IGFBP-rP1 acts as a potential tumor suppressor via the suppression of ERK signaling pathway in endometrial cancer cells

Ma,Yu; Jiang,Jue; Zhang,Yan; Ding,Yi; Xu,Ting; Lu,Bingjian

doi:10.3892/mmr.2017.6713

IGFBP-rP1 acts as a potential tumor suppressor via the suppression of ERK signaling pathway in endometrial cancer cells

Authors:
- Yu Ma
- Jue Jiang
- Yan Zhang
- Yi Ding
- Ting Xu
- Bingjian Lu
View Affiliations

Affiliations: Department of Clinical Laboratory, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, P.R. China, Institute of Bioinformatics, School of Agriculture and Biological Technology, Zhejiang University, Hangzhou, Zhejiang 310029, P.R. China, Department of Clinical Laboratory, Yiwu Hospital, School of Medicine, Zhejiang University, Yiwu, Zhejiang 322000, P.R. China, Department of Surgical Pathology, The Affiliated Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, P.R. China
Published online on: June 7, 2017 https://doi.org/10.3892/mmr.2017.6713
Pages: 1445-1450

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

Insulin-like growth factor binding protein-related protein 1 (IGFBP-rP1) is a potential tumor‑suppressor gene in various cancers. However, its biological role and underlying mechanism has not been well investigated in endometrial cancer yet. The aim of the present study aimed to investigate the role and underlying molecular mechanisms of IGFBP‑rP1 in endometrial cancer cells in vitro. The authors used transfection of IGFBP‑rP1 or small interfering (si)RNA in endometrial cancer HEC‑1A or Ishikawa cells, respectively. Biological functional alterations, such as cell growth and cell cycle were analyzed in endometrial cancer cells, combined with the use of PD98059. A panel of proteins including phospho‑retinoblastoma (p‑RB) and p‑extracellular signal‑regulated kinase (ERK)/ERK were detected by western blot analysis. It was observed that IGFBP‑rP1 transfection inhibited cell growth, and induced G1 phase arrest and cellular senescence in HEC‑1A cells while gene silencing presented the adverse functional changes. Moreover, p‑RB and p‑ERK were significantly downregulated or upregulated in HEC‑1A‑IGFBP‑rP1 cells or Ishikawa‑siRNA (IGFBP‑rP1) compared with control cells, respectively. These observations were reinforced in endometrial cancer cells by PD98059 treatment. The authors conclude that IGFBP‑rP1 acts as a potential tumor suppressor via the suppression of the ERK signaling pathway in endometrial cancer cells. These findings suggested that IGFBP‑rP1 may serve as a potential therapeutic target for cancer intervention in the future.

