Genetic Variants Modulating CRIPTO Serum Levels Identified by Genome-Wide Association Study in Cilento Isolates

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Cripto gene has a fundamental role in embryo development and is also involved in cancer. The protein is bound to the cell membrane through an anchor, that can be cleaved, causing the secretion of the protein, in a still active form. In the adult, CRIPTO is detected at very low levels in normal tissues and in the blood, while its increase in both tissues and blood is associated to pathological conditions, mainly cancer. As other GPI linked proteins such as the carcinoembryonic antigen (CEA), one of the most used tumor markers, CRIPTO is able to reach the bloodstream. Therefore, CRIPTO represents a new promising biomarker and potential therapeutic target, and blood CRIPTO levels might be associated to clinical features. Here we examined the variability of blood CRIPTO levels at a population level (population isolates from the Cilento region in South Italy) and we investigated the genetic architecture underlying this variability. We reported the association of common genetic variants with the levels of CRIPTO protein in the blood and we identified a main locus on chromosome 3 and additional five associated loci. Moreover, through functional analyses, we were able to uncover the mechanism responsible for the variation in CRIPTO levels, which is a regulation mediated by the transcriptional factor AP-1.

Vyšlo v časopise: Genetic Variants Modulating CRIPTO Serum Levels Identified by Genome-Wide Association Study in Cilento Isolates. PLoS Genet 11(1): e32767. doi:10.1371/journal.pgen.1004976
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004976

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Zdroje

1. Shen MM, Schier AF (2000) The EGF-CFC gene family in vertebrate development. Trends Genet 16: 303–309. 10858660

2. Bianco C, Normanno N, Salomon DS, Ciardiello F (2004) Role of the cripto (EGF-CFC) family in embryogenesis and cancer. Growth Factors 22: 133–139. 15518236

3. Minchiotti G, Parisi S, Liguori GL, D’Andrea D, Persico MG (2002) Role of the EGF-CFC gene cripto in cell differentiation and embryo development. Gene 287: 33–37. 11992720

4. Minchiotti G, Parisi S, Liguori G, Signore M, Lania G, et al. (2000) Membrane-anchorage of Cripto protein by glycosylphosphatidylinositol and its distribution during early mouse development. Mech Dev 90: 133–142. 10640699

5. Brandt R, Normanno N, Gullick WJ, Lin JH, Harkins R, et al. (1994) Identification and biological characterization of an epidermal growth factor-related protein: cripto-1. J Biol Chem 269: 17320–17328. 8006041

6. Yan YT, Liu JJ, Luo Y, E C, Haltiwanger RS, et al. (2002) Dual roles of Cripto as a ligand and coreceptor in the nodal signaling pathway. Mol Cell Biol 22: 4439–4449. 12052855

7. Ding J, Yang L, Yan YT, Chen A, Desai N, et al. (1998) Cripto is required for correct orientation of the anterior-posterior axis in the mouse embryo. Nature 395: 702–707. 9790191

8. Xu C, Liguori G, Persico MG, Adamson ED (1999) Abrogation of the Cripto gene in mouse leads to failure of postgastrulation morphogenesis and lack of differentiation of cardiomyocytes. Development 126: 483–494. 9876177

9. Liguori GL, Echevarria D, Improta R, Signore M, Adamson E, et al. (2003) Anterior neural plate regionalization in cripto null mutant mouse embryos in the absence of node and primitive streak. Dev Biol 264: 537–549. 14651936

10. Liguori GL, Echevarria D, Bonilla S, D’Andrea D, Liguoro A, et al. (2009) Characterization of the functional properties of the neuroectoderm in mouse Cripto(-/-) embryos showing severe gastrulation defects. Int J Dev Biol 53: 549–557. doi: 10.1387/ijdb.082650gl 19247965

11. Wechselberger C, Ebert AD, Bianco C, Khan NI, Sun Y, et al. (2001) Cripto-1 enhances migration and branching morphogenesis of mouse mammary epithelial cells. Exp Cell Res 266: 95–105. 11339828

12. Watanabe K, Bianco C, Strizzi L, Hamada S, Mancino M, et al. (2007) Growth factor induction of Cripto-1 shedding by glycosylphosphatidylinositol-phospholipase D and enhancement of endothelial cell migration. J Biol Chem 282: 31643–31655. 17720976

