Microsatellite polymorphism in the P1 promoter region of the IGF‑1 gene is associated with endometrial cancer

Kwasniewski,Wojciech; Gozdzicka‑Jozefiak,Anna; Wolun‑Cholewa,Maria; Polak,Grzegorz; Sierocinska‑Sawa,Jadwiga; Kwasniewska,Anna; Kotarski,Jan

doi:10.3892/mmr.2016.5181

Microsatellite polymorphism in the P1 promoter region of the IGF‑1 gene is associated with endometrial cancer

Authors:
- Wojciech Kwasniewski
- Anna Gozdzicka‑Jozefiak
- Maria Wolun‑Cholewa
- Grzegorz Polak
- Jadwiga Sierocinska‑Sawa
- Anna Kwasniewska
- Jan Kotarski
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Affiliations: Department of Gynecological Oncology and Gynecology, Medical University of Lublin, Lublin 20‑081, Poland, Department of Molecular Virology, Adam Mickiewicz University, Poznan 61‑614, Poland, Department of Cell Biology, Poznan University of Medical Sciences, Poznan 60‑806, Poland, Department of Pathomorphology, University Clinical Hospital 1, Lublin 20‑081, Poland, Department of Obstetrics and Gynecology, Medical University of Lublin, Lublin 20‑081, Poland
Published online on: April 25, 2016 https://doi.org/10.3892/mmr.2016.5181
Pages: 4950-4958
Copyright: © Kwasniewski et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Endometrial carcinoma (EC) is the most common type of gynecological malignancy. Studies have demonstrated that the insulin growth factor (IGF) pathway is implicated in the development of endometrial tumors and that the serum levels of IGF‑1 are affected by estrogen. Most EC cells with high microsatellite instability (MSI‑H) accumulate mutations at a microsatellite sequence in the IGF‑1 gene. The present study investigated the CA repeat polymorphism in the P1 promoter region of the IGF‑1 gene among Caucasian females with endometrial hyperplasia, EC and healthy control subjects, whose blood serum and surgical tissue specimens were analyzed. Differences or correlations between the analyzed parameters [serum levels of IGF-1 and IGF binding protein (IGFBP)‑1 and IGFBP‑3 as well as estrogens among the polymorphisms] were verified using the χ2, Mann-Whitney U, Kruskal-Wallis or Spearman’s rank correlation tests. A PCR amplification and DNA sequencing analysis was used for identification of (CA)n repeats in the P1 region of IGF‑1. ELISA was used to determine the blood serum levels of IGF‑1, IGFBP‑1, IGFBP‑3 and estrogens. Furthermore, IGF-1 was assessed in endometrial tissues by immunohistochemical analysis. The present study indicated no statistically significant differences between serum levels of IGF‑1, IGFBP‑1, IGFBP‑3 and estrone, estriol and estradiol in the control and study groups. A significant correlation was identified between the IGF-1 levels and estrone levels in the MSI-H polymorphism (r=-0.41, P=0.012) as well as a highly negative correlation between IGF-1 levels and the estradiol levels in the MSI-H polymorphism (r=-0.6, P=0.002). Genotypes without the 19 CA allele were predominantly found in EC. Furthermore, statistical analysis indicated that the number of IGF-1-expressing cells was significantly elevated in MSI-H type 18-20 (P=0.0072), MSI-L type 19-20 (P=0.025) and microsatellite-stable MSS type 19-19 (P=0.024) compared with those in the MSI-H 20-20 genotype. The present study suggested that it is rather likely that the polymorphisms in the IGF-1 promoter are associated with EC in Caucasian females with regard to its development. In the present study, polymorphisms of the IGF-1 promoter may have been introduced during the genesis of EC and contributed to it by leading to aberrant expression of IGF-1.

