Abstract
The programmed cell death 6 (PDCD6), discovered as a proapoptotic calcium-binding protein, has recently been found dysregulated in tumors of various origin and contributed to cancer cell viability. The aim of this study was to determine whether SNPs in PDCD6 are associated with cervical squamous cell carcinoma (CSCC). Polymerase chain reaction-restriction fragment length polymorphism method was used to genotype two tag SNPs (rs3756712 and rs4957014) of PDCD6 in 328 CSCC patients and 541 controls. Significantly increased CSCC risks were found to be associated with T allele of rs3756712 and G allele of rs4957014 (P = 0.017, OR = 1.320, and P = 0.007, OR = 1.321, respectively). CSCC risks were associated with these two SNPs in different genetic model (P = 0.04, OR = 1.78 for rs3756712 in a recessive model, and P = 0.006, OR = 2.01 for rs4957014 in a codominant model, respectively). Results of stratified analyses revealed that rs4957014 is associated with parametrial invasion of CSCC (P = 0.044, OR = 1.414). Our results suggest that these two tag SNPs of PDCD6 are associated with CSCC, indicating that PDCD6 may play an important role in the pathogenesis of CSCC.
Similar content being viewed by others
References
Forouzanfar MH, Foreman KJ, Delossantos AM et al (2011) Breast and cervical cancer in 187 countries between 1980 and 2010: a systematic analysis. Lancet 378(9801):1461–1484
Parkin DM, Whelan SL, Ferlay J, Teppo L, Thomas DB (2008) Cancer incidence in five continents. Volume IX. IARC scientific publications (160):1–837
Ko SM, Kua EH, Fones CS (1999) Stress and the undergraduates. Singapore Med J 40(10):627–630
Walboomers JM, Jacobs MV, Manos MM et al (1999) Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 189(1):12–19
Vink JM, van Kemenade FJ, Meijer CJ, Casparie MK, Meijer GA, Boomsma DI (2011) Cervix smear abnormalities: linking pathology data in female twins, their mothers and sisters. Eur J Hum Genet : EJHG 19(1):108–111
Magnusson PK, Sparen P, Gyllensten UB (1999) Genetic link to cervical tumours. Nature 400(6739):29–30
Couto E, Hemminki K (2006) Heritable and environmental components in cervical tumors. Int J Cancer 119(11):2699–2701
Ahlbom A, Lichtenstein P, Malmstrom H, Feychting M, Hemminki K, Pedersen NL (1997) Cancer in twins: genetic and nongenetic familial risk factors. J Natl Cancer Inst 89(4):287–293
de Freitas AC, Gurgel AP, Chagas BS, Coimbra EC, do Amaral CM (2012) Susceptibility to cervical cancer: an overview. Gynecol Oncol 126(2):304–311
Vito P, Lacana E, D’Adamio L (1996) Interfering with apoptosis: Ca2+-binding protein ALG-2 and Alzheimer’s disease gene ALG-3. Science 271(5248):521–525
Shibata H, Yamada K, Mizuno T et al (2004) The penta-EF-hand protein ALG-2 interacts with a region containing PxY repeats in Alix/AIP1, which is required for the subcellular punctate distribution of the amino-terminal truncation form of Alix/AIP1. J Biochem 135(1):117–128
Jung YS, Kim KS, Kim KD, Lim JS, Kim JW, Kim E (2001) Apoptosis-linked gene 2 binds to the death domain of Fas and dissociates from Fas during Fas-mediated apoptosis in Jurkat cells. Biochem Biophys Res Commun 288(2):420–426
Jang IK, Hu R, Lacana E, D’Adamio L, Gu H (2002) Apoptosis-linked gene 2-deficient mice exhibit normal T-cell development and function. Mol Cell Biol 22(12):4094–4100
Rao RV, Poksay KS, Castro-Obregon S et al (2004) Molecular components of a cell death pathway activated by endoplasmic reticulum stress. J Biol Chem 279(1):177–187
Mahul-Mellier AL, Hemming FJ, Blot B, Fraboulet S, Sadoul R (2006) Alix, making a link between apoptosis-linked gene-2, the endosomal sorting complexes required for transport, and neuronal death in vivo. J Neuroscience: Off J Soc Neurosci 26(2):542–549
Tarabykina S, Moller AL, Durussel I, Cox J, Berchtold MW (2000) Two forms of the apoptosis-linked protein ALG-2 with different Ca2+ affinities and target recognition. J Biol Chem 275(14):10514–10518
la Cour JM, Mollerup J, Winding P, Tarabykina S, Sehested M, Berchtold MW (2003) Up-regulation of ALG-2 in hepatomas and lung cancer tissue. Am J Pathol 163(1):81–89
la Cour JM, Hoj BR, Mollerup J, Simon R, Sauter G, Berchtold MW (2008) The apoptosis linked gene ALG-2 is dysregulated in tumors of various origin and contributes to cancer cell viability. Mol Oncol 1(4):431–439
Yamada Y, Arao T, Gotoda T et al (2008) Identification of prognostic biomarkers in gastric cancer using endoscopic biopsy samples. Cancer Sci 99(11):2193–2199
