Abstract
Background
Recepteur d’origine nantais (RON) protein expression has been demonstrated to correlate with tumor progression, metastasis, and prognosis, and its mRNA expression increases in deeply infiltrating endometriotic lesions. However, it remains unclear whether RON protein expression also increases in endometriotic lesions, and may be a risk factor of malignant transformation in endometriotic lesions.
Methods
The protein expression of RON in control (n = 19), eutopic (n = 16), and ectopic (n = 51) endometria, as well as in endometriosis-associated ovarian cancers (EAOC, n = 16) was determined by immunohistochemical (IHC) staining.
Results
Endometriotic lesions expressed low levels of RON protein, but no RON protein expression appeared in matched eutopic or control endometrium. EAOC exhibited high levels of RON protein. The frequency and IHC score of RON protein expression were both significantly higher in EAOC [100.0% (14/14), 5.37 ± 0.74] than those in endometriotic lesions [51.0% (26/51), 2.15 ± 1.12; P = 0.002, 0.001]. Multivariate analysis of covariance only revealed a correlation of RON protein expression and EAOC (P = 0.006), but no correlations of RON protein expression and clinical parameters (P > 0.05).
Conclusions
These obtained results suggest that increased RON expression might be involved in the pathogenesis of endometriosis and disease-associated ovarian cancers.
Similar content being viewed by others
References
Sun Y, Che X, Zhu L, Zhao M, Fu G, Huang X et al (2012) Pigment epithelium derived factor inhibits the growth of human endometrial implants in nude mice and of ovarian endometriotic stromal cells in vitro. PLoS One 7(9):e45223
Becker CM, D’Amato RJ (2007) Angiogenesis and antiangiogenic therapy in endometriosis. Microvasc Res 74(2):121–130
May K, Becker C (2008) Endometriosis and angiogenesis. Minerva Ginecol 60(3):245–254
Fukunaga M, Nomura K, Ishikawa E, Ushigome S (1997) Ovarian atypical endometriosis: its close association with malignant epithelial tumours. Histopathology 30(3):249–255
Bayramođlu H, Düzcan E (2001) Atypical epithelial changes and mutant p53 gene expression in ovarian endometriosis. Pathol Oncol Res 7(1):33–38
Moll UM, Chumas JC, Chalas E, Mann WJ (1990) Ovarian carcinoma arising in atypical endometriosis. Obstet Gynecol 75(3, Part 2):537–539
Mandai M, Yamaguchi K, Matsumura N, Baba T, Konishi I (2009) Ovarian cancer in endometriosis: molecular biology, pathology, and clinical management. Int J Clin Oncol 14(5):383–391
Ouellet V, Guyot MC, Le Page C, Filali-Mouhim A, Lussier C, Tonin PN et al (2006) Tissue array analysis of expression microarray candidates identifies markers associated with tumor grade and outcome in serous epithelial ovarian cancer. Int J Cancer 119(3):599–607
Park JH, Park EJ, Lee HS, Kim SJ, Hur SK, Imbalzano AN et al (2006) Mammalian SWI/SNF complexes facilitate DNA double-strand break repair by promoting γ-H2AX induction. EMBO J 25(17):3986–3997
Park J-H, Park E-J, Hur S-K, Kim S, Kwon J (2009) Mammalian SWI/SNF chromatin remodeling complexes are required to prevent apoptosis after DNA damage. DNA Repair 8(1):29–39
Lee HS, Park JH, Kim SJ, Kwon SJ, Kwon J (2010) A cooperative activation loop among SWI/SNF, γ-H2AX and H3 acetylation for DNA double-strand break repair. EMBO J 29(8):1434–1445
Yamamoto S, Tsuda H, Takano M, Tamai S, Matsubara O (2012) Loss of ARID1A protein expression occurs as an early event in ovarian clear-cell carcinoma development and frequently coexists with PIK3CA mutations. Mod Pathol 25(4):615–624
Chene G, Tchirkov A, Pierre-Eymard E, Dauplat J, Raoelfils I, Cayre A et al (2013) Early telomere shortening and genomic instability in tubo-ovarian preneoplastic lesions. Clin Cancer Res 19(11):2873–2882
