IGF1 mRNA isoform expression in the cervix of HPV-positive women with pre-cancerous and cancer lesions

Koczorowska,Maria   Magdalena; Kwasniewska,Anna; Gozdzicka-Jozefiak,Anna

doi:10.3892/etm.2010.174

IGF1 mRNA isoform expression in the cervix of HPV-positive women with pre-cancerous and cancer lesions

Authors:
- Maria Magdalena Koczorowska
- Anna Kwasniewska
- Anna Gozdzicka-Jozefiak
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Affiliations: Department of Molecular Virology, Adam Mickiewicz University, 61-614 Poznan, Poland, Department of Obstetrics and Gynecology, Medical University, 0-081 Lublin, Poland
Published online on: December 2, 2010 https://doi.org/10.3892/etm.2010.174
Pages: 149-156

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Abstract

Human papillomavirus (HPV) plays a crucial role in cervical cancer etiology. However, not all HPV-infected women develop cancer, indicating that additional cellular factors facilitate carcinogenesis. The aim of this study was to analyze the expression profile of insulin-like growth factor 1 (IGF1) isoforms in the context of FOX2, SP1 and IGF1 receptor (IGF1R) expression during HPV-dependent cervical carcinogenesis. One hundred and nine epithelial tissue samples from women with pre-cancerous and cancer lesions of the cervix were analyzed. HPV DNA was identified by PCR, and real-time PCR was used to quantify the expression levels of the analyzed genes. All IGF1 mRNA splicing isoforms were up-regulated in pre-cancerous cells, and a shift in the balance towards mitogenic IGF1Eb was observed in the cancer samples. IGF1 expression was controlled mainly by the P1 promoter, and an increase in P2 usage was observed in the cancer. Correlations between IGF1 mRNA splicing isoforms and the FOX2 splicing factor, as well as P1/P2 activity and SP1 transcription factor expression levels were detected. No correlation was observed between the expression of IGF1 and its receptor IGF1R. Our results suggest that IGF1, in particular its splicing profile, may be an additional prognostic factor in cervical carcinogenesis.

