Immunohistochemical expression of insulin‑like growth factor‑1Ec in primary endometrial carcinoma: Association with PTEN, p53 and survivin expression

Stavropoulos,Aggelis; Varras,Michail; Philippou,Anastassios; Vasilakaki,Thivi; Varra,Viktoria-Konstantina; Varra,Fani-Niki; Tsavari,Aikaterini; Lazaris,Andreas C.; Koutsilieris,Michael

doi:10.3892/ol.2020.12258

Immunohistochemical expression of insulin‑like growth factor‑1Ec in primary endometrial carcinoma: Association with PTEN, p53 and survivin expression

Authors:
- Aggelis Stavropoulos
- Michail Varras
- Anastassios Philippou
- Thivi Vasilakaki
- Viktoria-Konstantina Varra
- Fani-Niki Varra
- Aikaterini Tsavari
- Andreas C. Lazaris
- Michael Koutsilieris
View Affiliations

Affiliations: Fourth Obstetrics and Gynecology Department, ‘Elena Venizelou’ General Hospital, Athens 11521, Greece, Fifth Obstetrics and Gynecology Department, ‘Elena Venizelou’ General Hospital, Athens 11521, Greece, Department of Physiology, Medical School, National Kapodistrian University, Athens 11527, Greece, Pathology Department, ‘Tzaneio’ General Hospital, Piraeus 18536, Greece, Pharmacy Department, University of Patras, Patra 26504, Greece, Pharmacy Department, Frederick University, Nicosia 1036, Cyprus, First Pathology Department, Medical School, National Kapodistrian University, Athens 11527, Greece
Published online on: October 29, 2020 https://doi.org/10.3892/ol.2020.12258
Article Number: 395
Copyright: © Stavropoulos et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Chronic hyperinsulinemia due to insulin resistance and elevated levels of insulin‑like growth factor (IGF)‑1 and IGF‑2 are suggestive of a significantly higher risk of endometrial carcinoma. There is a wealth of evidence showing differential expression of IGF‑1 isoforms in various types of cancer. In the present study, 99 archived endometrial carcinoma tissue sections were retrospectively assessed by immunohistochemistry for IGF‑1Ec isoform expression. Expression of IGF‑1Ec was also assessed in nine cases of non‑neoplastic endometrial tissue adjacent to the tumor, in 30 cases with normal endometrium and in 30 cases with endometrial hyperplasia. Furthermore, the association between IGF‑1Ec and the concurrent expression of phosphatase and tensin homologue deleted on chromosome 10 (PTEN), p53 or survivin was assessed, as well as their combined expression in association with clinicopathological variables. In endometrial carcinoma, IGF‑1Ec expression was high in non‑endometrioid carcinoma (serous papillary or clear cell carcinoma) compared with that in endometrioid adenocarcinoma. IGF‑1Ec expression was also high in the presence of tumoral necrosis. Furthermore, there was a significant correlation between the histological differentiation and the sum of staining intensity and the number of IGF‑1Ec immunopositive cells in endometrial carcinoma. There was a moderate negative correlation between co‑expression of IGF‑1Ec and PTEN, for both the number of immunopositive cells (P=0.006, ρ=‑0.343) and the sum of staining (scores and intensity; P=0.006, ρ=‑0.343). Furthermore, there was a positive correlation between the sum of staining (scores and intensity) and co‑expression of IGF‑1Ec and survivin (P=0.043, ρ=0.225). However, there was no association between concomitant expression of IGF‑1Ec and p53. These results emphasized the importance of IGF‑1Ec expression during development of non‑estrogen dependent endometrial adenocarcinoma. IGF‑1Ec and PTEN may function opposingly during endometrial carcinogenesis. By contrast, IGF‑1Ec and survivin may share common molecular pathways and may promote, in parallel, tumoral development.

View Figures

View References

1	Creasman WT, Odicine F, Maisonneuve P, Quinn MA, Beller U, Benedet JL, Heintz AP, Ngan HY and Pecorelli S: Carcinoma of the corpus uteri. FIGO 26th annual report on the results of treatment in gynecological cancer. Int J Gynaecol Obstet. 95 (Suppl 1):S105–S143. 2006. View Article : Google Scholar
2	Jemal A, Siegel R, Xu J and Ward E: Cancer statistics, 2010. CA Cancer J Clin. 60:277–300. 2010. View Article : Google Scholar : PubMed/NCBI
3	Doll A, Abal M, Rigau M, Monge M, Gonzalez M, Demajo S, Colás E, Llauradó M, Alazzouzi H, Planagumá J, et al: Novel molecular profiles of endometrial cancer-new light through old windows. J Steroid Biochem Mol Biol. 108:221–229. 2008. View Article : Google Scholar : PubMed/NCBI
4	Bray F, Dos Santos Silva I, Moller H and Weiderpass E: Endometrial cancer incidence trends in Europe: Underlying determinants and prospects for prevention. Cancer Epidemiol Biomarkers Prev. 14:1132–1142. 2005. View Article : Google Scholar : PubMed/NCBI
5	Kourea HP, Nikolaou M, Tzelepi V, Adonakis G, Kardamakis D, Tsapanos V, Scopa CD, Kalofonos C and Decavalas G: Expression of phosphorylated Akt, mTOR and MAPK in type I endometrial carcinoma: Clinical significance. Anticancer Res. 35:2321–2331. 2015.PubMed/NCBI