13. Bianco C, Strizzi L, Ebert A, Chang C, Rehman A, et al. (2005) Role of human cripto-1 in tumor angiogenesis. J Natl Cancer Inst 97: 132–141. 15657343

14. Miharada K, Karlsson G, Rehn M, Rorby E, Siva K, et al. (2011) Cripto regulates hematopoietic stem cells as a hypoxic-niche-related factor through cell surface receptor GRP78. Cell Stem Cell 9: 330–344. doi: 10.1016/j.stem.2011.07.016 21982233

15. Wu C, Orozco C, Boyer J, Leglise M, Goodale J, et al. (2009) BioGPS: an extensible and customizable portal for querying and organizing gene annotation resources. Genome Biology 10. doi: 10.1186/gb-2009-10-12-115 20109167

16. Uhlen M, Bjorling E, Agaton C, Szigyarto CA, Amini B, et al. (2005) A human protein atlas for normal and cancer tissues based on antibody proteomics. Mol Cell Proteomics 4: 1920–1932. 16127175

17. Normanno N, De Luca A, Bianco C, Maiello MR, Carriero MV, et al. (2004) Cripto-1 overexpression leads to enhanced invasiveness and resistance to anoikis in human MCF-7 breast cancer cells. J Cell Physiol 198: 31–39. 14584041

18. Gong YP, Yarrow PM, Carmalt HL, Kwun SY, Kennedy CW, et al. (2007) Overexpression of Cripto and its prognostic significance in breast cancer: a study with long-term survival. Eur J Surg Oncol 33: 438–443. 17125961

19. Bianco C, Strizzi L, Mancino M, Rehman A, Hamada S, et al. (2006) Identification of cripto-1 as a novel serologic marker for breast and colon cancer. Clin Cancer Res 12: 5158–5164. 16951234

20. Jiang PC, Zhu L, Fan Y, Zhao HL (2013) Clinicopathological and biological significance of cripto overexpression in human colon cancer. World J Gastroenterol 19: 8630–8637. doi: 10.3748/wjg.v19.i46.8630 24379580

21. Friess H, Yamanaka Y, Buchler M, Kobrin MS, Tahara E, et al. (1994) Cripto, a member of the epidermal growth factor family, is over-expressed in human pancreatic cancer and chronic pancreatitis. Int J Cancer 56: 668–674. 8314343

22. Ertoy D, Ayhan A, Sarac E, Karaagaoglu E, Yasui W, et al. (2000) Clinicopathological implication of cripto expression in early stage invasive cervical carcinomas. Eur J Cancer 36: 1002–1007. 10885604

23. De Luca A, Lamura L, Strizzi L, Roma C, D’Antonio A, et al. (2011) Expression and functional role of CRIPTO-1 in cutaneous melanoma. Br J Cancer 105: 1030–1038. doi: 10.1038/bjc.2011.324 21863025

24. Wu Z, Li G, Wu L, Weng D, Li X, et al. (2009) Cripto-1 overexpression is involved in the tumorigenesis of nasopharyngeal carcinoma. BMC Cancer 9: 315. doi: 10.1186/1471-2407-9-315 19732464

25. Zhong XY, Zhang LH, Jia SQ, Shi T, Niu ZJ, et al. (2008) Positive association of up-regulated Cripto-1 and down-regulated E-cadherin with tumour progression and poor prognosis in gastric cancer. Histopathology 52: 560–568. doi: 10.1111/j.1365-2559.2008.02971.x 18312357

26. Miyoshi N, Ishii H, Mimori K, Sekimoto M, Doki Y, et al. (2010) TDGF1 is a novel predictive marker for metachronous metastasis of colorectal cancer. Int J Oncol 36: 563–568. 20126975

27. Tysnes BB, Satran HA, Mork SJ, Margaryan NV, Eide GE, et al. (2013) Age-Dependent Association between Protein Expression of the Embryonic Stem Cell Marker Cripto-1 and Survival of Glioblastoma Patients. Transl Oncol 6: 732–741. 24466376

28. Bianco C, Strizzi L, Normanno N, Khan N, Salomon DS (2005) Cripto-1: an oncofetal gene with many faces. Curr Top Dev Biol 67: 85–133. 15949532