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1	Jemal A, Siegel R, Ward E, Hao Y, Xu J and Thun MJ: Cancer statistics, 2009. CA Cancer J Clin. 59:225–249. 2009. View Article : Google Scholar : PubMed/NCBI
2	Bokhman JV: Two pathogenetic types of endometrial carcinoma. Gynecol Oncol. 15:10–17. 1983. View Article : Google Scholar : PubMed/NCBI
3	Clemmons DR: Modifying IGF1 activity: An approach to treat endocrine disorders atherosclerosis and cancer. Nat Rev Drug Discov. 6:821–833. 2007. View Article : Google Scholar : PubMed/NCBI
4	Yu H and Rohan T: Role of the insulin-like growth factor family in cancer development and progression. J Natl Cancer Inst. 92:1472–1489. 2000. View Article : Google Scholar : PubMed/NCBI
5	Bruchim I, Sarfstein R and Werner H: The IGF hormonal network in endometrial cancer: Functions, regulation and targeting approaches. Front Endocrinol (Lausanne). 5:762014.
6	Walker MP, Diaugustine RP, Zeringue E, et al: An IGF1/insulin receptor substrate-1 pathway stimulate a mitotic kinase (cdk1) in the uterine epithelium during the proliferative response to estradiol. J Endocrinol. 207:225–235. 2010. View Article : Google Scholar : PubMed/NCBI
7	Enders GH and Maude SL: Traffic safety for the cell: Influence of cyclic-dependent kinase activity on genomic stability. Gene. 371:1–6. 2006. View Article : Google Scholar : PubMed/NCBI
8	Tang H, Liao Y, Xu L, Zhang C, Liu Z, Deng Y, Jiang Z, Fu S, Chen Z and Zhou S: Estrogen and insulin-like growth factor 1 synergistically promote the development of lung adenocarcinoma in mice. Int J Cancer. 133:2473–2482. 2013. View Article : Google Scholar : PubMed/NCBI
9	Rotwein P, Pollock KM, Didier DK and Krivi GG: Organization and sequence of the human insulin-like growth factor I gene. Alternative RNA processing produces two insulin-like growth factor I precursor peptides. J Biol Chem. 261:4828–4832. 1986.PubMed/NCBI
10	Adamo ML, Neuenschwander S, LeRoith D and Roberts CT Jr: Structure, expression and regulation of the IGF-I gene. Adv Exp Med Biol. 343:1–11. 1993. View Article : Google Scholar
11	Yu H, Li BD, Smith M, Shi R, Berkel HJ and Kato I: Polymorphic CA repeats in the IGF-I-gene and breast cancer. Breast Cancer Res Treat. 70:117–122. 2001. View Article : Google Scholar
12	Coletta RR, Jorge AA, D'Alva CB, Pinto EM, Billerbeck AE, Pachi PR, Longui CA, Garcia RM, Boguszewski M, Arnhold IJ, et al: Insulin-like growth factor 1 gene (CA)n repeats and a variable number of tandem repeats of the insulin gene in Brazilian children born small for gestational age. Clinics (SaoPaulo). 68:785–791. 2013. View Article : Google Scholar
13	Bläker H, Warth A, Kloor M and Schirmacher P: Chromosomal instability, microsatellite instability and CpG island methylator phenotype: Roles in small intestinal carcinogenesis. Pathologe. 32(Suppl 2): 181–184. 2011. View Article : Google Scholar
14	Avruch J: MAP kinase pathway: The first twenty years. Biochim Biophys Acta. 1773:1150–1160. 2007. View Article : Google Scholar : PubMed/NCBI
15	Rutanen EM: Insulin-like growth factors and insulin-like growth factor binding proteins in the endometrium. Effect of intrauterine levonorgestrel delivery. Hum Reprod. 15(Suppl 3): 173–181. 2000. View Article : Google Scholar : PubMed/NCBI
16	Creasman W: Revised FIGO staging for carcinoma of the endometrium. Int J Gynaecol Obstet. 105:1092009. View Article : Google Scholar : PubMed/NCBI
17	Kaczmarek M, Pacholska-Bogalska J, Kwaśniewski W, Kotarski J, Halerz-Nowakowska B and Goździka-Józefiak A: A microsatellite polymorphism in IGF1 gene promoter and timing of natural menopause in Caucasian women. Int J Med Sci. 12:32–41. 2015. View Article : Google Scholar : PubMed/NCBI
18	Bruchim I and Werner H: Targeting IGF-1 signaling pathways in gynecological malignancies. Expert Opin Ther Targets. 17:307–320. 2013. View Article : Google Scholar : PubMed/NCBI
19	Werner HM and Salvesen HB: Current status of molecular biomarkers in endometrial cancer. Curr Oncol Rep. 16:403–414. 2014. View Article : Google Scholar : PubMed/NCBI
20	Bruchim I, Sarfestein R and Werner H: The IGF hormonal network in endometrial cancer: Functions, regulation and targeting approaches. Front Endocrinol (Lausanne). 5:762014.
21	Pollak M: Insulin-like growth factor signaling in neoplasia. Nat Rev Cancer. 8:915–928. 2008. View Article : Google Scholar : PubMed/NCBI