6	Shevra CR, Ghosh A and Kumar M: Cyclin D1 and Ki-67 expression in normal, hyperplastic and neoplastic endometrium. J Postgrad Med. 61:15–20. 2015. View Article : Google Scholar : PubMed/NCBI
7	Morice P, Leary A, Creutzberg C, Abu-Rustum N and Darai E: Endometrial cancer. Lancet. 387:1094–1108. 2016. View Article : Google Scholar : PubMed/NCBI
8	Takeshita S, Yamashita Y, Shiomi K, Suzuki N, Yoshida J, Naiki-Ito A, Suzuki S, Akatsuka S, Toyokuni S, Takahashi T, et al: Expression of P-REX2a is associated with poor prognosis in endometrial malignancies. Oncotarget. 9:24778–24786. 2018. View Article : Google Scholar : PubMed/NCBI
9	Bokhman JV: Two pathogenetic types of endometrial carcinoma. Gynecol Oncol. 15:10–17. 1983. View Article : Google Scholar : PubMed/NCBI
10	Parazzini F, La Vecchia C, Bocciolone L and Franceschi S: The epidemiology of endometrial cancer. Gynecol Oncol. 41:1–16. 1991. View Article : Google Scholar : PubMed/NCBI
11	Steiner E, Eicher O, Sagemuller J, Schmidt M, Pitch H, Tanner B, Hengstler JG, Hofmann M and Knapstein PG: Multivariate independent prognostic factors in endometrial carcinoma: A clinicopathological study in 181 patients: 10 experience at the department of obstetrics and gynecology of the mainz university. Int J Gynecol Cancer. 13:197–203. 2003. View Article : Google Scholar : PubMed/NCBI
12	Prat J: Prognostic parameters of endometrial carcinoma. Hum Pathol. 35:649–662. 2004. View Article : Google Scholar : PubMed/NCBI
13	Daughaday WH and Rotwein P: Insulin-like factors I and II. Peptide, messenger ribonucleic acid and gene structures, serum and tissue concentrations. Endocr Rev. 10:68–91. 1989. View Article : Google Scholar : PubMed/NCBI
14	De Meyts P and Whittaker J: Structural biology of insulin and IGF1 receptors: Implications for drug design. Nat Rev Drug Discov. 1:769–783. 2002. View Article : Google Scholar : PubMed/NCBI
15	Federici M, Porzio O, Zucaro L, Giovannone B, Borboni P, Marini MA, Lauro D and Sesti G: Increased abundance of insulin/IGF-I hybrid receptors in adipose tissue from NIDDM patients. Mol Cell Endocrinol. 135:41–47. 1997. View Article : Google Scholar : PubMed/NCBI
16	Nakae J, Kido Y and Accili D: Distinct and overlapping functions of insulin and IGF-I receptors. Endocr Rev. 22:818–835. 2001. View Article : Google Scholar : PubMed/NCBI
17	Baserga R, Peruzzi F and Reiss K: The IGF-1 receptor in cancer biology. Int J Cancer. 107:873–877. 2003. View Article : Google Scholar : PubMed/NCBI
18	Taguchi A and White MF: Insulin-like signaling, nutrient homeostasis, and life span. Annu Rev Physiol. 70:191–212. 2008. View Article : Google Scholar : PubMed/NCBI
19	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
20	Milingos DS, Philippou A, Armakolas A, Papageorgiou E, Sourla A, Protopapas A, Liapi A, Antsaklis A, Mastrominas M and Koutsilieris M: Insulin-like growth factor-1Ec (MGF) expression in eutropic and ectopic endometrium: Characterization of the MGF E-peptide actions in vitro. Mol Med. 17:21–28. 2011. View Article : Google Scholar : PubMed/NCBI
21	Jones JI and Clemmons DR: Insulin-like growth factors and their binding proteins: Biological actions. Endocr Rev. 13:3–34. 1995. View Article : Google Scholar
22	Majchrzak-Baczmańska D and Malinowski A: Does IGF-1 play a role in the biology of endometrial cancer? Ginekol Pol. 87:598–604. 2016. View Article : Google Scholar : PubMed/NCBI
23	Flannery CA, Saleh FL, Choe GH, Selen DJ, Kodaman PH, Kliman HJ, Wood TL and Taylor HS: Differential expression of IR-A, IR-B and IGF-1R in endometrial physiology and distinct signature in adenocarcinoma. J Clin Endocrinol Metab. 101:2883–2891. 2016. View Article : Google Scholar : PubMed/NCBI
24	Dai C, Li N, Song G, Yang Y and Ning X: Insulin-like growth factor 1 regulates growth of endometrial carcinoma through PI3k signaling pathway in insulin-resistant type 2 diabetes. Am J Transl Res. 8:3329–3336. 2016.PubMed/NCBI
25	Alexandraki KI, Philippou A, Boutzios G, Theohari I, Koutsilieris M, Delladetsima IK and Kaltsas GA: IGF-IEc expression is increased in secondary compared to primary foci in neuroendocrine neoplasms. Oncotarget. 8:79003–79011. 2017. View Article : Google Scholar : PubMed/NCBI
26	Mazerbourg S and Monget P: Insulin-like growth factor binding proteins and IGFBP proteases: A dynamic system regulating the ovarian folliculogenesis. Front Endocrinol (Lausanne). 9:1342018. View Article : Google Scholar : PubMed/NCBI
27	Rutanen EM, Nyman T, Lehtovirta P, Ammala M and Pekonen F: Suppressed expression of insulin-like growth factor binding protein-1 mRNA in the endometrium: A molecular mechanism associating endometrial cancer with its risk factors. Int J Cancer. 59:307–312. 1994. View Article : Google Scholar : PubMed/NCBI
28	Suvanto-Luukkonen E, Sundostrom H, Penttinen J, Kauppila A and Rutane EM: Insulin-like growth factor-binding protein-1: A biochemical marker of endometrial response to progestin during hormone replacement therapy. Maturitas. 22:255–262. 1995. View Article : Google Scholar : PubMed/NCBI