Chene G, Ouellet V, Rahimi K, Barres V, Caceres K, Meunier L et al (2015) DNA damage signaling and apoptosis in preinvasive tubal lesions of ovarian carcinoma. Int J Gynecol Cancer 25(5):761–769
Ronsin C, Muscatelli F, Mattei M, Breathnach R (1993) A novel putative receptor protein tyrosine kinase of the met family. Oncogene 8(5):1195–1202
Wang M-H, Wang D, Chen Y-Q (2003) Oncogenic and invasive potentials of human macrophage-stimulating protein receptor, the RON receptor tyrosine kinase. Carcinogenesis 24(8):1291–1300
Camp ER, Liu W, Fan F, Yang A, Somcio R, Ellis LM (2005) RON, a tyrosine kinase receptor involved in tumor progression and metastasis. Ann Surg Oncol 12(4):273–281
Kang CM, Babicky ML, Lowy AM (2014) The RON receptor tyrosine kinase in pancreatic cancer pathogenesis and its potential implications for future targeted therapies. Pancreas 43(2):183
Ferrandina G, Martinelli E, Petrillo M, Prisco MG, Zucconi A, Santaguida S et al (2008) Prognostic role of the recepteur d’origine nantais (RON) expression in ovarian cancer patients. Gynecol Oncol 111(2):237–243
Bieniasz M, Radhakrishnan P, Faham N, De La OJ-P, Welm AL (2015) Preclinical Efficacy of Ron Kinase Inhibitors Alone and in Combination with PI3 K Inhibitors for Treatment of sfRon-Expressing Breast Cancer Patient-Derived Xenografts. Clin Cancer Res 21(24):5588–5600
Zhang X, Qi C, Lin J (2010) Enhanced expressions of matrix metalloproteinase (MMP)-2 and–9 and vascular endothelial growth factors (VEGF) and increased microvascular density in the endometrial hyperplasia of women with anovulatory dysfunctional uterine bleeding. Fertil Steril 93(7):2362–2367
Matsuzaki S, Canis M, Pouly J, Dechelotte P, Okamura K, Mage G (2005) The macrophage stimulating protein/RON system: a potential novel target for prevention and treatment of endometriosis. Mol Hum Reprod 11(5):345–349
Matsuzaki S, Canis M, Vaurs-Barrière C, Boespflug-Tanguy O, Dastugue B, Mage G (2005) DNA microarray analysis of gene expression in eutopic endometrium from patients with deep endometriosis using laser capture microdissection. Fertil Steril 84:1180–1190
Huang X, Chen L, Fu G, Xu H, Zhang X (2012) Decreased expression of pigment epithelium-derived factor and increased microvascular density in ovarian endometriotic lesions in women with endometriosis. Euro J Obstet Gynecol Reprod Biol 165(1):104–109
Romero I, Bast RC Jr (2012) Minireview: human ovarian cancer: biology, current management, and paths to personalizing therapy. Endocrinology 153(4):1593–1602
Neto JS, Kho RM, dos Santos Siufi DF, Baracat EC, Anderson KS, Abrão MS (2014) Cellular, histologic, and molecular changes associated with endometriosis and ovarian cancer. J Mini Invasive Gynecol 21(1):55–63
Maggiora P, Lorenzato A, Fracchioli S, Costa B, Castagnaro M, Arisio R et al (2003) The RON and MET oncogenes are co-expressed in human ovarian carcinomas and cooperate in activating invasiveness. Exp Cell Res 288(2):382–389
Otsuka J, Okuda T, Sekizawa A, Amemiya S, Saito H, Okai T et al (2004) K-ras mutation may promote carcinogenesis of endometriosis leading to ovarian clear cell carcinoma. Med Electron Microsc 37(3):188–192
Dinulescu DM, Ince TA, Quade BJ, Shafer SA, Crowley D, Jacks T (2005) Role of K-ras and Pten in the development of mouse models of endometriosis and endometrioid ovarian cancer. Nat Med 11(1):63–70
Yamamoto S, Tsuda H, Takano M, Iwaya K, Tamai S, Matsubara O (2011) PIK3CA mutation is an early event in the development of endometriosis-associated ovarian clear cell adenocarcinoma. J Pathol 225(2):189–194
