Abstract
Epithelial ovarian cancer (EOC) is a heterogeneous disease that can be categorized into four major histological subtypes. Its etiology remains poorly understood due mainly to this heterogeneity. Follicle-stimulating hormone (FSH) has been implicated as a risk factor in EOC and has been suggested that may influence the development of specific subtypes. In addition, FSH regulates different aspects of ovarian cancer tumorigenesis. FSH downstream target genes in EOC have not been fully identified. Progranulin (PGRN) overexpression is associated with cell proliferation, invasion, chemoresistance, and shortened overall survival in ovarian cancer. Recently, we demonstrated that PGRN expression is regulated through the PI3K signaling pathway in clear cell ovarian carcinoma (CCOC) cells. In contrast, we also demonstrated that PGRN synthesis in serous ovarian cancer (SOC) cells is regulated via PKC but not by the PI3K signaling pathway. Several studies have demonstrated that FSH induces PKC and PI3K activation. Thus, this study was to investigate the effect of FSH on PGRN production in the CCOC cell line TOV-21G as compared to the SOC cell lines SKOV3 and OVCAR3. Cultured TOV-21G, SKOV3, and OVCAR3 cells were incubated with different concentrations of FSH for 48 h. PGRN mRNA and protein expression were assessed by RT-PCR and Western blotting, while PGRN secretion was measured by ELISA. PGRN mRNA and protein expression, as well as PGRN secretion, significantly increased after FSH stimulation in TOV-21G but not in SKOV3 and OVCAR3 cells. These data indicate that FSH induces PGRN expression and secretion only in CCOC cells. Establishing specific features for CCOC could reveal potential diagnostic and therapeutic targets.
References
Kossaï M, Leary A, Scoazec JY, Genestie C. Ovarian cancer: a heterogeneous disease. Pathobiology. 2018;85:41–9.
Cardenas C, Alvero AB, Yun BS, Mor G. Redefining the origin and evolution of ovarian cancer: a hormonal connection. Endocr Relat Cancer. 2016;23:R411–R422422.
Wentzensen N, Poole EM, Trabert B, et al. Ovarian cancer risk factors by histologic subtype: an analysis from the ovarian cancer cohort consortium. J Clin Oncol. 2016;34:2888–98.
Schiffenbauer YS, Meir G, Maoz M, Even-Ram SC, Bar-Shavit R, Neeman M. Gonadotropin stimulation of MLS human epithelial ovarian carcinoma cells augments cell adhesion mediated by CD44 and by alpha(v)-integrin. Gynecol Oncol. 2002;84:296–302.
Wang J, Luo F, Lu JJ, Chen PK, Liu P, Zheng W. VEGF expression and enhanced production by gonadotropins in ovarian epithelial tumors. Int J Cancer. 2002;97:163–7.
Lau MT, Wong AS, Leung PC. Gonadotropins induce tumor cell migration and invasion by increasing cyclooxygenases expression and prostaglandin E(2) production in human ovarian cancer cells. Endocrinology. 2010;151:2985–93.
Syed V, Ulinski G, Mok SC, Ho SM. Reproductive hormone-induced, STAT3-mediated interleukin 6 action in normal and malignant human ovarian surface epithelial cells. J Natl Cancer Inst. 2002;94:617–29.
Chen J, Bai M, Ning C, et al. Gankyrin facilitates follicle-stimulating hormone-driven ovarian cancer cell proliferation through the PI3K/AKT/HIF-1α/cyclin D1 pathway. Oncogene. 2016;35:2506–17.
Parrott JA, Doraiswamy V, Kim G, Mosher R, Skinner MK. Expression and actions of both the follicle stimulating hormone receptor and the luteinizing hormone receptor in normal ovarian surface epithelium and ovarian cancer. Mol Cell Endocrinol. 2001;172:213–22.
Huang Y, Hua K, Zhou X, et al. Activation of the PI3K/AKT pathway mediates FSH-stimulated VEGF expression in ovarian serous cystadenocarcinoma. Cell Res. 2008;18:780–91.
Cuevas-Antonio R, Cancino C, Arechavaleta-Velasco F, et al. Expression of progranulin (Acrogranin/PCDGF/Granulin-Epithelin Precursor) in benign and malignant ovarian tumors and activation of MAPK signaling in ovarian cancer cell line. Cancer Invest. 2010;28:452–8.
Davidson B, Alejandro E, Flørenes VA, et al. Granulin-epithelin precursor is a novel prognostic marker in epithelial ovarian carcinoma. Cancer. 2004;100:2139–47.
