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Fra-1 controls motility of bladder cancer cells via transcriptional upregulation of the receptor tyrosine kinase AXL

Oncogene volume 31, pages 1493–1503 (2012)Cite this article

Abstract

Fos-related antigen 1 (Fra-1) is a Fos family member overexpressed in several types of human cancers. Here, we report that Fra-1 is highly expressed in the muscle-invasive form of the carcinoma of the bladder (80%) and to a lesser extent in superficial bladder cancer (42%). We demonstrate that in this type of cancer Fra-1 is regulated via a C-terminal instability signal and C-terminal phosphorylation. We show that manipulation of Fra-1 expression levels in bladder cancer cell lines affects cell morphology, motility and proliferation. The gene coding for AXL tyrosine kinase is directly upregulated by Fra-1 in bladder cancer and in other cell lines. Importantly, our data demonstrate that AXL mediates the effect of Fra-1 on tumour cell motility but not on cell proliferation. We suggest that AXL may represent an attractive therapeutic target in cancers expressing high Fra-1 levels.

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References

  • Andersen H, Mahmood S, Tkach V, Cohn M, Kustikova O, Grigorian M et al. (2002). The ability of Fos family members to produce phenotypic changes in epithelioid cells is not directly linked to their transactivation potentials. Oncogene 21: 4843–4848.

    Article  CAS  PubMed  Google Scholar 

  • Andersen H, Mejlvang J, Mahmood S, Gromova I, Gromov P, Lukanidin E et al. (2005). Immediate and delayed effects of E-cadherin inhibition on gene regulation and cell motility in epidermoid carcinoma cells. Mol Cell Biol 20: 9138–9150.

    Article  Google Scholar 

  • Basbous J, Chalbos D, Hipskind R, Jariel-Encontre I, Piechaczyk M . (2007). Ubiquitin-independent degradation of Fra-1 is antagonized by Erk1/2 pathway-mediated phosphorylation of a unique C-terminal destabilize. Mol Cell Biol 27: 3936–3950.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Belguise K, Kersual N, Galtier F, Chalbos D . (2005). Fra-1 expression level regulates proliferation and invasiveness of breast cancer cells. Oncogene 24: 1434–1444.

    Article  CAS  PubMed  Google Scholar 

  • Bellosta P, Costa M, Lin DA, Basilico C . (1995). The receptor tyrosine kinase ARK mediates cell aggregation by homophilic binding. Mol Cell Biol 15: 614–625.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bergers G, Graninger P, Braselmann S, Wrighton C, Busslinger M . (1995). Transcriptional activation of the fra-1 gene by AP-1 is mediated by regulatory sequences in the first intron. Mol Cell Biol 15: 3748–3758.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Burch PM, Yuan Z, Loonen A, Heintz NH . (2004). An extracellular signal-regulated kinase 1- and 2-dependent program of chromatin trafficking of c-Fos and Fra-1 is required for cyclin D1 expression during cell cycle entry. Mol Cell Biol 24: 4696–4709.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Casalino L, Bakiri L, Talotta F, Weitzman JB, Fusco A, Yaniv M et al. (2007). Fra-1 promotes growth and survival in RAS-transformed thyroid cells by controlling cyclin A transcription. EMBO J 26: 1878–1890.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Casalino L, De Cesare D, Verde P . (2003). Accumulation of Fra-1 in ras-transformed cells depends on both transcriptional autoregulation and MEK-dependent posttranslational stabilization. Mol Cell Biol 23: 4401–4415.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chiappetta G, Ferraro A, Botti G, Monaco M, Pasquinelli R, Vuttariello E et al. (2007). FRA-1 protein overexpression is a feature of hyperplastic and neoplastic breast disorders. BMC Cancer 7: 17.

    Article  PubMed  PubMed Central  Google Scholar 

  • Chiappetta G, Tallini G, De Biaso MC, Pentimalli F, de Nigris F, Losito S et al. (2000). FRA-1 expression in hyperplastic and neoplastic thyroid diseases. Clin Cancer 6: 4300–4306.

    CAS  Google Scholar 

  • Debinski W, Gibo DM . (2005). Fos-related antigen 1 modulates malignant features of glioma cells. Mol Cancer Res 3: 237–249.