Lin K, Zhan H, Ma J, Xu K, Wu R, Zhou C et al (2014) Increased steroid receptor RNA activator protein (SRAP) accompanied by decreased estrogen receptor-beta (ER-β) levels during the malignant transformation of endometriosis associated ovarian clear cell carcinoma. Acta Histochem 116(5):878–882
De Bortoli M, Di Renzo MF, Costantino A, Sismondi P, Comoglio PM (1998) Overexpression of the RON gene in human breast carcinoma. Oncogene 16:2927–2933
Chen Y-Q, Zhou Y-Q, Angeloni D, Kurtz AL, Qiang X-Z, Wang M-H (2000) Overexpression and activation of the RON receptor tyrosine kinase in a panel of human colorectal carcinoma cell lines. Exp Cell Res 261(1):229–238
Wang M-H, Kurtz AL, Chen Y-Q (2000) Identification of a novel splicing product of the RON receptor tyrosine kinase in human colorectal carcinoma cells. Carcinogenesis 21(8):1507–1512
Cheng H, Liu H, Lin Y, Chen HH, Hsu P, Chang T et al (2005) Co-expression of RON and MET is a prognostic indicator for patients with transitional-cell carcinoma of the bladder. Br J Cancer 92(10):1906–1914
Xu X-M, Wang D, Shen Q, Chen Y-Q, Wang M-H (2004) RNA-mediated gene silencing of the RON receptor tyrosine kinase alters oncogenic phenotypes of human colorectal carcinoma cells. Oncogene 23(52):8464–8474
Chang K, Karnad A, Zhao S, Freeman JW (2015) Roles of c-Met and RON kinases in tumor progression and their potential as therapeutic targets. Oncotarget 6(6):3507–3518
Kim H, Kim T, Chung H, Song Y (2014) Risk and prognosis of ovarian cancer in women with endometriosis: a meta-analysis. Br J Cancer 110(7):1878–1890
Xiangming X, Yun Q, Guoliang Z, Jianjiang L, Lisong T (2011) Mechanisms of RON-mediated epithelial-mesenchymal transition in MDCK cells through the MAPK pathway. Brazilian J Medical and Biol Res = Revista brasileira de pesquisas médicas e biológicas/Sociedade Brasileira de Biofísica [et al] 44(7):634–641
Qi M, Guin S, Padhye SS, Zhou YQ, Zhang RW, Wang MH (2011) Ribosomal Protein S6 Kinase (RSK)-2 as a central effector molecule in RON receptor tyrosine kinase mediated epithelial to mesenchymal transition induced by macrophage-stimulating protein. Mol Cancer 10(1):1–15
Minetto M (1998) Point mutations in the tyrosine kinase domain release the oncogenic and metastatic potential of the ron receptor. Oncogene 17(6):741–749
Zhou YQ, He C, Chen YQ, Wang D, Wang MH (2003) Altered expression of the RON receptor tyrosine kinase in primary human colorectal adenocarcinomas: generation of different splicing RON variants and their oncogenic potential. Oncogene 22(2):186–197
Acknowledgements
We appreciate the financial support of the National Nature Science Foundation of China (Grant Nos. 81270672, 81471433, 81471495, and 81671429), the Nature Science Foundation of Zhejiang Province (Grant Nos. Y2110181, Y2110128, and LQ16H040001), the Science and Technology Fund of Zhejiang Province (Grant Nos. 2011C13028-1 and 2013C33149), and the Key Medical Science (Innovation) Project of Zhejiang Province.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
We declare no conflicts of interest. We have had full control of all primary data and that we agree to allow the Journal to review their data if requested.
Ethical approval
The study protocol was approved by the Human Ethics Committee of the Women’s Hospital, School of Medicine, Zhejiang University.
Informed consent
All subjects gave their informed consent to participate in this study.
Additional information
Ping Xu, Shaojie Ding, and Libo Zhu equally contribute to this manuscript.
Rights and permissions
About this article
Cite this article
Xu, P., Ding, S., Zhu, L. et al. Elevated RON protein expression in endometriosis and disease-associated ovarian cancers. Arch Gynecol Obstet 295, 631–639 (2017). https://doi.org/10.1007/s00404-016-4248-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00404-016-4248-x