Han JJ, Yu M, Houston N, Steinberg SM, Kohn EC. Progranulin is a potential prognostic biomarker in advanced epithelial ovarian cancers. Gynecol Oncol. 2011;120:5–10.
Miyanishi M, Mandai M, Matsumura N, et al. Immortalized ovarian surface epithelial cells acquire tumorigenicity by Acrogranin gene overexpression. Oncol Rep. 2007;17:329–33.
Pizarro GO, Zhou XC, Koch A, et al. Prosurvival function of the granulin-epithelin precursor is important in tumor progression and chemoresponse. Int J Cancer. 2007;120:2339–433.
Diaz-Cueto L, Arechavaleta-Velasco F, Diaz-Arizaga A, Dominguez-Lopez P, Robles-Flores M. PKC signaling is involved in the regulation of progranulin (acrogranin/PC-cell-derived growth factor/granulin-epithelin precursor) protein expression in human ovarian cancer cell lines. Int J Gynecol Cancer. 2012;22:945–50.
Perez-Juarez CE, Arechavaleta-Velasco F, Zeferino-Toquero M, Alvarez-Arellano L, Estrada-Moscoso I, Diaz-Cueto L. Inhibition of PI3K/AKT/mTOR and MAPK signaling pathways decreases progranulin expression in ovarian clear cell carcinoma (OCCC) cell line: a potential biomarker for therapy response to signaling pathway inhibitors. Med Oncol. 2019;37:4.
Mertens-Walker I, Baxter RC, Marsh DJ. Gonadotropin signalling in epithelial ovarian cancer. Cancer Lett. 2012;324:152–9.
Arechavaleta-Velasco F, Zeferino-Toquero M, Estrada-Moscoso I, et al. Ribosomal S6 kinase 4 (RSK4) expression in ovarian tumors and its regulation by antineoplastic drugs in ovarian cancer cell lines. Med Oncol. 2016;33:11.
Gloaguen P, Crépieux P, Heitzler D, Poupon A, Reiter E. Mapping the follicle-stimulating hormone-induced signaling networks. Front Endocrinol (Lausanne). 2011;2:45.
Zhou X, Paushter DH, Feng T, Sun L, Reinheckel T, Hu F. Lysosomal processing of progranulin. Mol Neurodegener. 2017;12:62.
Jiao J, Herl LD, Farese RV, Gao FB. MicroRNA-29b regulates the expression level of human progranulin, a secreted glycoprotein implicated in frontotemporal dementia. PLoS ONE. 2010;5:e10551.
Piscopo P, Grasso M, Fontana F, et al. Reduced miR-659-3p levels correlate with progranulin increase in hypoxic conditions: implications for frontotemporal dementia. Front Mol Neurosci. 2016;9:31.
Wang WX, Wilfred BR, Madathil SK, et al. miR-107 regulates granulin/progranulin with implications for traumatic brain injury and neurodegenerative disease. Am J Pathol. 2010;177:334–45.
Yao N, Lu CL, Zhao JJ, et al. A network of miRNAs expressed in the ovary are regulated by FSH. Front Biosci (Landmark Ed). 2009;14:3239–45.
Anglesio MS, Wiegand KC, Melnyk N, et al. Type-specific cell line models for type-specific ovarian cancer research. PLoS ONE. 2013;8:e72162.
Domcke S, Sinha R, Levine DA, Sander C, Schultz N. Evaluating cell lines as tumour models by comparison of genomic profiles. Nat Commun. 2013;4:2126.
Beaufort CM, Helmijr JC, Piskorz AM, et al. Ovarian cancer cell line panel (OCCP): clinical importance of in vitro morphological subtypes. PLoS ONE. 2014;9:e103988.
Acknowledgements
This study was supported by a Grant from the Fondo de Investigacion en Salud, Instituto Mexicano del Seguro Social (FIS/IMSS/PROT/G11/987) to Laura Diaz-Cueto, MD, PhD. Carlos Eduardo Perez-Juarez was a graduate student in the Posgrado en Ciencias Biologicas at the Universidad Nacional Autonoma de Mexico. He was supported by a scholarship from the CONACYT, México (Num. 365460/245530) and the Instituto Mexicano del Seguro Social (Matricula: 99095927), CDMX, Mexico.
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Perez-Juarez, C.E., Arechavaleta-Velasco, F., Mendez, C. et al. Progranulin expression induced by follicle-stimulating hormone in ovarian cancer cell lines depends on the histological subtype. Med Oncol 37, 59 (2020). https://doi.org/10.1007/s12032-020-01383-9
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DOI: https://doi.org/10.1007/s12032-020-01383-9