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Artemin Is Oncogenic for Human Mammary Carcinoma Cells

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Artemin Is Oncogenic for Human Mammary Carcinoma Cells Oncogene (2009) 28, 2034–2045 & 2009 Macmillan Publishers Limited All rights reserved 0950-9232/09 $32.00 www.nature.com/onc ORIGINAL ARTICLE Artemin is oncogenic for human mammary carcinoma cells J Kang1, JK Perry1, V Pandey1, GC Fielder1, B Mei2,3, PX Qian2,ZSWu4, T Zhu2, DX Liu1 and PE Lobie1,5 1The Liggins Institute, University of Auckland, Auckland, New Zealand; 2Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, PR China; 3Institute of Basic Medicine, Anhui Medical University, Hefei, Anhui, PR China; 4Department of Pathology, Anhui Medical University, Hefei, Anhui, PR China and 5Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand We report that artemin, a member of the glial cell line- All GFLs are potent neurotrophic factors (Airaksinen and derived neurotrophic factor family of ligands, is oncogenic Saarma, 2002). GDNF was identified as a trophic factor for human mammary carcinoma. Artemin is expressedin for midbrain dopaminergic neurons (Lin et al., 1993). It numerous human mammary carcinoma cell lines. Forced promotes survival of many types of neurons, including expression of artemin in mammary carcinoma cells results subpopulations of peripheral autonomic and sensory, as in increased anchorage-independent growth, increased well as central motor, dopamine and noradrenaline, colony formation in soft agar andin three-dimensional neurons (Airaksinen et al., 1999). GDNF, neurturin and Matrigel, andalso promotes a scatteredcell phenotype artemin all support the survival of peripheral sympathetic with enhancedmigration andinvasion. Moreover, forced and sensory neurons, as well as midbrain dopamine expression of artemin increases tumor size in xenograft neurons, whereas persephin supports central nervous models and leads to highly proliferative, poorly differ- system dopamine and motor neurons, but not peripheral entiatedandinvasive tumors. Expression datain Onco- neurons (Airaksinen et al., 1999). mine indicate that high artemin expression is significantly GDNF family ligands signal through a multi- associated with residual disease after chemotherapy, component receptor complex, which includes a glyco- metastasis, relapse and death. Artemin protein is detect- syl-phosphatidylinositol (GPI)-anchored co-receptor a able in 65% of mammary carcinoma andits expression (termed GFRa) as a ligand-binding component and the correlates to decreased overall survival in the cohort of RET receptor tyrosine kinase as a common signaling patients. Depletion of endogenous artemin with small component (Takahashi, 2001). Binding of GFLs to a interfering RNA, or antibody inhibition of artemin, specific GFRa determines the signaling specificity of decreases the oncogenicity and invasiveness of mammary the receptor complex: GDNF preferentially binds to carcinoma cells. Artemin is therefore oncogenic for GFRa1, neurturin to GFRa2, artemin to GFRa3 and human mammary carcinoma, andtargetedtherapeutic persephin to GFRa4 (Airaksinen and Saarma, 2002). approaches to inhibit artemin function in mammary However, these binding specificities are not exclusive. carcinoma warrant consideration. For example, GDNF can also bind to GFRa2 and Oncogene (2009) 28, 2034–2045; doi:10.1038/onc.2009.66; GFRa3 and artemin to GFRa1 (Bespalov and Saarma, published online 13 April 2009 2007). Apart from the GFRa–RET signaling mechan- ism, RET-independent signaling pathways have also Keywords: artemin; GDNF; mammary; carcinoma; been described (Poteryaev et al., 1999; Trupp et al., 1999; oncogenicity Meng et al., 2001b; Paratcha et al., 2003; Popsueva et al., 2003; Sariola and Saarma, 2003; Enomoto et al., 2004). GDNF, for example, has been shown to activate cytoplasmic Src family tyrosine kinases through GFRa1 Introduction in RET-deficient cells (Poteryaev et al., 1999). Some evidence also links GFLs to cancer. Targeted Glial cell line-derived neurotrophic factor (GDNF) expression of GDNF in undifferentiated spermatogonia family ligands (GFL), a distant subgroup of the promotes malignant testicular tumors (Meng et al., transforming growth factor b superfamily, include four 2000, 2001a). GDNF has also been reported to promote members: GDNF, neurturin, artemin and persephin tumor cell invasion in pancreatic cancer cell lines (Airaksinen et al., 1999; Airaksinen and Saarma, 2002). (Okada et al., 1999; Zhu et al., 2001; Veit et al., 2004). GDNF and artemin are expressed in pancreatic cancer Correspondence: Professor PE Lobie, The Liggins Institute, University and influence neural invasion of the tumor, contributing of Auckland, 2-6 Park Avenue, Private Bag 92019, Auckland, North to cancer cell