29	Vassilakos G, Philippou A, Tsakiroglou P and Koutsilieris M: Biological activity of the e domain of the IGF-1Ec as addressed by synthetic peptides. Hormones (Athens). 13:182–196. 2014. View Article : Google Scholar : PubMed/NCBI
30	Philippou A, Maridaki M, Pneumaticos S and Koutsilieris M: The complexity of the IGF1 gene splicing, posttranslational modification and bioactivity. Mol Med. 20:202–214. 2014. View Article : Google Scholar : PubMed/NCBI
31	Kornfeld S: Structure and function of the mannose-6-phosphate/insulinlike growth factor II receptors. Annu Rev Biochem. 61:307–330. 1992. View Article : Google Scholar : PubMed/NCBI
32	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
33	Baxter RC and Martin JL: Binding proteins for the insulin-like growth factors: Structure, regulation and function. Prog Growth Factor Res. 1:49–68. 1989. View Article : Google Scholar : PubMed/NCBI
34	Murphy LJ and Ghahary A: Uterine insulin-like growth factor-1: Regulation of expression and its role in estrogen-induced uterine proliferation. Endocr Rev. 11:443–453. 1990. View Article : Google Scholar : PubMed/NCBI
35	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
36	Mourmouras N, Philippou A, Christopoulos P, Kostoglou K, Grivaki C, Konstantinidis C, Serafetinides E, Delakas D and Koutsilieris M: Different expression of IGF-I transcripts in bladder cancer. Anticancer Res. 38:3453–3459. 2018. View Article : Google Scholar : PubMed/NCBI
37	Kelley KM, Oh Y, Gargosky SE, Gucev Z, Matsumoto T, Hwa V, Ng L, Simpson DM and Rosenfeld RG: Insulin-like growth factor-binding proteins (IBFBPs) and their regulatory dynamics. Int J Biochem Cell Biol. 28:619–637. 1996. View Article : Google Scholar : PubMed/NCBI
38	Clemmons DR: Insulin-like growth factor binding proteins and their role in controlling IGF actions. Cytokine Growth Factor Rev. 8:45–62. 1997. View Article : Google Scholar : PubMed/NCBI
39	Burroughs KD, Donn SE, Barrett JC and Taylor JA: Insulin-like growth factor-I: A key regulator of human cancer risk? J Natl Cancer Inst. 91:579–581. 1999. View Article : Google Scholar : PubMed/NCBI
40	Adamo ML, Ben-Hur H, LeReith D and Roberts CT Jr: Transcription initiation in the two leader exons of the rat IGF-1 gene occurs from disperse versus localized sites. Biochem Biophys Res Commun. 176:887–893. 1991. View Article : Google Scholar : PubMed/NCBI
41	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 : PubMed/NCBI
42	Adamo ML: Regulation of insulin-like growth factor I gene expression. Implications for normal and pathological growth. Diabetes Rev. 3:2–27. 1995.
43	Simmons JG, Van Wyk JJ, Hoyt EC and Lund PK: Multiple transcription start sites in the rat insulin-like growth factor-I gene give rise to IGF-I mRNAs that encode different IGF-I precursors and are processed differently in vitro. Growth Factors. 9:205–221. 1993. View Article : Google Scholar : PubMed/NCBI
44	Bell GI, Stempien MM, Fong NM and Rall LB: Sequences of liver cDNAs encoding two different mouse insulin-like growth factor 1 precursors. Nucleic Acids Res. 14:7873–7882. 1986. View Article : Google Scholar : PubMed/NCBI
45	Temmerman L, Slonimsky E and Rosenthal N: Class 2 IGF-1 isoforms are dispensabile for viability, growth and maintenance of IGF-1 serum levels. Growth Horm IGF Res. 20:255–263. 2010. View Article : Google Scholar : PubMed/NCBI
46	Matheny RW Jr, Nindl BC and Adamo ML: Minireview: Mechano-growth factor: A putative product of IGF-I gene expression involved in tissue repair and regeneration. Endocrinology. 151:865–875. 2010. View Article : Google Scholar : PubMed/NCBI
47	Kasprzak A, Szaflarski W, Szmeja J, Andrzejewska M, Przybyszewska W, Kaczmarek E, Koczorowska M, Kościński T, Zabel M and Drews M: Differential expression of IGF-1 mRNA isoforms in colorectal carcinoma and normal colon tissue. Int J Oncol. 42:305–316. 2013.PubMed/NCBI
48	Philippou A, Armakolas A and Koutsilieris M: Evidence for the possible biological significance of the igf-1 gene alternative splicing in prostate cancer. Front Endocrinol (Lausanne). 4:312013. View Article : Google Scholar : PubMed/NCBI
49	Jansen M, van Schaik FM, Richer AT, Bullock B, Woods DE, Gabbay KH, Nauubaum AL, Sussenbach JS and Van den Brande JL: Sequence of cDNA encoding human insulin-like growth factor I precursor. Nature. 306:609–611. 1983. View Article : Google Scholar : PubMed/NCBI
50	Brisson BK, Spinazzola J, Park S and Barton ER: Viral expression of insulin-like growth factor I E-peptide increases skeletal muscle mass but at the expense of strength. Am J Physiol Endocrinol Metab. 306:E965–E974. 2014. View Article : Google Scholar : PubMed/NCBI
51	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
52	Duguay SJ: Post-translational processing of insulin-like growth factors. Horm Metab Res. 31:43–49. 1999. View Article : Google Scholar : PubMed/NCBI