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1.	Doorbar J: Molecular biology of human papillomavirus infection and cervical cancer. Clin Sci. 110:525–541. 2006. View Article : Google Scholar : PubMed/NCBI
2.	Madkan VK, Cook-Norris RH, Steadman MC, Arora A, Mendoza N and Tyring SK: The oncogenic potential of human papillomaviruses: a review on the role of host genetics and environmental cofactors. Br J Dermatol. 157:228–241. 2007. View Article : Google Scholar : PubMed/NCBI
3.	Samani AA, Yakar S, LeRoith D and Brodt P: The role of the IGF system in cancer growth and metastasis: overview and recent insights. Endocr Rev. 28:20–47. 2007. View Article : Google Scholar : PubMed/NCBI
4.	Cohen P: Overview of the IGF-I system. Horm Res. 65(Suppl 1): 3–8. 2006. View Article : Google Scholar
5.	Pollak M: Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer. 8:915–928. 2008. View Article : Google Scholar : PubMed/NCBI
6.	Mittanck DW, Kim SW and Rotwein P: Essential promoter elements are located within the 5′ untranslated region of human insulin-like growth factor-I exon I. Mol Cell Endocrinol. 126:153–163. 1997.
7.	Wierstra I: Sp1: emerging roles – beyond constitutive activation of TATA-less housekeeping genes. Biochem Biophys Res Commun. 372:1–13. 2008.
8.	LeRoith D and Roberts CT Jr: The insulin-like growth factor system and cancer. Cancer Lett. 195:127–137. 2003. View Article : Google Scholar : PubMed/NCBI
9.	Musarò A, Dobrowolny G and Rosenthal N: The neuroprotective effects of a locally acting IGF-1 isoform. Exp Gerontol. 42:76–80. 2007.PubMed/NCBI
10.	Gee SL, Aoyagi K, Lersch R, Hou V, Wu M and Conboy JG: Alternative splicing of protein 4.1R exon 16: ordered excision of flanking introns ensures proper splice site choice. Blood. 95:692–699. 2000.PubMed/NCBI
11.	Baraniak AP, Chen JR and Garcia-Blanco A: Fox-2 mediates epithelial cell-specific fibroblast growth factor receptor 2 exon choice. Mol Cell Biol. 26:1209–1222. 2006. View Article : Google Scholar : PubMed/NCBI
12.	Zhang C, Zhang Z, Castle J, Sun S, Jahnson J, Krainer AR and Zhang MQ: Defining the regulatory network of the tissue-specific splicing factors FOX-1 and FOX-2. Genes Dev. 22:2550–2563. 2008. View Article : Google Scholar : PubMed/NCBI
13.	Jozefiak A, Pacholska-Bogalska J, Myga-Nowak M, Kedzia W, Kwasniewska A, Luczak M, Kedzia H and Gozdzicka-Jozefiak A: Serum and tissue levels of insulin-like growth factor-I in women with dysplasia and HPV-positive cervical cancer. Mol Med Rep. 1:231–237. 2008.PubMed/NCBI
14.	Serrano ML, Sánchez-Gómez M and Bravo MM: Insulin-like growth factor system gene expression in cervical scrapes from women with squamous intraepithelial lesions and cervical cancer. Growth Horm IGF Res. 17:492–499. 2007. View Article : Google Scholar : PubMed/NCBI
15.	Tan DS, Cook A and Chew SL: Nucleolar localization of an isoform of the IGF-I precursor. BMC Cell Biol. 3:172002. View Article : Google Scholar : PubMed/NCBI
16.	Tavassoli FA and Deville P; World Health Organization Classification of Tumors: Pathology, Genetics. Tumours of the Breast and Female Genital Organs. IRAC Press; Lyon: 2003
17.	Kosary CL: FIGO stage, histology, histologic grade, age and race as prognostic factors in determining survival for cancers of the female gynecological system: an analysis of 1973–87 SEER cases of cancers of the endometrium, cervix, ovary, vulva, and vagina. Semin Surg Oncol. 10:31–46. 1994.PubMed/NCBI
18.	Manos MM, Ting Y, Wright DK, Lewis AI, Broker TR and Wolinsky SM: The use of polymerase chain reaction amplification for the detection of genital human papillomaviruses. Cancer Cells. 7:209–214. 1989.
19.	Daud II and Scott ME: Validation of reference genes in cervical cell samples from human papillomavirus-infected and -uninfected women for quantitative reverse transcription-PCR assays. Clin Vaccine Immunol. 15:1369–1373. 2008. View Article : Google Scholar : PubMed/NCBI
20.	Philippou A, Papageorgiou E, Bogdanis G, Halapas A, Sourla A, Maridaki M, Pissimissis N and Koutsilieris M: Expression of IGF-1 isoforms after exercise-induced muscle damage in humans: characterization of the MGF E peptide actions in vitro. In Vivo. 23:567–575. 2009.PubMed/NCBI
21.	Matheny RW, Nindl BC and Adamo MI: Mechano-growth factor: a putative product of IGF 1 gene expression involved in tissue repair and regeneration. Endocrinology. 151:3865–3875. 2010. View Article : Google Scholar : PubMed/NCBI
22.	Barton ER: The ABC of IGF 1 isoforms: impact on muscle hypertrophy and implication for repair. Appl Physiol Nutr Metab. 31:791–797. 2006. View Article : Google Scholar : PubMed/NCBI
