ATX‑LPA axis facilitates estrogen‑induced endometrial cancer cell proliferation via MAPK/ERK signaling pathway

Zhang,Guo; Cheng,Yuan; Zhang,Qi; Li,Xiaoping; Zhou,Jingwei; Wang,Jianliu; Wei,Lihui

doi:10.3892/mmr.2018.8392

ATX‑LPA axis facilitates estrogen‑induced endometrial cancer cell proliferation via MAPK/ERK signaling pathway

Authors:
- Guo Zhang
- Yuan Cheng
- Qi Zhang
- Xiaoping Li
- Jingwei Zhou
- Jianliu Wang
- Lihui Wei
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Affiliations: Department of Gynecology and Obstetrics, Peking University People's Hospital, Beijing 100044, P.R. China
Published online on: January 8, 2018 https://doi.org/10.3892/mmr.2018.8392
Pages: 4245-4252
Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Autotaxin (ATX) is a key enzyme that converts lysophosphatidylcholine to lysophosphatidic acid (LPA). ATX is a crucial factor that facilitates cancer progression; however, the effect of ATX on endometrial cancer has not been explored. The aim of the present study was to investigate the role of ATX in the progression of endometrial cancer. The immunohistochemical results revealed higher protein expression levels of ATX and LPA receptors (LPA 1, 2 and 3) in human endometrial cancer tissue than in non‑carcinoma tissue. In addition, reverse transcription‑quantitative polymerase chain reaction and western blotting analysis demonstrated that ATX and LPA receptor mRNA and protein expression was greater in Ishikawa cells, which are positive for estrogen receptor (ER), than in Hec‑1A cells that exhibit low ER expression. Short interfering RNA knockdown of ATX in Ishikawa cells led to decreased cell proliferation and cell colony number, as determined by Cell Counting kit‑8 and colony formation assays. Estrogen stimulated ATX mRNA expression. Inhibition of ATX decreased estrogen and LPA‑induced cell proliferation. High LPA levels markedly elevated the phosphorylation levels of extracellular signal‑regulated kinase (ERK). ATX downregulation moderately decreased estrogen‑ and LPA‑induced phosphorylation of ERK. In addition, the ERK inhibitor, PD98059, reduced cell proliferation with estrogen, ATX and LPA treatment. The present study suggested that the ATX‑LPA axis may facilitate estrogen‑induced cell proliferation in endometrial cancer via the mitogen‑activated protein kinase/ERK signaling pathway. The present study may provide ideas and an experimental basis for clinicians to identify new molecular targeted drugs for the treatment of endometrial cancer.

