Cervical Scrapes Levels of Insulin-like Growth Factor-II and Insulin-like Growth Factor Binding Protein 3 in Women with Squamous Intraepithelial Lesions and Cervical Cancer

Abstract

A growing number of studies have demonstrated an association between serum levels of insulin-like growth factors (IGFs) and IGF binding protein-3 (IGFBP-3) and increased risk for various cancers. The aim of this study was to evaluate the relationship between levels of IGF-II or IGFBP-3 in cervical scrapes with cervical cancer and precancerous lesions: low-grade squamous intraepithelial lesion (LSIL) and high-grade squamous intraepithelial lesion (HSIL). 4 groups of cases were examined: LSIL (n=20), HSIL (n=28), cervical cancer (n=45), and controls (n=51). Control subjects were women with normal, HPV DNA-negative Papanicolau (Pap) test. IGF-II and IGFBP-3 levels in cervical scrapes were measured by ELISA. Results show that median protein levels of IGF-II were significantly lower in cervical cancer cases vs. controls (446.5 ng/mg vs. 1 168.6 ng/mg, p<0.001). Significantly higher values of IGFBP-3 were found in HSIL vs. controls (median: 549.5 ng/mg vs. 216 ng/mg; p=0.018), and were not affected by HR HPV infection, meanwhile no significant differences were observed in IGFBP-3 levels between LSIL or cervical cancer as compared to controls. These data suggests that the progression to cervical cancer is associated with alterations in the IGF system and not affected by HR HPV infection. More studies are needed to understand the possible role of IGFBP-3 in cervical carcinogenesis.

Key words

low-grade squamous intraepithelial lesion (LSIL) - high-grade squamous intraepithelial lesion (HSIL) - pap smear - human papilloma virus (HPV) - Colombia