23.	Górecki DC, Beręsewicz M and Zabłocka B: Neuroprotective effects of short peptides derived from the insulin-like growth factor 1. Neurochem Int. 51:451–458. 2007.PubMed/NCBI
24.	Vinciquerra M, Santini MP, Claycomb WC, Ladurner AG and Rosenthal N: Local-IGF-1 isoform protects cardiomyocytes from hypertrophic and oxidative stresses via Sirt1 activity. Aging (Albany NY). 43–62. 2010.PubMed/NCBI
25.	Ohtsuki T, Otsuki M, Murakami Y, Maekowa T, Yamamoto T, Kasaka K, Takenchi S and Takahashi S: Organ-specific and age-dependent expression of insulin-like growth factor-I (IGF-I) mRNA variants: IGF-IA and IB mRNAs in the mouse. Zoolog Sci. 22:1011–1021. 2005. View Article : Google Scholar : PubMed/NCBI
26.	Pfeffer LA, Brisson BK, Lei H and Barton ER: The insulin-like growth factor (IGF)-I E-peptides modulate cell entry of the mature IGF-I protein. Mol Biol Cell. 20:3810–3817. 2009. View Article : Google Scholar : PubMed/NCBI
27.	Bell I, Martin A and Roberts S: The E1^E4 protein of human papillomavirus interacts with the serine-arginine-specific protein kinase SRPK1. J Virol. 81:5437–5448. 2007. View Article : Google Scholar : PubMed/NCBI
28.	Bodaghi S, Jia R and Zheng ZM: Human papillomavirus type 16 E2 and E6 are RNA-binding proteins and inhibit in vitro splicing of pre-mRNAs with suboptimal splice sites. Virology. 386:32–43. 2009. View Article : Google Scholar : PubMed/NCBI
29.	Cheunim T, Zhang J, Milligan SG, McPhillips MG and Graham SV: The alternative splicing factor hnRNP A1 is up-regulated during virus-infected epithelial cell differentiation and binds the human papillomavirus type 16 late regulatory element. Virus Res. 131:189–198. 2008. View Article : Google Scholar
30.	Mole S, McFarlane M, Chuen-Im T, Milligan SG, Millan D and Graham SV: RNA splicing factors regulated by HPV16 during cervical tumour progression. J Pathol. 219:383–391. 2009. View Article : Google Scholar : PubMed/NCBI
31.	Venables JP, Klinck R, Koh C, et al: Cancer-associated regulation of alternative splicing. Nat Struct Mol Biol. 16:670–676. 2009. View Article : Google Scholar : PubMed/NCBI
32.	Li T, Chen YH, Liu TJ, Jia J, Hampson S, Shan YX, Kibler D and Wang PH: Using DNA microarray to identify Sp1 as a transcriptional regulatory element of insulin-like growth factor 1 in cardiac muscle cells. Circ Res. 93:1202–1209. 2003. View Article : Google Scholar : PubMed/NCBI
33.	Gloss B and Bernard HU: The E6/E7 promoter of human papillomavirus type 16 is activated in the absence of E2 proteins by a sequence-aberrant Sp1 distal element. J Virol. 64:5577–5584. 1990.PubMed/NCBI
34.	McPhillips MG, Veerapraditsin T, Cumming SA, Karali D, Milligan SG, Boner W, Morgan IM and Graham SV: SF2/ASF binds the human papillomavirus type 16 late RNA control element and is regulated during differentiation of virus-infected epithelial cells. J Virol. 78:10598–10605. 2004. View Article : Google Scholar
35.	Li B, Wang X, Zhou F, Saunders NA, Frazer IH and Zhao KN: Up-regulated expression of Sp1 protein coincident with a viral protein in human and mouse differentiating keratinocytes may act as a cell differentiation marker. Differentiation. 76:1068–1080. 2008. View Article : Google Scholar
36.	Carboni JM, Lee AV, Hadsell DL, et al: Tumor development by transgenic expression of a constitutively active insulin-like growth factor I receptor. Cancer Res. 65:3781–3787. 2005. View Article : Google Scholar : PubMed/NCBI
37.	Linnerth NM, Siwicky MD, Campbell CI, Watson KL, Petrik JJ, Whitsett JA and Moorehead RA: Type I insulin-like growth factor receptor induces pulmonary tumorigenesis. Neoplasia. 11:672–682. 2009.PubMed/NCBI
38.	Chong YM, Colston K, Jiang WG, Sharma AK and Mokbel K: The relationship between the insulin-like growth factor-1 system and the oestrogen metabolising enzymes in breast cancer tissue and its adjacent non-cancerous tissue. Breast Cancer Res Treat. 99:275–288. 2006. View Article : Google Scholar : PubMed/NCBI
39.	Weber MM, Fottner C, Liu SB, Jung MC, Engelhardt D and Baretton GB: Overexpression of the insulin-like growth factor I receptor in human colon carcinomas. Cancer. 95:2086–2095. 2002. View Article : Google Scholar : PubMed/NCBI
40.	Werner H, Shalita-Chesner M, Abramovitch S, Idelman G, Shaharabani-Gargir L and Glaser T: Regulation of the insulin-like growth factor-I receptor gene by oncogenes and antioncogenes: implications in human cancer. Mol Genet Metab. 71:315–320. 2000. View Article : Google Scholar : PubMed/NCBI
41.	Kuramoto H, Hongo A, Liu Y, Ojima Y, Nahamura K, Seki N, Kodama J and Hiramatsu Y: Immunohistochemical evaluation of insulin-like growth factor 1, receptor status in cervical cancer specimens. Acta Medica Okayama. 62:251–259. 2008.PubMed/NCBI