53	Barton ER: The ABCs of IGF-I isoforms: Impact on muscle hypertrophy and implications for repair. Appl Physiol Nutr Metab. 31:791–797. 2006. View Article : Google Scholar : PubMed/NCBI
54	Wallis M: New insulin-like growth factor (IGF)-precursor sequences from mammalian genomes: The molecular evolution of IGFs and associated peptides in primates. Growth Horm IGF Res. 19:12–23. 2009. View Article : Google Scholar : PubMed/NCBI
55	Siegfriend JM, Kasprzyk PG, Treston AM, Mulshine JL, Quinn KA and Cuttitta F: A mitogenic peptide amide encoded within the E peptide domain of the insulin-like growth factor IB prohormone. Proc Natl Acad Sci USA. 89:8107–8111. 1992. View Article : Google Scholar : PubMed/NCBI
56	Kuo YH and Chen TT: Novel activities of pro-IGF-I E peptides: Regulation of morphological differentiation and anchorage-independent growth in human neuroblastoma cells. Exp Cell Res. 280:75–89. 2002. View Article : Google Scholar : PubMed/NCBI
57	Chew SL, Lavender P, Clark AJ and Ross RJ: An alternatively spliced human insulin-like growth factor-1 transcript with hepatic tissue expression that diverts away from mitogenic IBE1 peptide. Endocrinology. 136:1939–1944. 1995. View Article : Google Scholar : PubMed/NCBI
58	Tian XC, Chen MJ, Pantschenko AG, Yang TJ and Chen TT: Recombinant E-peptides of pro-IGF-I have mitogenic activity. Endocrinology. 140:3387–3390. 1999. View Article : Google Scholar : PubMed/NCBI
59	Chen MJ, Chiou PP, Lin P, Lin CM, Siri S, Peck K and Chen TT: Suppression of growth and cancer-induced angiogenesis of aggressive human breast cancer cells (MDA-MB-231) on the chorionallantoic membrane of developing chicken embryos by E-peptide of pro-IGF-I. J Cell Biochem. 101:1316–1327. 2007. View Article : Google Scholar : PubMed/NCBI
60	Armakolas A, Dimakakos A, Loucogiannaki C, Armakolas N, Antonopoulos A, Florou C, Tsioli P, Papageorgiou E, Alexandrou TP, Stathaki M, et al: IL-6 is associated to IGF-1Ec upregulation and Ec peptide secretion, from prostate tumors. Mol Med. 24:62018. View Article : Google Scholar : PubMed/NCBI
61	Garrouste F, Remacle-Bonnet M, Fauriat C, Marvaldi J, Luis J and Pommier G: Prevention of cytokine-induced apoptosis by insulin-like growth factor-I is independent of cell adhesion molecules ijn HT29-D4 colon carcinoma cells-evidence for a NF-kappaB-dependent survival mechanism. Cell Death Differ. 9:768–779. 2002. View Article : Google Scholar : PubMed/NCBI
62	Alexia C, Fallot G, Lasfer M, Schweizer-Groyer G and Groyer A: An evaluation of the role of insulin-like growth factors (IGF) and of type-I IGF receptor signaling in hepatocarcinogenesis and in the resistance of hepatocarcinoma cells against drug-induced apoptosis. Biochem Pharmacol. 86:1003–1015. 2004. View Article : Google Scholar
63	Wang HS and Chard T: IGFs and IGF-binding proteins in the regulation of human ovarian and endometrial function. J Endocrinol. 161:1–13. 1999. View Article : Google Scholar : PubMed/NCBI
64	Bogdanos J, Karamanolakis D, Tenta R, Tsintavis A, Milathianakis C, Mitsiades C and Koutsilieris M: Endocrine/paracrine/autocrine survival factor activity of bone microenviroment participates in the development of androgen ablation and chemotherpay refractoriness of prostate cancer metastasis in skeleton. Endocr Relat Cancer. 10:279–289. 2003. View Article : Google Scholar : PubMed/NCBI
65	Koutsilieris M: Pathophysiology of uterine leiomyomas. Biochem Cell Biol. 70:273–278. 1992. View Article : Google Scholar : PubMed/NCBI
66	Koutsilieris M, Mitsiades C and Sourla A: Insulin-like growth factor I and urokinase-type plasminogen activator bioregulation system as a survival mechanism of prostate cancer cells in osteoblastic metastases: Development of anti-survival factor therapy for hormone-reflactory prostate cancer. Mol Med. 6:251–267. 2000. View Article : Google Scholar : PubMed/NCBI
67	Hernandez AV, Pasupuleti V, Benites-Zapata VA, Thota P, Deshpande A and Perez-Lopez FR: Insulin resistance and endometrial cancer risk: A systemic review and meta-analysis. Eur J Cancer. 51:2747–2758. 2015. View Article : Google Scholar : PubMed/NCBI
68	Pavelic J, Radakovic B and Pavelic K: Insulin-like growth factor 2 and its receptors (IGF 1R and IGF 2R/mannose 6-phospate) in endometrial adenocarcinoma. Gynecol Oncol. 105:727–735. 2007. View Article : Google Scholar : PubMed/NCBI
69	Stavropoulos A, Varras M, Vasilakaki T, Varra VK, Tsavari A, Varra FN, Nonni A, Kavantzas N and Lazaris AC: Expression of p53 and PTEN in human primary endometrial carcinomas: Clinicopathological and immunohistochemical analysis and study of their concomitant expression. Oncol Lett. 17:4575–4589. 2019.PubMed/NCBI
70	Stavropoulos A, Varras M, Vasilakaki T, Varra VK, Varra FN, Tsavari A, Nonni A, Kavantzas N and Lazaris AC: Expression of anti-apoptotic protein survivin in human endometrial carcinoma: Clinical and pathological correlations as a separate factor and in combination with concomitant PTEN and p53 expression. Oncol Lett. 20:1033–1054. 2020. View Article : Google Scholar : PubMed/NCBI
