, Gulden C, Do A, Offit K, Baron JA, Ahsan H, Mantzoros C, Pasche B (2008) Variants of the adiponectin (ADIPOQ) and adiponectin receptor 1 (ADIPOR1) genes and colorectal cancer risk. JAMA 300(13):1523–1531. https://doi.org/10.1001/jama.300.13.1523
Li L, Liang S, Wasylishen AR, Zhang Y, Yang X, Zhou B, Shan L, Han X, Mu T, Wang G, Xiong S (2016) PLA2G16 promotes osteosarcoma metastasis and drug resistance via the MAPK pathway. Oncotarget 7(14):18021–18035. https://doi.org/10.18632/oncotarget.7694
Lin R, Ju H, Yuan Z, Zeng L, Sun Y, Su Z, Yang Y, Wang Y, Jin L (2017) Association of maternal and fetal LEPR common variants with maternal glycemic traits during pregnancy. Sci Rep 7(1):3112. https://doi.org/10.1038/s41598-017-03518-x
Liu Y, Zhang X, Han C, Wan G, Huang X, Ivan C, Jiang D, Rodriguez-Aguayo C, Lopez-Berestein G, Rao PH, Maru DM, Pahl A, He X, Sood AK, Ellis LM, Anderl J, Lu X (2015) TP53 loss creates therapeutic vulnerability in colorectal cancer. Nature 520(7549):697–701. https://doi.org/10.1038/nature14418
Nazarenko I, Kristiansen G, Fonfara S, Guenther R, Gieseler C, Kemmner W, Schafer R, Petersen I, Sers C (2006) H-REV107-1 stimulates growth in non-small cell lung carcinomas via the activation of mitogenic signaling. Am J Pathol 169(4):1427–1439. https://doi.org/10.2353/ajpath.2006.051341
Nazarenko I, Fer RS, Sers C (2007) Mechanisms of the HRSL3 tumor suppressor function in ovarian carcinoma cells. J Cell Sci 120:1393–1404
Peng Y, Li X, Wu M, Yang J, Liu M, Zhang W, Xiang B, Wang X, Li X, Li G, Shen S (2012) New prognosis biomarkers identified by dynamic proteomic analysis of colorectal cancer. Mol BioSyst 8(11):3077–3088. https://doi.org/10.1039/c2mb25286d
Pugh S, Thomas GA (1994) Patients with adenomatous polyps and carcinomas have increased colonic mucosal prostaglandin E2. Gut 35(5):675–678
Rohrig F, Schulze A (2016) The multifaceted roles of fatty acid synthesis in cancer. Nat Rev Cancer 16(11):732–749. https://doi.org/10.1038/nrc.2016.89
Sato H, Taketomi Y, Ushida A, Isogai Y, Kojima T, Hirabayashi T, Miki Y, Yamamoto K, Nishito Y, Kobayashi T, Ikeda K, Taguchi R, Hara S, Ida S, Miyamoto Y, Watanabe M, Baba H, Miyata K, Oike Y, Gelb MH, Murakami M (2014) The adipocyte-inducible secreted phospholipases PLA2G5 and PLA2G2E play distinct roles in obesity. Cell Metab 20(1):119–132. https://doi.org/10.1016/j.cmet.2014.05.002
Sers C, Husmann K, Nazarenko I, Reich S, Wiechen K, Zhumabayeva B, Adhikari P, Schroder K, Gontarewicz A, Schafer R (2002) The class II tumour suppressor gene H-REV107-1 is a target of interferon-regulatory factor-1 and is involved in IFNgamma-induced cell death in human ovarian carcinoma cells. Oncogene 21(18):2829–2839. https://doi.org/10.1038/sj.onc.1205377
Sheehan KM, Sheahan K, O'Donoghue DP, MacSweeney F, Conroy RM, Fitzgerald DJ, Murray FE (1999) The relationship between cyclooxygenase-2 expression and colorectal cancer. JAMA 282(13):1254–1257
Sheng H, Shao J, Morrow JD, Beauchamp RD, DuBois RN (1998) Modulation of apoptosis and Bcl-2 expression by prostaglandin E2 in human colon cancer cells. Cancer Res 58(2):362–366
Shyu RY, Wu CC, Wang CH, Tsai TC, Wang LK (2013) H-rev107 regulates prostaglandin D2 synthase-mediated suppression of cellular invasion in testicular cancer cells. J Biomed Sci 20:30
Siegel RL, Miller KD, Fedewa SA, Ahnen DJ, Meester R, Barzi A, Jemal A (2017a) Colorectal cancer statistics, 2017. CA Cancer J Clin 67(3):177–193. https://doi.org/10.3322/caac.21395
Siegel RL, Miller KD, Jemal A (2017b) Cancer statistics, 2017. CA Cancer J Clin 67(1):7–30. https://doi.org/10.3322/caac.21387
Sostres C, Gargallo CJ, Lanas A (2014) Aspirin, cyclooxygenase inhibition and colorectal cancer. World J Gastrointest Pharmacol Ther 5(1):40–49. https://doi.org/10.4292/wjgpt.v5.i1.40
Tan SC (2018) Low penetrance genetic polymorphisms as potential biomarkers for colorectal cancer predisposition. J Gene Med 20:e3010. https://doi.org/10.1002/jgm.3010
Tania M, Khan MA, Song Y (2010) Association of lipid metabolism with ovarian cancer. Curr Oncol 17(5):6–11
Tian J, Du Q, Li B, Zhang D (2014) Single-nucleotide polymorphisms in the 5' UTR of UDP-glucose dehydrogenase (PtUGDH) associate with wood properties in Populus tomentosa. Tree Genet Genomes 10(2):339–354. https://doi.org/10.1007/s11295-013-0689-6