29. Strizzi L, Bianco C, Normanno N, Seno M, Wechselberger C, et al. (2004) Epithelial mesenchymal transition is a characteristic of hyperplasias and tumors in mammary gland from MMTV-Cripto-1 transgenic mice. J Cell Physiol 201: 266–276. 15334661

30. Strizzi L, Bianco C, Hirota M, Watanabe K, Mancino M, et al. (2007) Development of leiomyosarcoma of the uterus in MMTV-CR-1 transgenic mice. J Pathol 211: 36–44. 17072826

31. Sun Y, Strizzi L, Raafat A, Hirota M, Bianco C, et al. (2005) Overexpression of human Cripto-1 in transgenic mice delays mammary gland development and differentiation and induces mammary tumorigenesis. Am J Pathol 167: 585–597. 16049342

32. Wechselberger C, Strizzi L, Kenney N, Hirota M, Sun Y, et al. (2005) Human Cripto-1 overexpression in the mouse mammary gland results in the development of hyperplasia and adenocarcinoma. Oncogene 24: 4094–4105. 15897912

33. Giorgio E, Liguoro A, D’Orsi L, Mancinelli S, Barbieri A, et al. (2014) Cripto haploinsufficiency affects in vivo colon tumor development. Int J Oncol 45: 31–40. doi: 10.3892/ijo.2014.2412 24805056

34. Adkins HB, Bianco C, Schiffer SG, Rayhorn P, Zafari M, et al. (2003) Antibody blockade of the Cripto CFC domain suppresses tumor cell growth in vivo. J Clin Invest 112: 575–587. 12925698

35. Bianco C, Salomon DS (2010) Targeting the embryonic gene Cripto-1 in cancer and beyond. Expert Opin Ther Pat 20: 1739–1749. doi: 10.1517/13543776.2010.530659 21073352

36. Klauzinska M, Castro NP, Rangel MC, Spike BT, Gray PC, et al. (2014) The multifaceted role of the embryonic gene Cripto-1 in cancer, stem cells and epithelial-mesenchymal transition. Semin Cancer Biol. doi: 10.1016/j.semcancer.2014.08.003 25153355

37. Pilgaard L, Mortensen JH, Henriksen M, Olesen P, Sorensen P, et al. (2014) Cripto-1 Expression in Glioblastoma Multiforme. Brain Pathol. doi: 10.1111/bpa.12241 25534128

38. Ciccodicola A, Dono R, Obici S, Simeone A, Zollo M, et al. (1989) Molecular characterization of a gene of the ‘EGF family’ expressed in undifferentiated human NTERA2 teratocarcinoma cells. EMBO J 8: 1987–1991. 2792079

39. Gray PC, Vale W (2012) Cripto/GRP78 modulation of the TGF-beta pathway in development and oncogenesis. FEBS Lett 586: 1836–1845. doi: 10.1016/j.febslet.2012.01.051 22306319

40. Gray PC, Shani G, Aung K, Kelber J, Vale W (2006) Cripto binds transforming growth factor beta (TGF-beta) and inhibits TGF-beta signaling. Mol Cell Biol 26: 9268–9278. 17030617

41. Nagaoka T, Karasawa H, Turbyville T, Rangel MC, Castro NP, et al. (2013) Cripto-1 enhances the canonical Wnt/beta-catenin signaling pathway by binding to LRP5 and LRP6 co-receptors. Cell Signal 25: 178–189. doi: 10.1016/j.cellsig.2012.09.024 23022962

42. Mancino M, Strizzi L, Wechselberger C, Watanabe K, Gonzales M, et al. (2008) Regulation of human Cripto-1 gene expression by TGF-beta1 and BMP-4 in embryonal and colon cancer cells. J Cell Physiol 215: 192–203. 17941089

43. Hamada S, Watanabe K, Hirota M, Bianco C, Strizzi L, et al. (2007) beta-Catenin/TCF/LEF regulate expression of the short form human Cripto-1. Biochem Biophys Res Commun 355: 240–244. 17291450

44. Bianco C, Cotten C, Lonardo E, Strizzi L, Baraty C, et al. (2009) Cripto-1 is required for hypoxia to induce cardiac differentiation of mouse embryonic stem cells. Am J Pathol 175: 2146–2158. doi: 10.2353/ajpath.2009.090218 19834060