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1	Globocan. 2012, http://globocan.iarc.fr/Pages/online.aspx4–July. 2016
2	National Cancer Institute, . PDQ^® screening and prevention editorial board. PDQ endometrial cancer prevention. Bethesda, MD: National Cancer Institute; 2016, http://www.cancer.gov/types/uterine/hp/endometrial-prevention-pdq11–January. 2015[PMID: 26389477].
3	Jeppesen MM, Mogensen O, Hansen DG, Iachina M, Korsholm M and Jensen PT: Detection of recurrence in early stage endometrial cancer-the role of symptoms and routine follow-up. Acta Oncol. 56:262–269. 2017. View Article : Google Scholar
4	Busch EL, Crous-Bou M, Prescott J, Chen MM, Downing MJ, Rosner B, Mutter GL and De Vivo I: Endometrial cancer risk factors, hormone receptors, and mortality prediction. Cancer Epidemiol Biomarkers Prev. 26:727–735. 2017. View Article : Google Scholar
5	Benesch MG, Tang X, Venkatraman G, Bekele RT and Brindley DN: Recent advances in targeting the autotaxin-lysophosphatidate-lipid phosphate phosphatase axis in vivo. J Biomed Res. 30:272–284. 2016.
6	Volden PA, Skor MN, Johnson MB, Singh P, Patel FN, McClintock MK, Brady MJ and Conzen SD: Mammary adipose tissue-derived lysophospholipids promote estrogen receptor-negative mammary epithelial cell proliferation. Cancer Prev Res (Phila). 9:367–378. 2016. View Article : Google Scholar :
7	Gaetano CG, Samadi N, Tomsig JL, Macdonald TL, Lynch KR and Brindley DN: Inhibition of autotaxin production or activity blocks lysophosphatidylcholine-induced migration of human breast cancer and melanoma cells. Mol Carcinog. 48:801–809. 2009. View Article : Google Scholar :
8	Ptaszynska MM, Pendrak ML, Bandle RW, Stracke ML and Roberts DD: Positive feedback between vascular endothelial growth factor-A and autotaxin in ovarian cancer cells. Mol Cancer Res. 6:352–363. 2008. View Article : Google Scholar :
9	Hope JM, Wang FQ, Whyte JS, Ariztia EV, Abdalla W, Long K and Fishman DA: LPA receptor 2 mediates LPA-induced endometrial cancer invasion. Gynecol Oncol. 112:215–223. 2009. View Article : Google Scholar
10	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar
11	Wasniewski T, Woclawek-Potocka I, Boruszewska D, Kowalczyk-Zieba I, Sinderewicz E and Grycmacher K: The significance of the altered expression of lysophosphatidic acid receptors, utotaxin and phospholipase A2 as the potential biomarkers in type 1 endometrial cancer biology. Oncol Rep. 34:2760–2767. 2015. View Article : Google Scholar
12	Droog M, Nevedomskaya E, Dackus GM, Fles R, Kim Y, Hollema H, Mourits M, Nederlof PM, van Boven HH, Linn SC, et al: Estrogen receptor α wields treatment-specific enhancers between morphologically similar endometrial tumors. Proc Natl Acad Sci USA. 114:pp. E1316–E1325. 2017; View Article : Google Scholar :
13	Kehlen A, Englert N, Seifert A, Klonisch T, Dralle H, Langner J and Hoang-Vu C: Expression, regulation and function of autotaxin in thyroid carcinomas. Int J Cancer. 109:833–838. 2004. View Article : Google Scholar
14	Kehlen A, Lauterbach R, Santos AN, Thiele K, Kabisch U, Weber E, Riemann D and Langner J: IL-1 beta- and IL-4-induced down-regulation of autotaxin mRNA and PC-1 in fibroblast-like synoviocytes of patients with rheumatoid arthritis(RA). Clin Exp Immunol. 123:147–154. 2001. View Article : Google Scholar :
15	Sawada K, Morishige Ki, Tahara M, Ikebuchi Y, Kawagishi R, Tasaka K and Murata Y: Lysophosphatidic acid induces focal adhesion assembly through Rho/Rho-associated kinase pathway in human ovarian cancer cells. Gynecol Oncol. 87:252–259. 2002. View Article : Google Scholar
16	Fishman DA, Liu Y, Ellerbroek SM and Stack MS: Lysophosphatidic acid promotes matrix metalloproteinase (MMP) activation and MMP-dependent invasion in ovarian cancer cells. Cancer Res. 61:3194–3199. 2001.
17	Meng Y, Kang S and Fishman DA: Lysophosphatidic acid inhibits anti-Fas-mediated apoptosis enhanced by actin depolymerization in epithelial ovarian cancer. FEBS Lett. 579:1311–1319. 2005. View Article : Google Scholar
18	Sun H, Zhu Q, Ren J, Wu L, Kong FZ, Li G and Hu HF: Influence of lysophosphatidic acid on proliferation, adhesion, migration and apoptosis of cervical cancer HeLa cells. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 25:702–705. 2009.(In Chinese).
19	Benesch MG, Tang X, Dewald J, Dong WF, Mackey JR, Hemmings DG, McMullen TP and Brindley DN: Tumor-induced inflammation in mammary adipose tissue stimulates a vicious cycle of autotaxin expression and breast cancer progression. FASEB J. 29:3990–4000. 2015. View Article : Google Scholar