Hoj BR, la Cour JM, Mollerup J, Berchtold MW (2009) ALG-2 knockdown in HeLa cells results in G2/M cell cycle phase accumulation and cell death. Biochem Biophys Res Commun 378(1):145–148
Yoon JH, Choi YJ, Kim SG, Nam SW, Lee JY, Park WS (2012) Programmed cell death 6 (PDCD6) as a prognostic marker for gastric cancers. Tumour Biol 33(2):485–494
Su D, Xu H, Feng J et al (2012) PDCD6 is an independent predictor of progression free survival in epithelial ovarian cancer. J Transl Med 10:31
Ke X, Collins A, Ye S (2001) PIRA PCR designer for restriction analysis of single nucleotide polymorphisms. Bioinformatics 17(9):838–839
Sole X, Guino E, Valls J, Iniesta R, Moreno V (2006) SNPStats: a web tool for the analysis of association studies. Bioinformatics 22(15):1928–1929
Maki M, Suzuki H, Shibata H (2011) Structure and function of ALG-2, a penta-EF-hand calcium-dependent adaptor protein. Sci China Life Sci 54(8):770–779
Subramanian L, Crabb JW, Cox J et al (2004) Ca2+ binding to EF hands 1 and 3 is essential for the interaction of apoptosis-linked gene-2 with Alix/AIP1 in ocular melanoma. Biochemistry 43(35):11175–11186
Lo KW, Zhang Q, Li M, Zhang M (1999) Apoptosis-linked gene product ALG-2 is a new member of the calpain small subunit subfamily of Ca2+-binding proteins. Biochemistry 38(23):7498–7508
Maki M, Yamaguchi K, Kitaura Y, Satoh H, Hitomi K (1998) Calcium-induced exposure of a hydrophobic surface of mouse ALG-2, which is a member of the penta-EF-hand protein family. J Biochem 124(6):1170–1177
Missotten M, Nichols A, Rieger K, Sadoul R (1999) Alix, a novel mouse protein undergoing calcium-dependent interaction with the apoptosis-linked-gene 2 (ALG-2) protein. Cell Death Differ 6(2):124–129
Vito P, Pellegrini L, Guiet C, D’Adamio L (1999) Cloning of AIP1, a novel protein that associates with the apoptosis-linked gene ALG-2 in a Ca2+-dependent reaction. J Biol Chem 274(3):1533–1540
Trioulier Y, Torch S, Blot B et al (2004) Alix, a protein regulating endosomal trafficking, is involved in neuronal death. J Biol Chem 279(3):2046–2052
Mahul-Mellier AL, Strappazzon F, Petiot A et al (2008) Alix and ALG-2 are involved in tumor necrosis factor receptor 1-induced cell death. J Biol Chem 283(50):34954–34965
Lee JH, Rho SB, Chun T (2005) Programmed cell death 6 (PDCD6) protein interacts with death-associated protein kinase 1 (DAPk1): additive effect on apoptosis via caspase-3 dependent pathway. Biotechnol Lett 27(14):1011–1015
Venables JP (2004) Aberrant and alternative splicing in cancer. Cancer Res 64(21):7647–7654
Montaville P, Dai Y, Cheung CY et al (2006) Nuclear translocation of the calcium-binding protein ALG-2 induced by the RNA-binding protein RBM22. Biochim Biophys Acta 1763(11):1335–1343
Lee KH, Kim E, Lee JS, Lee KS, Kim JW (2001) Mapping of the interaction sites between apoptosis linked gene ALG-2 and HEED. Mol Cells 12(3):298–303
Aviel-Ronen S, Coe BP, Lau SK et al (2008) Genomic markers for malignant progression in pulmonary adenocarcinoma with bronchioloalveolar features. Proc Natl Acad Sci USA 105(29):10155–10160
Ambatipudi S, Gerstung M, Gowda R et al (2011) Genomic profiling of advanced-stage oral cancers reveals chromosome 11q alterations as markers of poor clinical outcome. PLoS One 6(2):e17250
Rho SB, Song YJ, Lim MC, Lee SH, Kim BR, Park SY (2012) Programmed cell death 6 (PDCD6) inhibits angiogenesis through PI3K/mTOR/p70S6K pathway by interacting of VEGFR-2. Cell Signal 24(1):131–139
Park SH, Lee JH, Lee GB et al (2012) PDCD6 additively cooperates with anti-cancer drugs through activation of NF-κB pathways. Cell Signal 24(3):726–733
Acknowledgments
This work was supported by the National Natural Science Foundation of China (No. 81172440, No. 81272821, No. 81172494 and No. 30901596); the Applied Basic Research Programs of Science and Technology Commission Foundation of Sichuan Province (No. 2013JY0008 and No. 2013JY0013); and Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT0935).
Conflict of interest
The authors declare that they have no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Additional information
Bin Zhou and Peng Bai have contributed equally to this work.
Rights and permissions
About this article
Cite this article
Zhou, B., Bai, P., Xue, H. et al. Single nucleotide polymorphisms in PDCD6 gene are associated with the development of cervical squamous cell carcinoma. Familial Cancer 14, 1–8 (2015). https://doi.org/10.1007/s10689-014-9767-7
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10689-014-9767-7