45. Behrens AN, Ren Y, Ferdous A, Garry DJ, Martin CM (2012) Nkx2–5 Regulates Tdgf1 (Cripto) Early During Cardiac Development. J Clin Exp Cardiolog Suppl 11: 1–4. 24069547

46. Bianco C, Castro NP, Baraty C, Rollman K, Held N, et al. (2013) Regulation of human Cripto-1 expression by nuclear receptors and DNA promoter methylation in human embryonal and breast cancer cells. J Cell Physiol 228: 1174–1188. doi: 10.1002/jcp.24271 23129342

47. Hentschke M, Kurth I, Borgmeyer U, Hubner CA (2006) Germ cell nuclear factor is a repressor of CRIPTO-1 and CRIPTO-3. J Biol Chem 281: 33497–33504. 16954206

48. Chen F, Hou SK, Fan HJ, Liu YF (2014) MiR-15a-16 represses Cripto and inhibits NSCLC cell progression. Mol Cell Biochem 391: 11–19. doi: 10.1007/s11010-014-1981-y 24500260

49. Kotepui M, Thawornkuno C, Chavalitshewinkoon-Petmitr P, Punyarit P, Petmitr S (2012) Quantitative real-time RT-PCR of ITGA7, SVEP1, TNS1, LPHN3, SEMA3G, KLB and MMP13 mRNA expression in breast cancer. Asian Pac J Cancer Prev 13: 5879–5882. 23317273

50. Burghel GJ, Lin WY, Whitehouse H, Brock I, Hammond D, et al. (2013) Identification of candidate driver genes in common focal chromosomal aberrations of microsatellite stable colorectal cancer. PLoS One 8: e83859. doi: 10.1371/journal.pone.0083859 24367615

51. Ashktorab H, Daremipouran M, Goel A, Varma S, Leavitt R, et al. (2014) DNA methylome profiling identifies novel methylated genes in African American patients with colorectal neoplasia. Epigenetics 9: 503–512. doi: 10.4161/epi.27644 24441198

52. Ronneberg JA, Fleischer T, Solvang HK, Nordgard SH, Edvardsen H, et al. (2011) Methylation profiling with a panel of cancer related genes: association with estrogen receptor, TP53 mutation status and expression subtypes in sporadic breast cancer. Mol Oncol 5: 61–76. doi: 10.1016/j.molonc.2010.11.004 21212030

53. Lo SH, Janmey PA, Hartwig JH, Chen LB (1994) Interactions of tensin with actin and identification of its three distinct actin-binding domains. J Cell Biol 125: 1067–1075. 8195290

54. Chen H, Lo SH (2003) Regulation of tensin-promoted cell migration by its focal adhesion binding and Src homology domain 2. Biochem J 370: 1039–1045. 12495434

55. Chen H, Ishii A, Wong WK, Chen LB, Lo SH (2000) Molecular characterization of human tensin. Biochem J 351 Pt 2: 403–411. 11023826

56. Rhodes DR, Yu J, Shanker K, Deshpande N, Varambally R, et al. (2004) ONCOMINE: a cancer microarray database and integrated data-mining platform. Neoplasia 6: 1–6. 15068665

57. Hall EH, Daugherty AE, Choi CK, Horwitz AF, Brautigan DL (2009) Tensin1 requires protein phosphatase-1alpha in addition to RhoGAP DLC-1 to control cell polarization, migration, and invasion. J Biol Chem 284: 34713–34722. doi: 10.1074/jbc.M109.059592 19826001

58. Strizzi L, Postovit LM, Margaryan NV, Seftor EA, Abbott DE, et al. (2008) Emerging roles of nodal and Cripto-1: from embryogenesis to breast cancer progression. Breast Dis 29: 91–103. 19029628

59. She BR, Liou GG, Lin-Chao S (2002) Association of the growth-arrest-specific protein Gas7 with F-actin induces reorganization of microfilaments and promotes membrane outgrowth. Exp Cell Res 273: 34–44. 11795944

60. Gotoh A, Hidaka M, Hirose K, Uchida T (2013) Gas7b (growth arrest specific protein 7b) regulates neuronal cell morphology by enhancing microtubule and actin filament assembly. J Biol Chem 288: 34699–34706. doi: 10.1074/jbc.M113.513119 24151073