References

• 1 Parkin DM, Bray F, Ferlay J, Pisani P. Estimating the world cancer burden: Globocan 2000.  Int J Cancer. 2001;  94 153-156
• 2 International Agency for Research on cancer (IARC). . Globocan. Cancer incidence and mortality worldwide. IARC 1998; 
• 3 Walboomers JM, Jacobs MV, Manos MM, Bosch FX, Kummer JA, Shah KV, Snijders PJ, Peto J, Meijer CJ, Munoz N. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide.  J Pathol. 1999;  189 12-19
• 4 Solomon D, Davey D, Kurman R, Moriarty A, O’Connor D, Prey M, Raab S, Sherman M, Wilbur D, Wright Jr T, Young N. The 2001 Bethesda System: terminology for reporting results of cervical cytology.  JAMA. 2002;  287 2114-2119
• 5 Woodman CB, Collins S, Winter H, Bailey A, Ellis J, Prior P, Yates M, Rollason TP, Young LS. Natural history of cervical human papillomavirus infection in young women: a longitudinal cohort study.  Lancet. 2001;  357 1831-1836
• 6 Baserga R, Sell C, Porcu P, Rubini M. The role of the IGF-I receptor in the growth and transformation of mammalian cells.  Cell Prolif. 1994;  27 63-71
• 7 Werner H, LeRoith D. The role of the insulin-like growth factor system in human cancer.  Adv Cancer Res. 1996;  68 183-223
• 8 LeRoith D, Werner H, Beitner-Johnson D, Roberts Jr CT. Molecular and cellular aspects of the insulin-like growth factor I receptor.  Endocr Rev. 1995;  16 143-163
• 9 Ricort JM, Binoux M. Insulin-like growth factor (IGF) binding protein-3 inhibits type 1 IGF receptor activation independently of its IGF binding affinity.  Endocrinology. 2001;  142 108-113
• 10 Renehan AG, Harvie M, Howell A. Insulin-like growth factor (IGF)-I, IGF binding protein-3, and breast cancer risk: 8 years on.  Endocr Relat Cancer. 2006;  13 273-278
• 11 Renehan AG, Zwahlen M, Minder C, O’Dwyer ST, Shalet SM, Egger M. Insulin-like growth factor (IGF)-I, IGF binding protein-3, and cancer risk: systematic review and meta-regression analysis.  Lancet. 2004;  363 1346-1353
• 12 Roddam AW, Allen NE, Appleby P, Key TJ, Ferrucci L, Carter HB, Metter EJ, Chen C, Weiss NS, Fitzpatrick A, Hsing AW, Lacey Jr JV, Helzlsouer K, Rinaldi S, Riboli E, Kaaks R, Janssen JA, Wildhagen MF, Schroder FH, Platz EA, Pollak M, Giovannucci E, Schaefer C, Quesenberry Jr CP, Vogelman JH, Severi G, English DR, Giles GG, Stattin P, Hallmans G, Johansson M, Chan JM, Gann P, Oliver SE, Holly JM, Donovan J, Meyer F, Bairati I, Galan P. Insulin-like growth factors, their binding proteins, and prostate cancer risk: analysis of individual patient data from 12 prospective studies.  Ann Intern Med. 2008;  149 461-468
• 13 Trojan L, Bode C, Weiss C, Mayer D, Grobholz R, Alken P, Michel MS. IGF-II serum levels increase discrimination between benign prostatic hyperplasia and prostate cancer and improve the predictive value of PSA in clinical staging.  Eur Urol. 2006;  49 286-292
• 14 Espelund U, Cold S, Frystyk J, Orskov H, Flyvbjerg A. Elevated free IGF2 levels in localized, early-stage breast cancer in women.  Eur J Endocrinol. 2008;  159 595-601
• 15 Kim K, Visintin I, Alvero AB, Mor G. Development and validation of a protein-based signature for the detection of ovarian cancer.  Clin Lab Med. 2009;  29 47-55
• 16 Serrano ML, Romero A, Cendales R, Sánchez-Gómez M, Bravo MM. Serum levels of insulin-like growth factor-I and -II and insulin-like growth factor binding protein 3 in women with squamous intraepithelial lesions and cervical cancer.  Biomedica. 2006;  26 258-268
• 17 Steigen SE, Schaeffer DF, West RB, Nielsen TO. Expression of insulin-like growth factor 2 in mesenchymal neoplasms.  Mod Pathol. 2009;  22 914-921
• 18 Tennant MK, Thrasher JB, Twomey PA, Drivdahl RH, Birnbaum RS, Plymate SR. Protein and messenger ribonucleic acid (mRNA) for the type 1 insulin-like growth factor (IGF) receptor is decreased and IGF-II mRNA is increased in human prostate carcinoma compared to benign prostate epithelium.  J Clin Endocrinol Metab. 1996;  81 3774-3782
• 19 Brady G, Crean SJ, Naik P, Kapas S. Upregulation of IGF-2 and IGF-1 receptor expression in oral cancer cell lines.  Int J Oncol. 2007;  31 875-881
