Autocrine motility factor promotes epithelial-mesenchymal transition in endometrial cancer via MAPK signaling pathway

Li,Yiran; Che,Qi; Bian,Yiding; Zhou,Qian; Jiang,Feizhou; Tong,Huan; Ke,Jieqi; Wang,Kai; Wan,Xiao-Ping

doi:10.3892/ijo.2015.3091

Autocrine motility factor promotes epithelial-mesenchymal transition in endometrial cancer via MAPK signaling pathway

Authors:
- Yiran Li
- Qi Che
- Yiding Bian
- Qian Zhou
- Feizhou Jiang
- Huan Tong
- Jieqi Ke
- Kai Wang
- Xiao-Ping Wan
View Affiliations

Affiliations: Department of Obstetrics and Gynecology, Shanghai First People's Hospital Affiliated to Shanghai Jiao Tong University, Shanghai 200040, P.R. China, Department of Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 200040, P.R. China, Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 200040, P.R. China
Published online on: July 20, 2015 https://doi.org/10.3892/ijo.2015.3091
Pages: 1017-1024

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

Autocrine motility factor (AMF) as a cytokine and a growth factor, is known to regulate tumor cell growth and motility in the progress of various human malignant tumors, however, its role in endometrial cancer (EC) has not been fully studied. In the present study, using immunohistochemistry, we found that AMF was highly expressed in EC tissues compared with normal endometrial tissues and tissue micrioarray technology showed positive correlation between AMF expression and epithelial-to-mesenchymal transition (EMT) related markers E-cadherin, vimentin and Snail. Next, we detected that silencing of AMF by stable transfection with shRNA induced mesenchymal-to-epithelial transition phenotype in Ishikawa and HEC-1B cells by qRT-PCR, western blotting and immunofluorescence. Gene expression profile revealed that AMF silencing resulted in altered expression of EMT related molecular mediators including Snail and transforming growth factor β receptor 1, and involvement of mitogen-activated protein kinase (MAPK) signaling pathway. Additionally, we found that EMT related markers were downregulated with pretreatment of the MAPK-specific inhibitor U0126 by western blotting. The present study is the first to support a role for AMF mediating EMT in endometrial cancer through MAPK signaling. Therefore, AMF may provide a potential prognostic and therapeutic target in preventing EC progression.