    CAS  PubMed  Google Scholar 

  • Dixon JM, Lubomirski M, Amaratunga D, Morrison TB, Brenan CJH, Ilyin SE . (2009). Nanoliter high-throughput RT-qPCR: statistical analysis and assessment. Biotechniques 46: ii–vii.

    Article  PubMed  Google Scholar 

  • Doehn U, Hauge C, Frank SR, Jensen CJ, Duda K, Nielsen JV et al. (2009). RSK is a principal effector of the RAS-ERK pathway for eliciting a coordinate promotile/invasive gene prgram and phenotype in epithelial cells. Mol Cell 35: 511–522.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Eferl R, Wagner EF . (2003). AP-1: a double-edged sword in tumorigenesis. Nat Rev Cancer 3: 859–868.

    Article  CAS  PubMed  Google Scholar 

  • Hafizi S, Dahlbaeck B . (2006). Signalling and functional diversity within the Axl subfamily of receptor tyrosine kinases. Cytokine Growth Factor Rev 17: 295–304.

    Article  CAS  PubMed  Google Scholar 

  • Heiring C, Dahlbaeck B, Muller YA . (2004). Ligand recognition and homophilic interactions in Tyro3: structural insights into the Axl/Tyro3 receptor tyrosine kinase family. J Biol Chem 279: 6952–6958.

    Article  CAS  PubMed  Google Scholar 

  • Holland SJ, Pan A, Franci C, Hu Y, Chang B, Li W et al. (2010). R428, a selective small molecule inhibitor of Axl kinase, blocks tumor spread and prolongs survival in models of metastatic breast cancer. Cancer Res 70: 1544–1554.

    Article  CAS  PubMed  Google Scholar 

  • Hu CY, King YL, Law S, Wong J, Srivastava G . (2001). Identification of differently expressed genes in esophageal squamous cell carcinoma (ESCC) by cDNA expression array. Clin Cancer Res 7: 2213–2221.

    CAS  PubMed  Google Scholar 

  • Hutterer M, Knyazev P, Abate A, Reschke M, Maier H, Stefanova N et al. (2008). Axl and growth arrest-specific gene 6 are frequently overexpressed in human gliomas and predict poor prognosis in patients with glioblastoma multiforme. Clin Cancer Res 14: 130–138.

    Article  CAS  PubMed  Google Scholar 

  • Kakumoto K, Sasai K, Sukezane T, Oneyama C, Ishimaru S, Shibutani K et al. (2006). FRA1 is a determinant for the difference in RAS-induced transformation between human and rat fibroblasts. Proc Natl Acad Sci USA 103: 5490–5495.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Knowles MA . (2008). Molecular pathogenesis of bladder cancer. Int J Clin Oncol 13: 287–297.

    Article  CAS  PubMed  Google Scholar 

  • Kustikova O, Kramerov D, Grigorian M, Berezin V, Bock E, Lukanidin E et al. (1998). Fra-1 induces morphological transformation and increases in vitro invasiveness and motility of epithelioid adenocarcinoma cells. Mol Cell Biol 18: 7095–7105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Linger RM, Keating AK, Earp HS, Graham DK . (2008). TAM receptor tyrosine kinases: biological functions, signalling, and potential therapeutic targeting in human cancer. Adv Cancer Res 100: 35–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mann B, Gelos M, Siedow A, Hanski ML, Gratchev A, Ilyas M et al. (1999). Target genes of beta-catenin-T-cell-factor/lymphoid-enhancer-factor signalling in human colorectal carcinomas. Proc Natl Acad Sci USA 96: 1603–1608.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McHugh LA, Sayan AE, Mejlvang J, Griffiths TR, Sun Y, Manson MM et al. (2009). Lapatinib, a dual inhibitor of ErbB-1/-2 receptors, enhances effects of combination chemotherapy in bladder cancer cells. Int J Oncol 34: 1155–1163.

    CAS  PubMed  Google Scholar 

  • Milde-Langosh K . (2005). The Fos family of transcription factors and their role in tumourigenesis. Eur J Cancer 16: 2449–2461.

    Article  Google Scholar 

  • Mitra AP, Cote RJ . (2009). Molecular pathogenesis and diagnostics in bladder cancer. Annu Rev Pathol 4: 251–285.