View Figures

View References

1	Kitson SJ, Evans DG and Crosbie EJ: Identifying high-risk women for endometrial cancer prevention strategies: Proposal of an endometrial cancer risk prediction model. Cancer Prev Res (Phila). 10:1–13. 2017. View Article : Google Scholar : PubMed/NCBI
2	Wei KR, Chen WQ, Zhang SW, Zheng RS, Wang YN and Liang ZH: Epidemiology of uterine corpus cancer in some cancer registering areas of China from 2003–2007. Zhonghua Fu Chan Ke Za Zhi. 47:445–451. 2012.(In Chinese). PubMed/NCBI
3	Esposito K, Chiodini P, Capuano A, Bellastella G, Maiorino MI and Giugliano D: Metabolic syndrome and endometrial cancer: A meta-analysis. Endocrine. 45:28–36. 2014. View Article : Google Scholar : PubMed/NCBI
4	Bruchim I, Sarfstein R and Werner H: The IGF hormonal network in endometrial cancer: Functions, regulation, and targeting approaches. Front Endocrinol (Lausanne). 5:762014.PubMed/NCBI
5	McGrath M, Lee IM, Buring J and De Vivo I: Common genetic variation within IGFI, IGFII, IGFBP-1, and IGFBP-3 and endometrial cancer risk. Gynecol Oncol. 120:174–178. 2011. View Article : Google Scholar : PubMed/NCBI
6	Yamanaka Y, Wilson EM, Rosenfeld RG and Oh Y: Inhibition of insulin receptor activation by insulin-like growth factor binding proteins. J Biol Chem. 272:30729–30734. 1997. View Article : Google Scholar : PubMed/NCBI
7	Ricort JM: Insulin-like growth factor binding protein (IGFBP) signalling. Growth Horm IGF Res. 14:277–286. 2004. View Article : Google Scholar : PubMed/NCBI
8	Hwa V, Oh Y and Rosenfeld RG: The insulin-like growth factor-binding protein (IGFBP) superfamily. Endocr Rev. 20:761–787. 1999. View Article : Google Scholar : PubMed/NCBI
9	Oh Y, Nagalla SR, Yamanaka Y, Kim HS, Wilson E and Rosenfeld RG: Synthesis and characterization of insulin-like growth factor-binding protein (IGFBP)-7. Recombinant human mac25 protein specifically binds IGF-I and -II. J Biol Chem. 271:30322–30325. 1996. View Article : Google Scholar : PubMed/NCBI
10	Zhan Y, Wang J, Ma Y, Liu Z, Xu H, Lu S and Lu B: Serum insulin-like, growth factor binding protein-related protein 1 (IGFBP-rP1) and endometrial cancer risk in Chinese women. Int J Cancer. 132:411–416. 2013. View Article : Google Scholar : PubMed/NCBI
11	Serafim MK, Silva GM, Duarte AB, Araújo VR, Silva TF, Lima AK, Chaves RN, Campello CC, Silva LD and Figueiredo JR: High insulin concentrations promote the in vitro growth and viability of canine preantral follicles. Reprod Fertil Dev. 25:927–934. 2013. View Article : Google Scholar : PubMed/NCBI
12	Chen Y, Pacyna-Gengelbach M, Ye F, Knösel T, Lund P, Deutschmann N, Schlüns K, Kotb WF, Sers C, Yasumoto H, et al: Insulin-like growth factor binding protein-related protein 1 (IGFBP-rP1) has potential tumour-suppressive activity in human lung cancer. J Pathol. 211:431–438. 2007. View Article : Google Scholar : PubMed/NCBI
13	Vizioli MG, Sensi M, Miranda C, Cleris L, Formelli F, Anania MC, Pierotti MA and Greco A: IGFBP7: An oncosuppressor gene in thyroid carcinogenesis. Oncogene. 29:3835–3844. 2010. View Article : Google Scholar : PubMed/NCBI
14	Benatar T, Yang W, Amemiya Y, Evdokimova V, Kahn H, Holloway C and Seth A: IGFBP7 reduces breast tumor growth by induction of senescence and apoptosis pathways. Breast Cancer Res Treat. 133:563–573. 2012. View Article : Google Scholar : PubMed/NCBI
15	Chen D, Yoo BK, Santhekadur PK, Gredler R, Bhutia SK, Das SK, Fuller C, Su ZZ, Fisher PB and Sarkar D: Insulin-like growth factor-binding protein-7 functions as a potential tumor suppressor in hepatocellular carcinoma. Clin Cancer Res. 17:6693–6701. 2011. View Article : Google Scholar : PubMed/NCBI
16	Verhagen HJ, de Leeuw DC, Roemer MG, Denkers F, Pouwels W, Rutten A, Celie PH, Ossenkoppele GJ, Schuurhuis GJ and Smit L: IGFBP7 induces apoptosis of acute myeloid leukemia cells and synergizes with chemotherapy in suppression of leukemia cell survival. Cell Death Dis. 5:e13002014. View Article : Google Scholar : PubMed/NCBI
17	Ma Y, Lu B, Ruan W, Wang H, Lin J, Hu H, Deng H, Huang Q and Lai M: Tumor suppressor gene insulin-like growth factor binding protein-related protein 1 (IGFBP-rP1) induces senescence-like growth arrest in colorectal cancer cells. Exp Mol Pathol. 85:141–145. 2008. View Article : Google Scholar : PubMed/NCBI
18	Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, Medrano EE, Linskens M, Rubelj I, Pereira-Smith O, et al: A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci USA. 92:9363–9367. 1995. View Article : Google Scholar : PubMed/NCBI
19	Rosato V, Zucchetto A, Bosetti C, Dal Maso L, Montella M, Pelucchi C, Negri E, Franceschi S and La Vecchia C: Metabolic syndrome and endometrial cancer risk. Ann Oncol. 22:884–889. 2011. View Article : Google Scholar : PubMed/NCBI
20	Ni J, Zhu T, Zhao L, Che F, Chen Y, Shou H and Yu A: Metabolic syndrome is an independent prognostic factor for endometrial adenocarcinoma. Clin Transl Oncol. 17:835–839. 2015. View Article : Google Scholar : PubMed/NCBI
21	Swisshelm K, Ryan K, Tsuchiya K and Sager R: Enhanced expression of an insulin growth factor-like binding protein (mac25) in senescent human mammary epithelial cells and induced expression with retinoic acid. Proc Natl Acad Sci USA. 92:4472–4476. 1995. View Article : Google Scholar : PubMed/NCBI
22	Wajapeyee N, Serra RW, Zhu X, Mahalingam M and Green MR: Oncogenic BRAF induces senescence and apoptosis through pathways mediated by the secreted protein IGFBP7. Cell. 132:363–374. 2008. View Article : Google Scholar : PubMed/NCBI
23	Xue W, Zender L, Miething C, Dickins RA, Hernando E, Krizhanovsky V, Cordon-Cardo C and Lowe SW: Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature. 445:656–660. 2007. View Article : Google Scholar : PubMed/NCBI
24	Dimova DK and Dyson NJ: The E2F transcriptional network: Old acquaintances with new faces. Oncogene. 24:2810–2826. 2005. View Article : Google Scholar : PubMed/NCBI
25	Rowland BD and Bernards R: Re-evaluating cell-cycle regulation by E2Fs. Cell. 127:871–874. 2006. View Article : Google Scholar : PubMed/NCBI
26	Gil J and Peters G: Regulation of the INK4b-ARF-INK4a tumour suppressor locus: All for one or one for all. Nat Rev Mol Cell Biol. 7:667–677. 2006. View Article : Google Scholar : PubMed/NCBI
27	Meloche S and Pouysségur J: The ERK1/2 mitogen-activated protein kinase pathway as a master regulator of the G1- to S-phase transition. Oncogene. 26:3227–3239. 2007. View Article : Google Scholar : PubMed/NCBI
28	Amemiya Y, Yang W, Benatar T, Nofech-Mozes S, Yee A, Kahn H, Holloway C and Seth A: Insulin like growth factor binding protein-7 reduces growth of human breast cancer cells and xenografted tumors. Breast Cancer Res Treat. 126:373–384. 2011. View Article : Google Scholar : PubMed/NCBI