22	Gunter MJ, Hoover DR, Herbert Yu, Wassertheil-Smoller S, Manson JE, Li J, Harris TG, Rohan TE, Xue X, Ho GY, et al: A prospective evaluation of insulin and insulin-like growth factor-I as risk factors for endometrial cancer. Cancer Epidemiol Biomarkers Prev. 17:921–929. 2008. View Article : Google Scholar : PubMed/NCBI
23	Ayabe I, Tsutsumi O, Sakai A, Yoshikawa H, Yano T, Kurimoto F and Taketani Y: Increased circulating levels of insulin-like growth factor-I and decreased circulating levels of insulin-like growth factor binding protein-1 in postmenoausal women endometrial cancer. Endocr J. 44:419–424. 1997. View Article : Google Scholar : PubMed/NCBI
24	Petridou E, Koukoulomatis P, Alexe DM, Voulgaris Z, Spanos E and Trichopoulos D: Endometrial cancer and the IGF system: A case-control study in Greece. Oncology. 64:341–345. 2003. View Article : Google Scholar : PubMed/NCBI
25	Cao Y, Nimptsch K, Shui IM, Platz EA, Wu K, Pollak MN, Kenfield SA, Stampfer MJ and Giovannucci EL: Prediagnostic plasma IGFBP-1, IGF-1 and risk of prostate cancer. Inter J Cancer. 10:2418–2426. 2015. View Article : Google Scholar
26	Ma J, Sawai H, Matsuo Y, Ochi N, Yasuda A, Takahashi H, Wakasugi T, Funahashi H, Sato M and Takeyama H: IGF-1 mediates PTEN suppression and enhances cell invasion and proliferation via activation of the IGF-1/PI3K/Akt signaling pathway in pancreatic cancer cells. J Surg Res. 160:90–101. 2010. View Article : Google Scholar
27	Cleveland RI, Gammon MD, Edmiston SN, Teitelbaum SL, Britton JA, Terry MB, Eng SM, Neugut AI, Santella RM and Conway K: IGF1 CA repeat polymorphisms, lifestyle factors and breast cancer risk in the long island breast cancer study project. Carcinogenesis. 27:758–765. 2006. View Article : Google Scholar
28	Rietveld I, Janssen J, Hofman A, Pols HA, van Duijn CM and Lamberts SW: A polymorphism in the IGF-1 gene influence the age-related decline in circulating total IGF-1 levels. Eur J Endocrinol. 148:171–175. 2003. View Article : Google Scholar : PubMed/NCBI
29	Jernström H, Chu W, Vesprini D, et al: Genetic factors related to racial variation in plasma levels of insulin-like growth factor 1: Implications for premenopausal breast cancer risk. Mol Genet Metab. 72:144–154. 2001. View Article : Google Scholar
30	Chrostopoulos PF, Msaouel P and Koutsilieris M: The role of the insulin-like growth factor-1 system in breast cancer. Mol Cancer. 14:432015. View Article : Google Scholar
31	Javadi M, Hematti S and Tavassoli M: Polymorphic CA repeat length in insulin-like growth factor 1 and risk of breast cancer in Iranian women. Med Oncol. 29:516–520. 2012. View Article : Google Scholar
32	Zecevic M, Amos CHI, Gu X, Campos IM, Jones JS, Lynch PM, Rodriguez-Bigas MA and Frazier ML: IGF1 gene polymorphism and risk for hereditary nonpolyposis colorectal cancer. J Natl Cancer Inst. 98:139–143. 2006. View Article : Google Scholar : PubMed/NCBI
33	Liang YJ, Hao Q, Zhang HM, Wu YZ and Wang JD: Insulin like growth factors in endometroid adenocarcinomas: Correlation with clinic-pathological features and estrogen receptor expression. BMC Cancer. 12:262–274. 2012. View Article : Google Scholar
34	Billard J, Grewal SS, Lukaeskol P, Stork PJ and Rotwein P: Hormonal control of insulin like growth factor 1 gene transcription in human osteoblasts: Dual actions of cAMP dependent protein kinase on CCAAT/enhancer-binding protein delta. J Biol Chem. 276:31238–31246. 2001. View Article : Google Scholar
35	Bender D, Buekers T and Leslie KK: Hormones and receptors in endometrial cancer. Proc Obstet Gyn. 2:1–25. 2011.
36	Groothuis PG, Dassen HH, Romano A and Punyadeera C: Estrogen and the endometrium: Lessons learned from gene expression profiling in rodents and human. Hum Reprod Update. 13:405–417. 2007. View Article : Google Scholar : PubMed/NCBI
37	Denduluri SK, Idowu O, Wang Z, Liao Z, Yan Z, Mohammed MK, Ye J, Wei Q, Wang J, Zhao L and Luu HH: Insulin-like growth factor (IGF) signaling in tumorigenesis and the development of cancer drug resistance. Genes Dis. 2:13–25. 2015. View Article : Google Scholar : PubMed/NCBI
38	Broniarczyk J, Kedzia A, Nowak W, Koscinski ł, Lewandowski M and Gozdzicka-Jozefiak A: Polymorphisms in the P1 promoter of the IGF-1 gene in children with growth disorders. Pediatr Endocrinol Diabetes Metab. 20:136–142. 2015. View Article : Google Scholar : PubMed/NCBI