Valle L (2014) Genetic predisposition to colorectal cancer: where we stand and future perspectives. World J Gastroenterol 20(29):9828–9849. https://doi.org/10.3748/wjg.v20.i29.9828
van Duijnhoven FJ, Bueno-De-Mesquita HB, Calligaro M, Jenab M, Pischon T, Jansen EH, Frohlich J, Ayyobi A, Overvad K, Toft-Petersen AP, Tjonneland A, Hansen L, Boutron-Ruault MC, Clavel-Chapelon F, Cottet V, Palli D, Tagliabue G, Panico S, Tumino R, Vineis P, Kaaks R, Teucher B, Boeing H, Drogan D, Trichopoulou A, Lagiou P, Dilis V, Peeters PH, Siersema PD, Rodriguez L, Gonzalez CA, Molina-Montes E, Dorronsoro M, Tormo MJ, Barricarte A, Palmqvist R, Hallmans G, Khaw KT, Tsilidis KK, Crowe FL, Chajes V, Fedirko V, Rinaldi S, Norat T, Riboli E (2011) Blood lipid and lipoprotein concentrations and colorectal cancer risk in the European prospective investigation into cancer and nutrition. Gut 60(8):1094–1102. https://doi.org/10.1136/gut.2010.225011
Wang D, DuBois RN (2008) Pro-inflammatory prostaglandins and progression of colorectal cancer. Cancer Lett 267(2):197–203. https://doi.org/10.1016/j.canlet.2008.03.004
Wang D, Wang H, Shi Q, Katkuri S, Walhi W, Desvergne B, Das SK, Dey SK, DuBois RN (2004) Prostaglandin E(2) promotes colorectal adenoma growth via transactivation of the nuclear peroxisome proliferator-activated receptor delta. Cancer Cell 6(3):285–295. https://doi.org/10.1016/j.ccr.2004.08.011
Wang D, Wang H, Brown J, Daikoku T, Ning W, Shi Q, Richmond A, Strieter R, Dey SK, DuBois RN (2006) CXCL1 induced by prostaglandin E2 promotes angiogenesis in colorectal cancer. J Exp Med 203(4):941–951. https://doi.org/10.1084/jem.20052124
Westbrook TF, Martin ES, Schlabach MR, Leng Y, Liang AC, Feng B, Zhao JJ, Roberts TM, Mandel G, Hannon GJ, Depinho RA, Chin L, Elledge SJ (2005) A genetic screen for candidate tumor suppressors identifies REST. Cell 121(6):837–848. https://doi.org/10.1016/j.cell.2005.03.033
Wong HL, Koh WP, Probst-Hensch NM, Van den Berg D, Yu MC, Ingles SA (2008) Insulin-like growth factor-1 promoter polymorphisms and colorectal cancer: a functional genomics approach. Gut 57(8):1090–1096. https://doi.org/10.1136/gut.2007.140855
Xu XM, Ni XB, Yang GL, Luo ZG, Niu YM, Shen M (2016) CCND1 G870A polymorphism and colorectal cancer risk: an updated meta-analysis. Mol Clin Oncol 4(6):1078–1084. https://doi.org/10.3892/mco.2016.844
Yang X, Zhang Z, Jia X, Zhang Y, Mu T, Zhou B, Li L, Fu D, Hu X, Xiong S (2017) High expression of PLA2G16 is associated with a better prognosis in HER2-positive breast cancer. J Thorac Dis 9(4):1002–1011. https://doi.org/10.21037/jtd.2017.03.108
Yuan CJ, Mandal AK, Zhang Z, Mukherjee AB (2000) Transcriptional regulation of cyclooxygenase-2 gene expression: novel effects of nonsteroidal anti-inflammatory drugs. Cancer Res 60(4):1084–1091
Zhang SY, Shi J (2016) rs61764370 polymorphism of Kras and risk of cancer in Caucasian population: a meta-analysis. J Cancer Res Ther 12(2):699–704. https://doi.org/10.4103/0973-1482.147379
Zhou W, Liu Y, Zhong DW (2013) Adiponectin (ADIPOQ) rs2241766 G/T polymorphism is associated with risk of cancer: evidence from a meta-analysis. Tumour Biol 34(1):493–504. https://doi.org/10.1007/s13277-012-0574-1
Funding
This study was supported by The Research of Major Disease Prevention and Control of Precision Medical Research of Hunan Province Education Department (no. 2016JC2069), The National Development of Key Novel Drugs for Special Projects of China (nos. 2018ZX09736007-004 and SQ2017ZX090361-02), and The Graduate Student Innovation Project of Central South University (no. 2018zzts904).
Author information
Authors and Affiliations
Contributions
All authors performed experiments and contributed to the writing of the manuscript.
Corresponding author
Ethics declarations
Conflicts of interest
The authors declare that they have no conflicts of interest.
Rights and permissions
About this article
Cite this article
Xie, XN., Yu, J., Zhang, LH. et al. Relationship between polymorphisms of the lipid metabolism-related gene PLA2G16 and risk of colorectal cancer in the Chinese population. Funct Integr Genomics 19, 227–236 (2019). https://doi.org/10.1007/s10142-018-0642-8
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10142-018-0642-8