71	Galimi F, Torti D, Sassi F, Isella C, Corà D, Gastaldi S, Ribero D, Muratore A, Massucco P, Siatis D, et al: Genetic and expression analysis of MET, MACC1, and HGF in metastatic colorectal cancer: Response to met inhibition in patient xenografts and pathologic correlations. Clin Cancer Res. 17:3146–3156. 2011. View Article : Google Scholar : PubMed/NCBI
72	Li M, Xin X, Wu T, Hua T and Wang H and Wang H: Stromal cells of endometrial carcinoma promotes proliferation of epithelial cells through the HGF/c-Met/Akt signaling pathway. Tumour Biol. 36:6239–6248. 2015. View Article : Google Scholar : PubMed/NCBI
73	Harpaz N, Taboada S, Ko HM, Yu J, Yang Q, Xu H and Cao W: Expression of MACC1 and MET in inflammatory bowel disease-associated colonic neoplasia. Inflamm Bowel Dis. 20:703–711. 2014. View Article : Google Scholar : PubMed/NCBI
74	Zhang Q, Xu P, Lu Y and Dou H: Correlation of MACC1/c-Myc expression in endometrial carcinoma with clinical/pathlogical features or prognosis. Med Sci Monit. 24:4738–4744. 2018. View Article : Google Scholar : PubMed/NCBI
75	Yang E and Yan H: Expression of ELF5 in endometrial carcinoma tissues and its clinical significance. Oncol Lett. 16:3473–3480. 2018.PubMed/NCBI
76	Singh N, Hirschowitz L, Zaino R, Alvarado-Cabrero I, Duggan MA, Ali-Fehmi R, Euscher E, Hecht JL, Horn LC, Ioffe O, et al: Pathologic prognostic factors in endometrial carcinoma (other than tumor type and grade). Int J Gynecol Pathol. 38 (Suppl 1):S93–S113. 2019. View Article : Google Scholar : PubMed/NCBI
77	Sadlecki P, Bodnar M, Grabiec M, Marszalek A, Walentowicz P, Sokup A, Zegarska J and Walentowicz-Sadlecka M: The role of Hypoxia-inducible factor-1α, Glucose thransporter-1, (GLUT-1) and carbon anhydrase IX in endometrial cancer patients. Biomed Res Int. 2014:6168502014. View Article : Google Scholar : PubMed/NCBI
78	Liu F, Sun Y, Liu B, Lu J, Li H, Zhu H, Gao H, Zhou X and Chang H: Insulin-like growth factor-1 induces epithelial-mesenchymanl transition in hepatocellular carcinoma by activating survivin. Oncol Rep. 40:952–958. 2018.PubMed/NCBI
79	Bansal N, Yendluri V and Wenham RM: The molecular biology of endometrial cancers and the implications for pathogenesis, classification, and targeted therapies. Cancer Control. 16:8–13. 2009. View Article : Google Scholar : PubMed/NCBI
80	Llauradó M, Ruiz A, Majem B, Ertekin T, Colás E, Pedrola N, Devis L, Rigau M, Sequeiros T, Montes M, et al: Molecular bases of endometrial cancer: New roles for new actors in the diagnosis and the therapy of the disease. Mol Cell Endocrinol. 358:244–255. 2012. View Article : Google Scholar : PubMed/NCBI
81	Meng X, Dizon DS, Yang S, Wang X, Zhu D, Thiel KW and Leslie KK: Strategies for molecularly enhanced chemotherpay to achieve synthetic lethality in endometrial tumors with mutant p53. Obstet Gynecol Int. 2013:8281652013. View Article : Google Scholar : PubMed/NCBI
82	Sugihara T: Loss of adherens junction protein E-cadherin is a biomarker of high grade histology and poor prognosis in endometrial cancer. Ann Clin Lab Res. 4:12016. View Article : Google Scholar
83	Gómez-Macías GS, Garza-Rodríguez ML, Garza-Guajardo R, Monsiváis-Ovalle D, Ancer-Rodríguez J, Barrera-Saldaña HA and Barboza-Quintana O: Overexpression of the matrix metalloproteinase 11 gene is a potential biomarker for type 1 endometrial cancer. Oncol Lett. 16:1073–1078. 2018.PubMed/NCBI
84	Buchynska LG, Brieiva OV and Iurchenko NP: Assessment of HER-2/neu, c-MYC and CCNE1 gene copy number variations and protein expression in endometrial carcinomas. Exp Oncol. 41:138–143. 2019.PubMed/NCBI
85	Reaven GM: Banting lecture 1988. Role of insulin resistance in human disease. Diabetes. 37:1595–1607. 1988. View Article : Google Scholar : PubMed/NCBI
86	Lee DY and Lee TS: Associations between metabolic syndrome and gynecologic cancer. Obstet Gynecol Sci. 63:215–224. 2020. View Article : Google Scholar : PubMed/NCBI
87	Esposito K, Capuano A and Giugliano D: Metabolic syndrome and cancer: Holistic or reductionist? Endocrine. 45:362–364. 2014. View Article : Google Scholar : PubMed/NCBI
88	Esposito K, Chiodini P, Colao A, Lenzi A and Giugliano D: Metabolic syndrome and risk of cancer: A systematic review and meta-analysis. Diabetes Care. 35:2402–2411. 2012. View Article : Google Scholar : PubMed/NCBI
89	Trabert B, Wentzensen N, Felix AS, Yang HP, Sherman ME and Brinton LA: Metabolic syndrome and risk of endometrial cancer in the united states: A study in the SEER-medicare linked database. Cancer Epidemiol Biomarkers Prev. 24:261–267. 2015. View Article : Google Scholar : PubMed/NCBI
90	Jee SH, Kim HJ and Lee J: Obesity, insulin resistance and cancer risk. Yonsei Med J. 46:449–455. 2005. View Article : Google Scholar : PubMed/NCBI