spreading along pancreatic nerves (Ito Island 1010, New Zealand. et al., 2005; Ceyhan et al., 2006, 2007). Furthermore, E-mail: [email protected] Received 9 July 2008; revised 24 February 2009; accepted 4 March 2009; mutation of the common GFL receptor RET results in published online 13 April 2009 its constitutive activation, leading to thyroid cancer, Oncogenic properties of artemin J Kang et al 2035 pheochromocytoma and multiple endocrine neoplasia tion (RT)–PCR. As observed in Figure 1b, artemin was type 2 (MEN2) (MEN2A and MEN2B) (Pasini et al., expressed in all the cancer cell lines examined. Highest 1996; Saarma and Sariola, 1999; Ichihara et al., 2004). expression was detected in DLD-1 colon, PC3 prostate We demonstrate herein that forced expression of and RL95-2 endometrial carcinoma cell lines. Moderate artemin in mammary carcinoma cells increased onco- expression was observed in the BxPC3 pancreas genicity, resulted in increased invasion and increased carcinoma cell line and in four breast cancer cell lines, tumor growth in xenograft models. Depletion or of which two (T47Dand MCF-7) are estrogen receptor functional inhibition of artemin in mammary carcinoma (ER) þ and two (BT549 and MDA-231) are ERÀ. cells concordantly reduced their oncogenic properties. Limited, but detectable, expression was observed in Artemin expression in breast cancer predicted metas- A549 lung, AGS stomach, Colo320DM colon, DU145 tasis, residual disease after chemotherapy, recurrence prostate and HepG2 liver cancer cell lines. and death. We thereby provide evidence that artemin is The expression of GFRa isoforms and RET was also important in human mammary neoplastic processes. determined by RT–PCR in MCF-7, T47Dand BT549 mammary carcinoma cells (Figure 1c). Expression of GFRa1, GFRa3 and RET was easily detected in MCF-7 Results cells, whereas expression of GFRa2 was weak and required more cycles to detect. GFRa4 was not detected Expression of artemin in human tissues and carcinoma in any of the three cell lines. The expression pattern of cell lines these receptors in T47Dand BT549 cells was quite similar We first determined the expression profile of artemin in to that in MCF-7 cells, except that T47Dexhibited a normal human tissues by the use of a commercially much lower level of GFRa1 expression and BT549 available panel of cDNAs (Figure 1a). Screening for exhibited considerably higher expression of GFRa2. mRNA expression by PCR with primers specific for human artemin revealed that the artemin gene is also Effect of forced expression of artemin on mammary expressed in a number of non-neural tissues, with carcinoma cell number highest expression observed in the cerebellum followed A cell model system was established to determine the by the colon. Expression was also detected in the functional consequences of artemin expression in prostate, uterus, stomach, kidney, trachea, fetal brain, mammary carcinoma cells. MCF-7 cells were stably adipose and cartilage. Artemin was not expressed or transfected with the artemin expression plasmid pIR- expressed at a low level in other remaining tissues. ESneo3-ARTN (designated as MCF7-ARTN) or with The expression of artemin in a number of human the empty vector pIRESneo3 (designated as MCF7- cancer cell lines was also examined by reverse transcrip- Vec). The forced expression of artemin in MCF7-ARTN Figure 1 mRNA expression patterns of artemin in human normal tissues and carcinoma cell lines. (a) Artemin (ARTN) was amplified by PCR with specific primers in a panel of cDNAs derived from different human tissues (Primgen, Bothell, WA, USA). The tissue of origin is indicated above each lane. The b2-microglobulin (b2M) gene was used as the cDNA input control. (b) The expression of artemin in human cancer cell lines was examined by RT–PCR with the same artemin-specific primer pairs. b-actin was included as the RNA input control. (c) The expression of GFRa1–4 and RET in three breast cancer cell lines by reverse transcription (RT)–PCR as in b. The number of PCR cycles is indicated on the right. The bp sizes of amplified products are shown on the left. Oncogene Oncogenic properties of artemin J Kang et al 2036 cells was verified at both the mRNA (Figure 2a) and 7 cells did not affect entry into S-phase, as assessed by protein (middle panel, Figure 2b) levels compared with bromodeoxyuridine (BrdU) incorporation (Figure 2e). control MCF7-Vec cells. Forced expression of artemin also resulted in increased artemin protein in conditioned media (top panel, Figure 2b). Forced expression of artemin increased cell survival We first determined whether forced expression of The effect of forced expression of artemin on the artemin affected total mammary carcinoma cell number survival of MCF-7 cells in serum-deprived
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