• 20 Hewish M, Chau I, Cunningham D. Insulin-like growth factor 1 receptor targeted therapeutics: novel compounds and novel treatment strategies for cancer medicine.  Recent Pat Anticancer Drug Discov. 2009;  4 54-72
• 21 Steller MA, Delgado CH, Bartels CJ, Woodworth CD, Zou Z. Overexpression of the insulin-like growth factor-1 receptor and autocrine stimulation in human cervical cancer cells.  Cancer Res. 1996;  56 1761-1765
• 22 Hirano S, Ito N, Takahashi S, Tamaya T. Clinical implications of insulin-like growth factors through the presence of their binding proteins and receptors expressed in gynecological cancers.  Eur J Gynaecol Oncol. 2004;  25 187-191
• 23 Berger AJ, Baege A, Guillemette T, Deeds J, Meyer R, Disbrow G, Schlegel R, Schlegel R. Insulin-like growth factor-binding protein 3 expression increases during immortalization of cervical keratinocytes by human papillomavirus type 16 E6 and E7 proteins.  Am J Pathol. 2002;  161 603-610
• 24 Baege AC, Disbrow GL, Schlegel R. IGFBP-3, a marker of cellular senescence, is overexpressed in human papillomavirus-immortalized cervical cells and enhances IGF-1-induced mitogenesis.  J Virol. 2004;  78 5720-5727
• 25 Saiki RK, Scharf S, Faloona F, Mullis KB, Horn GT, Erlich HA, Arnheim N. Enzymatic amplification of beta-globin genomic sequences and restriction site analysis for diagnosis of sickle cell anemia.  Science. 1985;  230 1350-1354
• 26 Molano M, Posso H, Weiderpass E, van den Brule AJ, Ronderos M, Franceschi S, Meijer CJ, Arslan A, Munoz N. Prevalence and determinants of HPV infection among Colombian women with normal cytology.  Br J Cancer. 2002;  87 324-333
• 27 Jacobs MV, Snijders PJ, van den Brule AJ, Helmerhorst TJ, Meijer CJ, Walboomers JM. A general primer GP5+/GP6(+)-mediated PCR-enzyme immunoassay method for rapid detection of 14 high-risk and 6 low-risk human papillomavirus genotypes in cervical scrapings.  J Clin Microbiol. 1997;  35 791-795
• 28 Pollak M. Insulin and insulin-like growth factor signalling in neoplasia.  Nat Rev Cancer. 2008;  8 915-928
• 29 Serrano ML, Sánchez-Gómez M, Bravo MM, Yakar S, LeRoith D. Differential expression of IGF-I and insulin receptor isoforms in HPV positive and negative human cervical cancer cell lines.  Horm Metab Res. 2008;  40 661-667
• 30 Serrano ML, Sanchez-Gomez M, 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. 2007;  17 492-499
• 31 Tennant MK, Thrasher JB, Twomey PA, Drivdahl RH, Birnbaum RS, Plymate SR. Protein and messenger ribonucleic acid (mRNA) for the type 1 insulin-like growth factor (IGF) receptor is decreased and IGF-II mRNA is increased in human prostate carcinoma compared to benign prostate epithelium.  J Clin Endocrinol Metab. 1996;  81 3774-3782
• 32 Haselbacher GK, Irminger JC, Zapf J, Ziegler WH, Humbel RE. Insulin-like growth factor II in human adrenal pheochromocytomas and Wilms tumors: expression at the mRNA and protein level.  Proc Natl Acad Sci USA. 1987;  84 1104-1106
• 33 Hultberg BM, Haselbacher G, Nielsen FC, Wulff BS, Gammeltoft S. Gene expression of insulin-like growth factor II in human intracranial meningioma.  Cancer. 1993;  72 3282-3286
• 34 Liao B, Hu Y, Herrick DJ, Brewer G. The RNA-binding protein IMP-3 is a translational activator of insulin-like growth factor II leader-3 mRNA during proliferation of human K562 leukemia cells.  J Biol Chem. 2005;  280 18517-18524
• 35 Gu L, Shigemasa K, Ohama K. Increased expression of IGF II mRNA-binding protein 1 mRNA is associated with an advanced clinical stage and poor prognosis in patients with ovarian cancer.  Int J Oncol. 2004;  24 671-678
• 36 Fujimoto T, Nishikawa A, Iwasaki M, Akutagawa N, Teramoto M, Kudo R. Gene expression profiling in 2 morphologically different uterine cervical carcinoma cell lines derived from a single donor using a human cancer cDNA array.  Gynecol Oncol. 2004;  93 446-453
• 37 Achary MP, Jaggernauth W, Gross E, Alfieri A, Klinger HP, Vikram B. Cell lines from the same cervical carcinoma but with different radiosensitivities exhibit different cDNA microarray patterns of gene expression.  Cytogenet Cell Genet. 2000;  91 39-43

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