91	van Kruijsdijk RC, van der Wall E and Visseren FL: Obesity and cancer: The role of dysfunctional adipose tissue. Cancer Epidemiol Biomarkers Prev. 18:2569–2578. 2009. View Article : Google Scholar : PubMed/NCBI
92	Iyengar NM, Hudis CA and Dannenberg AJ: Obesity and cancer: Local and systemic mechanisms. Annu Rev Med. 66:297–309. 2015. View Article : Google Scholar : PubMed/NCBI
93	Yagen JD and Davidson NE: Estrogen carcinogenesis in breast cancer. N Engl J Med. 354:270–282. 2006. View Article : Google Scholar : PubMed/NCBI
94	André F, Rigot V, Remacle-Bonnet M, Luis J, Pommier G and Marvaldi J: Protein kinases C-gamma and -delta are involved in insulin-like growth factor I-induced migration of colonic epithelial cells. Gastroenterology. 116:64–77. 1999. View Article : Google Scholar : PubMed/NCBI
95	André F, Rigot V, Thimonier J, Montixi C, Parat F, Pommier G, Marvaldi J and Luis J: Integrins and E-cadherin cooperate with IGF-I to induce migration of epithelial colonic cells. Int J Cancer. 83:497–505. 1999. View Article : Google Scholar : PubMed/NCBI
96	Akagi Y, Liu W, Zebrowski B, Xie K and Ellis LM: Regulation of vascular endothelial growth factor expression in human colon cancer by insulin-like growth factor-I. Cancer Res. 58:4008–4014. 1998.PubMed/NCBI
97	Wu Y, Yakar S, Zhao L, Hemminghausen L and LeRoith D: Circulating insulin-like growth factor-I levels regulate colon cancer growth and metastasis. Cancer Res. 62:1030–1035. 2002.PubMed/NCBI
98	Fader AN, Arriba LN, Frasure HE and von Gruenigen VE: Endometrial cancer and obesity: Epidiomiology, biomarkers, prevention and survivorship. Gynecol Oncol. 114:121–127. 2009. View Article : Google Scholar : PubMed/NCBI
99	Koczorowska MM, Kwasniewska A and Gozdzicka-Jozefiak A: IGF1 mRNA isoform expression in the cervix of HPV-positive woman with pre-cancerous and cancerous lesions. Exp Ther Med. 2:149–156. 2011. View Article : Google Scholar : PubMed/NCBI
100	Philippou A, Armakolas A, Pantleakou Z, Pissimissis N, Nezos A, Theos A, Kaparelou M, Armakolas N, Pneumaticos SG and Koutsilieris M: IGFF1Ec expression in MG-63 human osteoblast-like osteosarcoma cells. Anticancer Res. 31:4259–4265. 2011.PubMed/NCBI
101	McKoy G, Ashley W, Mander J, Yang SY, Williams N, Russell B and Goldspink G: Expression of insulin-like growth factor-1 splice variants and structural genes in rabbit skeletal muscle induced by stretch and stimulation. J Physiol. 516:583–592. 1999. View Article : Google Scholar : PubMed/NCBI
102	Hameed M, Orrell RW, Cobbold M, Goldspink G and Harridge SD: Expression of IGF-I splice variants in young and old human skeletal muscle after high resistance exercise. J Physiol. 547:247–254. 2003. View Article : Google Scholar : PubMed/NCBI
103	Hameed M, Lange KH, Andersen JL, Schjerling P, Kjaer M, Harrigde SD and Goldspink G: The effect of recombinant human growth hormone and resistance training of IGF-I mRNA expression in the muscles of elderly men. J Physiol. 555:231–240. 2004. View Article : Google Scholar : PubMed/NCBI
104	Bickel CS, Slade J, Mahoney E, Haddad F, Dudley GA and Adams GR: Time course of molecular responses of human skeletal muscle to acute bouts or resistance exercise. J Appl Physiol (1985). 98:482–488. 2005. View Article : Google Scholar : PubMed/NCBI
105	Kim JS, Cross JM and Bamman MM: Impact of resistance loading on myostatin expression and cell cycle regulation in young and older men and women. Am J Physiol Endocrinol Metab. 288:E1110–E1119. 2005. View Article : Google Scholar : PubMed/NCBI
106	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
107	Carpenter V, Matthews K, Devlin G, Stuart S, Jensen J, Conaglen J, Jeanplong F, Goldspink P, Yang SY, Goldspink G, et al: Mechano-growth factor reduces loss of cardiac function in acute myocardial infarction. Heart Lung Circ. 17:33–39. 2008. View Article : Google Scholar : PubMed/NCBI
108	Stavropoulou A, Halapas A, Sourla A, Philippou A, Papageorgiou E, Papalois A and Koutsilieris M: IGF-1 expression in infarcted myocardium and MGF E peptide actions in rat cardiomyocytes in vitro. Mol Med. 15:127–135. 2009. View Article : Google Scholar : PubMed/NCBI
109	Armakolas A, Philippou A, Panteleakou Z, Nezos A, Sourla A, Petraki C and Koutsilieris M: Preferential expression of IGF-IEc (MGF) transcript in cancerous tissues of human prostate: Evidence for a novel and autonomous growth factor activity of MGF E peptide in human prostate cancer cells. Prostate. 70:1233–1242. 2010. View Article : Google Scholar : PubMed/NCBI
110	Liu JP, Baker J, Perkins AS, Robertson EJ and Efstratiadis A: Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r). Cell. 75:59–72. 1993. View Article : Google Scholar : PubMed/NCBI
111	Siddle K, Ursø B, Niesler CA, Cope DL, Molina L, Surinya KH and Soos MA: Specificity in ligand binding and intracellular signaling by insulin and insulin-like growth factor receptors. Biochem Soc Trans. 29:513–525. 2001. View Article : Google Scholar : PubMed/NCBI