View Figures

View References

1	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2015. CA Cancer J Clin. 65:5–29. 2015. View Article : Google Scholar : PubMed/NCBI
2	Salvesen HB, Haldorsen IS and Trovik J: Markers for individualised therapy in endometrial carcinoma. Lancet Oncol. 13:e353–e361. 2012. View Article : Google Scholar : PubMed/NCBI
3	Sorosky JI: Endometrial cancer. Obstet Gynecol. 120:383–397. 2012. View Article : Google Scholar : PubMed/NCBI
4	Watanabe H, Takehana K, Date M, Shinozaki T and Raz A: Tumor cell autocrine motility factor is the neuroleukin/phosphohexose isomerase polypeptide. Cancer Res. 56:2960–2963. 1996.PubMed/NCBI
5	Niinaka Y, Paku S, Haga A, Watanabe H and Raz A: Expression and secretion of neuroleukin/phosphohexose isomerase/maturation factor as autocrine motility factor by tumor cells. Cancer Res. 58:2667–2674. 1998.PubMed/NCBI
6	Kim JW and Dang CV: Multifaceted roles of glycolytic enzymes. Trends Biochem Sci. 30:142–150. 2005. View Article : Google Scholar : PubMed/NCBI
7	Gurney ME, Apatoff BR, Spear GT, Baumel MJ, Antel JP, Bania MB and Reder AT: Neuroleukin: A lymphokine product of lectin-stimulated T cells. Science. 234:574–581. 1986. View Article : Google Scholar : PubMed/NCBI
8	Xu W, Seiter K, Feldman E, Ahmed T and Chiao JW: The differentiation and maturation mediator for human myeloid leukemia cells shares homology with neuroleukin or phosphoglucose isomerase. Blood. 87:4502–4506. 1996.PubMed/NCBI
9	Kho DH, Zhang T, Balan V, Wang Y, Ha SW, Xie Y and Raz A: Autocrine motility factor modulates EGF-mediated invasion signaling. Cancer Res. 74:2229–2237. 2014. View Article : Google Scholar : PubMed/NCBI
10	Kho DH, Nangia-Makker P, Balan V, Hogan V, Tait L, Wang Y and Raz A: Autocrine motility factor promotes HER2 cleavage and signaling in breast cancer cells. Cancer Res. 73:1411–1419. 2013. View Article : Google Scholar :
11	Bayo J, Fiore E, Aquino JB, Malvicini M, Rizzo M, Peixoto E, Andriani O, Alaniz L, Piccioni F, Bolontrade M, et al: Increased migration of human mesenchymal stromal cells by autocrine motility factor (AMF) resulted in enhanced recruitment towards hepatocellular carcinoma. PLoS One. 9:e951712014. View Article : Google Scholar : PubMed/NCBI
12	Shih WL, Liao MH, Lin PY, Chang CI, Cheng HL, Yu FL and Lee JW: PI 3-kinase/Akt and STAT3 are required for the prevention of TGF-beta-induced Hep3B cell apoptosis by autocrine motility factor/phosphoglucose isomerase. Cancer Lett. 290:223–237. 2010. View Article : Google Scholar
13	Niinaka Y, Harada K, Fujimuro M, Oda M, Haga A, Hosoki M, Uzawa N, Arai N, Yamaguchi S, Yamashiro M, et al: Silencing of autocrine motility factor induces mesenchymal-to-epithelial transition and suppression of osteosarcoma pulmonary metastasis. Cancer Res. 70:9483–9493. 2010. View Article : Google Scholar : PubMed/NCBI
14	Funasaka T, Hogan V and Raz A: Phosphoglucose isomerase/autocrine motility factor mediates epithelial and mesenchymal phenotype conversions in breast cancer. Cancer Res. 69:5349–5356. 2009. View Article : Google Scholar : PubMed/NCBI
15	Thiery JP and Sleeman JP: Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol. 7:131–142. 2006. View Article : Google Scholar : PubMed/NCBI
16	Greenburg G and Hay ED: Epithelia suspended in collagen gels can lose polarity and express characteristics of migrating mesenchymal cells. J Cell Biol. 95:333–339. 1982. View Article : Google Scholar : PubMed/NCBI
17	Hay ED: The mesenchymal cell, its role in the embryo, and the remarkable signaling mechanisms that create it. Dev Dyn. 233:706–720. 2005. View Article : Google Scholar : PubMed/NCBI
18	Lee JM, Dedhar S, Kalluri R and Thompson EW: The epithelial-mesenchymal transition: New insights in signaling, development, and disease. J Cell Biol. 172:973–981. 2006. View Article : Google Scholar : PubMed/NCBI
19	Thiery JP, Acloque H, Huang RY and Nieto MA: Epithelial-mesenchymal transitions in development and disease. Cell. 139:871–890. 2009. View Article : Google Scholar : PubMed/NCBI
20	De Craene B and Berx G: Regulatory networks defining EMT during cancer initiation and progression. Nat Rev Cancer. 13:97–110. 2013. View Article : Google Scholar : PubMed/NCBI
21	Dong P, Karaayvaz M, Jia N, Kaneuchi M, Hamada J, Watari H, Sudo S, Ju J and Sakuragi N: Mutant p53 gain-of-function induces epithelial-mesenchymal transition through modulation of the miR-130b-ZEB1 axis. Oncogene. 32:3286–3295. 2013. View Article : Google Scholar :
22	Ahmad A, Aboukameel A, Kong D, Wang Z, Sethi S, Chen W, Sarkar FH and Raz A: Phosphoglucose isomerase/autocrine motility factor mediates epithelial-mesenchymal transition regulated by miR-200 in breast cancer cells. Cancer Res. 71:3400–3409. 2011. View Article : Google Scholar : PubMed/NCBI
23	Funasaka T, Hu H, Yanagawa T, Hogan V and Raz A: Down-regulation of phosphoglucose isomerase/autocrine motility factor results in mesenchymal-to-epithelial transition of human lung fibrosarcoma cells. Cancer Res. 67:4236–4243. 2007. View Article : Google Scholar : PubMed/NCBI
24	Kyo S, Sakaguchi J, Ohno S, Mizumoto Y, Maida Y, Hashimoto M, Nakamura M, Takakura M, Nakajima M and Masutomi K: High Twist expression is involved in infiltrative endometrial cancer and affects patient survival. Hum Pathol. 37:431–438. 2006. View Article : Google Scholar : PubMed/NCBI
25	Massagué J: TGFβ signalling in context. Nat Rev Mol Cell Biol. 13:616–630. 2012. View Article : Google Scholar
26	Cano A, Pérez-Moreno MA, Rodrigo I, Locascio A, Blanco MJ, del Barrio MG, Portillo F and Nieto MA: The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol. 2:76–83. 2000. View Article : Google Scholar : PubMed/NCBI
27	Subarsky P and Hill RP: The hypoxic tumour microenvironment and metastatic progression. Clin Exp Metastasis. 20:237–250. 2003. View Article : Google Scholar : PubMed/NCBI
28	Tsutsumi S, Yanagawa T, Shimura T, Fukumori T, Hogan V, Kuwano H and Raz A: Regulation of cell proliferation by autocrine motility factor/phosphoglucose isomerase signaling. J Biol Chem. 278:32165–32172. 2003. View Article : Google Scholar : PubMed/NCBI
29	Yang J and Weinberg RA: Epithelial-mesenchymal transition: At the crossroads of development and tumor metastasis. Dev Cell. 14:818–829. 2008. View Article : Google Scholar : PubMed/NCBI
30	Peinado H, Olmeda D and Cano A: Snail, Zeb and bHLH factors in tumour progression: An alliance against the epithelial phenotype? Nat Rev Cancer. 7:415–428. 2007. View Article : Google Scholar : PubMed/NCBI
31	Prindull G and Zipori D: Environmental guidance of normal and tumor cell plasticity: Epithelial mesenchymal transitions as a paradigm. Blood. 103:2892–2899. 2004. View Article : Google Scholar : PubMed/NCBI
32	Otto T, Birchmeier W, Schmidt U, Hinke A, Schipper J, Rübben H and Raz A: Inverse relation of E-cadherin and autocrine motility factor receptor expression as a prognostic factor in patients with bladder carcinomas. Cancer Res. 54:3120–3123. 1994.PubMed/NCBI
33	Batlle E, Sancho E, Francí C, Domínguez D, Monfar M, Baulida J and García De Herreros A: The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nat Cell Biol. 2:84–89. 2000. View Article : Google Scholar : PubMed/NCBI
34	Pickup M, Novitskiy S and Moses HL: The roles of TGFβ in the tumour microenvironment. Nat Rev Cancer. 13:788–799. 2013. View Article : Google Scholar : PubMed/NCBI
35	Lamouille S, Xu J and Derynck R: Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 15:178–196. 2014. View Article : Google Scholar : PubMed/NCBI