61. Ebinger M, Senf L, Wachowski O, Scheurlen W (2006) Expression of GAS7 in childhood CNS tumors. Pediatr Blood Cancer 46: 325–328. 16078223

62. Chang Y, Ueng SW, Lin-Chao S, Chao CC (2008) Involvement of Gas7 along the ERK1/2 MAP kinase and SOX9 pathway in chondrogenesis of human marrow-derived mesenchymal stem cells. Osteoarthritis Cartilage 16: 1403–1412. doi: 10.1016/j.joca.2008.03.018 18455446

63. Munroe DG, Gupta AK, Kooshesh F, Vyas TB, Rizkalla G, et al. (1999) Prototypic G protein-coupled receptor for the intestinotrophic factor glucagon-like peptide 2. Proc Natl Acad Sci U S A 96: 1569–1573. 9990065

64. Yusta B, Huang L, Munroe D, Wolff G, Fantaske R, et al. (2000) Enteroendocrine localization of GLP-2 receptor expression in humans and rodents. Gastroenterology 119: 744–755. 10982769

65. Lovshin J, Estall J, Yusta B, Brown TJ, Drucker DJ (2001) Glucagon-like peptide (GLP)-2 action in the murine central nervous system is enhanced by elimination of GLP-1 receptor signaling. J Biol Chem 276: 21489–21499. 11262390

66. Yusta B, Somwar R, Wang F, Munroe D, Grinstein S, et al. (1999) Identification of glucagon-like peptide-2 (GLP-2)-activated signaling pathways in baby hamster kidney fibroblasts expressing the rat GLP-2 receptor. J Biol Chem 274: 30459–30467. 10521425

67. Velazquez E, Ruiz-Albusac JM, Blazquez E (2003) Glucagon-like peptide-2 stimulates the proliferation of cultured rat astrocytes. Eur J Biochem 270: 3001–3009. 12846833

68. Lan L, Han H, Zuo H, Chen Z, Du Y, et al. (2010) Upregulation of myosin Va by Snail is involved in cancer cell migration and metastasis. Int J Cancer 126: 53–64. doi: 10.1002/ijc.24641 19521958

69. Colonna V, Nutile T, Ferrucci RR, Fardella G, Aversano M, et al. (2009) Comparing population structure as inferred from genealogical versus genetic information. Eur J Hum Genet 17: 1635–1641. doi: 10.1038/ejhg.2009.97 19550436

70. Colonna V, Nutile T, Astore M, Guardiola O, Antoniol G, et al. (2007) Campora: a young genetic isolate in South Italy. Hum Hered 64: 123–135. 17476112

71. Almasy L, Blangero J (1998) Multipoint quantitative-trait linkage analysis in general pedigrees. Am J Hum Genet 62: 1198–1211. 9545414

72. Li Y, Willer CJ, Ding J, Scheet P, Abecasis GR (2010) MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes. Genet Epidemiol 34: 816–834. doi: 10.1002/gepi.20533 21058334

73. Aulchenko YS, Ripke S, Isaacs A, van Duijn CM (2007) GenABEL: an R library for genome-wide association analysis. Bioinformatics 23: 1294–1296. 17384015

74. Aulchenko YS, Struchalin MV, van Duijn CM (2010) ProbABEL package for genome-wide association analysis of imputed data. BMC Bioinformatics 11: 134. doi: 10.1186/1471-2105-11-134 20233392

75. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, et al. (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81: 559–575. 17701901

76. Willer CJ, Li Y, Abecasis GR (2010) METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26: 2190–2191. doi: 10.1093/bioinformatics/btq340 20616382

77. Neter J (1996) Applied linear statistical models. Chicago; London: Irwin.

78. Ward LD, Kellis M (2012) HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res 40: D930–934. doi: 10.1093/nar/gkr917 22064851

79. Kajanne R, Miettinen P, Tenhunen M, Leppa S (2009) Transcription factor AP-1 promotes growth and radioresistance in prostate cancer cells. Int J Oncol 35: 1175–1182. 19787273

80. Pruim RJ, Welch RP, Sanna S, Teslovich TM, Chines PS, et al. (2010) LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics 26: 2336–2337. doi: 10.1093/bioinformatics/btq419 20634204