112	Laviola L, Natalicchio A and Giorgiono F: The IGF-I signaling pathway. Curr Pharm Des. 13:663–669. 2007. View Article : Google Scholar : PubMed/NCBI
113	Barton ER, Park S, James JK, Makarewich CA, Philippou A, Eletto D, Lei H, Brisson B, Ostrovsky O, Li Z and Argon Y: Deletion of muscle GRP94 impairs both muscle and body growth by inhibiting local IGF production. FASEB J. 26:3691–3702. 2012. View Article : Google Scholar : PubMed/NCBI
114	Wu JW, Boudreau DM, Park Y, Simonds NI and Freedman AN: Commonly used diabetes and cardiovascular medications and cancer recurrence and cancer-specific mortality: A review of the literature. Expert Opin Drug Saf. 13:1071–1099. 2014. View Article : Google Scholar : PubMed/NCBI
115	Zhang ZJ and Li S: The prognostic value of metformin for cancer patients with concurrent diabetes: A systematic review and meta-analysis. Diabetes Obes Metab. 16:707–710. 2014. View Article : Google Scholar : PubMed/NCBI
116	Bredholt G, Mannelqvist M, Stefansson IM, Birkeland E, Bø TH, Øyan AM, Trovik J, Kalland KH, Jonassen I, Salvesen HB, et al: Tumor necrosis is an important hallmark of aggressive endometrial cancer and associates with hypoxia, angiogenesis and inflammation responses. Oncotarget. 6:39676–39691. 2015. View Article : Google Scholar : PubMed/NCBI
117	Armakolas A, Kararelou M, Dimakakos A, Papageorgiou E, Armakolas N, Antonopoulos A, Petraki C, Lekarakou M, Lelovas P, Stathaki M, et al: Oncogenic role of the Ec peptide of the IGF-1Ec isoform in prostate cancer. Mol Med. 21:167–179. 2015. View Article : Google Scholar : PubMed/NCBI
118	Papageorgiou E, Philippou A, Armakolas A, Christopoulos PF, Dimakakos A and Koutsilieris M: The human Ec peptide: The active core of a progression growth factor with species-specific mode of action. Hormones (Athens). 15:423–434. 2016. View Article : Google Scholar : PubMed/NCBI
119	Karagiannis AK, Philippou A, Tseleni-Balafouta S, Zevolis E, Nakouti T, Tsopanomichalou-Gklotsou M, Psarras V and Koutsilieris M: IGF-IEc expression is associeted with advanced differentied thyroid cancer. Anticancer Res. 39:2811–2819. 2019. View Article : Google Scholar : PubMed/NCBI
120	Irwin JC, de las Fuentes L, Dsupin BA and Giudice LC: Insulin-like growth factor regulation of human endometrial stromal cell function: Coordinate effects on insulin-like growth factor binding protein-1, cell proliferation and prolactin secretion. Regul Pept. 48:165–177. 1993. View Article : Google Scholar : PubMed/NCBI
121	Tang XM, Rossi MJ, Mastrerson BJ and Chegini N: Insulin-like growth factor I (IGF-I), IGF-I receptors, and IGF binding proteins 1–4 in human uterine tissue: Tissue localization and IGF-I action in endometrial stromal and myometrial smooth muscle cells in vitro. Biol Reprod. 50:1113–1125. 1994. View Article : Google Scholar : PubMed/NCBI
122	Giudice LC, Dsupin BA, Jin IH, Vu TH and Hoffman AF: Differential expression of messenger ribonucleic acids encoding insulin-like growth factors and their receptors in human uterine endometrium and decidua. J Clin Endocrinol Metab. 76:1115–1122. 1993. View Article : Google Scholar : PubMed/NCBI
123	Zhou J, Dsupin BA, Giudice LC and Bondy CA: Insulin-like growth factor system gene expression in human endometrium during menstrual cycle. J Clin Endocrinol Metab. 79:1723–1734. 1994. View Article : Google Scholar : PubMed/NCBI
124	Laatikainen TJ, Toma EI and Voutilainen RJ: The expression of insulin-like growth factor and its binding protein RNA in the endometrium of postmenopausal patients with breast cancer receiving tamoxifen. Cancer. 76:1406–1410. 1995. View Article : Google Scholar : PubMed/NCBI
125	Elkas J, Gray K, Howard L, Petit N, Pohl J and Armstrong A: The effects of tamoxifen on endometrial insulin-like growth factor-1 expression. Obstet Gynecol. 91:45–50. 1998. View Article : Google Scholar : PubMed/NCBI
126	Mairano E, Loverro G, Viale G, Giannini T, Napoli A and Perlino E: Insulin-like growth factor-I expression in normal and diseased endometrium. Int J Cancer. 80:188–193. 1999. View Article : Google Scholar : PubMed/NCBI
127	O'Toole SA, Dunn E, Sheppard BL, Sheils O, O'Leary JJ, Wuttke W and Seidlova-Wuttke D: Oestrogen regulated gene expression in normal and malignant endometrial tissue. Maturitas. 51:187–198. 2005. View Article : Google Scholar : PubMed/NCBI
128	Bruchim I, Sarfstein R and Werner H: The IGF hormonal network in endometrial cancer: Functions, regulation, and targeting approaches. Front Endocrinol (Lausanne). 5:762014. View Article : Google Scholar : PubMed/NCBI
129	Soufla G, Sifakis S and Spandidos DA: FGF2 transcript levels are positively correlated with EGF and IGF-1 in the malignant endometrium. Cancer Lett. 259:146–155. 2008. View Article : Google Scholar : PubMed/NCBI
130	Pengchong H and Tao H: Expression of IGF-1R, VEGF-C and D2-40 and their correlation with lymph node metastasis in endometrial adenocarcinoma. Eur J Gynecol Oncol. 32:660–664. 2011.
131	Yi HK, Kim SY, Hwang PH, Kim CY, Yang DH, Oh Y and Lee DY: Impact of PTEN on the expression of insulin-like growth factors (IGFs) and IGF-binding proteins in human gastric adenocarcinoma cells. Biochem Biophys Res Commun. 330:760–767. 2005. View Article : Google Scholar : PubMed/NCBI
132	McCamplell AS, Broaddus RR, Loose DS and Davies PJ: Overexpression of the insulin-like growth factor I receptor and activation of the AKT pathway in hyperplastic endometrium. Clin Cancer Res. 12:6373–6378. 2006. View Article : Google Scholar : PubMed/NCBI
133	Dong L, Du M and Lv Q: Picropodophyllin inhibits type I endometrial cancer cell proliferation via disruption of the PI3K/Akt pathway. Acta Biochim Biophys Sin (Shanghai). 51:753–760. 2019. View Article : Google Scholar : PubMed/NCBI
134	Leung PS, Aronson WJ, Ngo TH, Golding LA and Barnard RJ: Exercise alters the IGF axis in vivo and increases p53 protein in prostate tumor cells in vitro. J Appl Physiol (1985). 96:450–454. 2004. View Article : Google Scholar : PubMed/NCBI
135	Tucci P: Caloric restriciton: Is mammalian life exptension linked to p53? Aging (Albany NY). 4:525–534. 2012. View Article : Google Scholar : PubMed/NCBI
136	Luo X, Jiang X, Li J, Bai Y, Li Z, Wei P, Sun S, Liang Y, Han S, Li X and Zhang B: Insulin-like growth factor-1 attenuates oxidative stress-induced hepatocyte premature senescence in liver fibrogenesis via regulating nuclear p53-progerin interaction. Cell Death Dis. 10:4512019. View Article : Google Scholar : PubMed/NCBI
137	Tran D, Bergholz J, Zhang H, He H, Wang Y, Zhang Y, Li Q, Kirkland JL and Xiao ZX: Insulin-like growth factor-1 regulates the SIRT1-p53 pathway in cellular senescence. Aging Cell. 13:669–678. 2014. View Article : Google Scholar : PubMed/NCBI
138	Attias-Geva Z, Bentov I, Kidrom D, Amichay K, Sarfstein R, Fishman A, Bruchim I and Werner H: p53 regulates insulin-like growth factor-I receptor gene expression in uterine serous carcinoma and predicts responsiveness to an insulin-like growth factor-I receptor-directed targeted therapy. Eur J Cancer. 48:1570–1580. 2012. View Article : Google Scholar : PubMed/NCBI
139	Altieri DC: Survivin, cancer networks and pathway-directed drug discovery. Nat Rev Cancer. 8:61–70. 2008. View Article : Google Scholar : PubMed/NCBI
140	Takai N, Miyazaki T, Nishida M, Nasu K and Miyakawa I: Survivin expression correlates with clinical stage, histological grade, invasive behavior and survival rate in endometrial carcinoma. Cancer Lett. 184:105–116. 2002. View Article : Google Scholar : PubMed/NCBI
141	Tran J, Master Z, Yu JL, Rak J, Dumont DJ and Kerbel RS: A role for survivin in chemoresistance of endothelial cells mediated by VEGF. Proc Natl Acad Sci USA. 99:4349–4354. 2002. View Article : Google Scholar : PubMed/NCBI
142	Altieri DC: Survivin, versatile modulation of cell division and apoptosis in cancer. Oncogene. 22:8581–8589. 2003. View Article : Google Scholar : PubMed/NCBI
143	Altieri DC: Survivin and apoptosis control. Adv Cancer Res. 88:31–35. 2003. View Article : Google Scholar : PubMed/NCBI
144	Mita AC, Mita MM, Nawrocki ST and Giles FJ: Survivin: Key regular of mitosis and apoptosis and novel target for cancer therapeutics. Clin Cancer Res. 14:5000–5005. 2008. View Article : Google Scholar : PubMed/NCBI
145	Liu X, Chen H, Hou Y, Ma X, Ye M, Huang R, Hu B, Cao H, Xu L, Liu M, et al: Adaptive EGF expression sensitizes pancreatic cancer cells to ionizing radiation through activation of the cyclin D1/P53/PARP pathway. Int J Oncol. 54:1466–1480. 2019.PubMed/NCBI
146	Vaira V, Lee CW, Goel HL, Bosari S, Languino LR and Altieri DC: Regulation of surivivn expression by IGF-I/mTOR signaling. Oncogene. 26:2678–2684. 2007. View Article : Google Scholar : PubMed/NCBI
147	Song K, Shankar E, Yang J, Bane KL, Wahdan-Alaswad R and Danielpour D: Critical role of a survivin/TGF-β/mTORC1 axis in IGF-I-mediated growth of prostate epithelial cells. PLoS One. 8:e618962013. View Article : Google Scholar : PubMed/NCBI
148	Sato A, Oya M, Ito K, Mizuno R, Horiguchi Y, Umezawa K, Hayakawa M and Murai M: Survivin associates with cell proliferation in renal cancer cells: Regulation of survivin expression by insulin-like growth factor-1, interferon-gamma and a novel NK-kappaB inhibitor. Int J Oncol. 28:841–846. 2006.PubMed/NCBI
149	Oh SH, Jin Q, Kim ES, Khuri FR and Lee HY: Insulin-like growth factor-I receptor signaling pathway induces resistance to the apoptotic activitis of SCH66336 (lonafarnib) through Akt/mammalian target of rapamycin-mediated increases in survivin expression. Clin Cancer Res. 14:1581–1589. 2008. View Article : Google Scholar : PubMed/NCBI
150	Morgillo F, Woo JK, Kim ES, Hong WK and Lee HY: Heterodimerization of insulin-like growth factor receptor/epidermal growth factor receptor and induction of survivin expression counteract the antitumor action of erlotinid. Cancer Res. 66:10100–10111. 2006. View Article : Google Scholar : PubMed/NCBI