    Article  CAS  PubMed  Google Scholar 

  • Murphy LO, MacKeigan JP, Blenis J . (2004). A network of immediate early gene products propagates subtle differences in mitogen-activated protein kinase signal amplitude and duration. Mol Cell Biol 24: 144–153.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ozanne BW, Spence HJ, McGarry LC, Hennigan RF . (2006). Invasion is a genetic program regulated by transcription factors. Curr Opin Genet Dev 16: 65–70.

    Article  CAS  PubMed  Google Scholar 

  • Pollock CB, Shirasawa S, Sasazuki T, Kolch W, Dhillon AS . (2005). Oncogenic K-RAS is required to maintain changes in cytoskeletal organization, adhesion, and motility in colon cancer cells. Cancer Res 65: 1244–1250.

    Article  CAS  PubMed  Google Scholar 

  • Ramos-Nino ME, Scapoli L, Martinelli M, Land S, Mossman BT . (2003). Microarray analysis and RNA silencing link fra-1 to cd44 and c-met expression in mesothelioma. Cancer Res 63: 3539–3545.

    CAS  PubMed  Google Scholar 

  • Rankin EB, Fuh KC, Taylor TE, Krieg AJ, Musser M, Yuan J et al. (2010). AXL is an essential factor and therapeutic target for metastatic ovarian cancer. Cancer Res 70: 7570–7579.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sainaghi PP, Castello L, Bergamasco L, Galletti M, Bellosta P, Avanzi GC . (2005). Gas6 induces proliferation in prostate carcinoma cell lines expressing the Axl receptor. J Cell Physiol 204: 36–44.

    Article  CAS  PubMed  Google Scholar 

  • Shaulian E, Karin M . (2002). AP-1 as a regulator of cell life and death. Nat Cell Biol 4: E131–E136.

    Article  CAS  PubMed  Google Scholar 

  • Shieh YS, Lai CY, Kao YR, Shiah SG, Chu YW, Lee HS et al. (2005). Expression of axl in lung adenocarcinoma and correlation with tumor progression. Neoplasia 7: 1058–1064.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shin S, Dimitri CA, Yoon SO, Dowdle W, Blenis J . (2010). ERK2 but not ERK1 induces epithelial-to-mesenchymal transformation via DEF motif-dependent signalling events. Mol Cell 38: 114–127.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Verde P, Casalino L, Talotta F, Yaniv M, Weitzman JB . (2007). Deciphering AP-1 function in tumorigenesis: fra-ternizing on target promoters. Cell Cycle 6: 2633–2639.

    Article  CAS  PubMed  Google Scholar 

  • Vial E, Marshall CJ . (2003). Elevated ERK-MAP kinase activity protects the FOS family member FRA-1 against proteasomal degradation in colon carcinoma cells. J Cell Sci 116: 4957–4963.

    Article  CAS  PubMed  Google Scholar 

  • Vial E, Sahai E, Marshall CJ . (2003). ERK-MAPK signalling co-ordinately regulates activity of Rac1 and RhoA for tumor cell motility. Cancer Cell 4: 67–79.

    Article  CAS  PubMed  Google Scholar 

  • Vikhanskaya F, Toh WH, Dulloo I, Wu Q, Boominathan L, Ng HH et al. (2007). p73 supports cellular growth through c-Jun-dependent AP-1 transactivation. Nat Cell Biol 6: 698–705.

    Article  Google Scholar 

  • Yeh CY, Shin SM, Yeh HH, Wu TJ, Shin JW, Chang TY et al. (2011). Transcriptional activation of the Axl and PDGFR-a by c-Met throudg a ras- and Src-independent mechanism in human bladder cancer. BMC Cancer 11: 139.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Young MR, Colburn NH . (2006). Fra-1 a target for cancer prevention or intervention. Gene 379: 1–11.

    Article  CAS  PubMed  Google Scholar 

  • Zhang Y-X, Knyazev PG, Cheburkin YV, Sharma K, Knyazev YP, Orfi L et al. (2008). AXL is a potential target for therapeutic intervention in breast cancer progression. Cancer Res 68: 1905–1915.

    Article  CAS  PubMed  Google Scholar 

  • Zhang W, Hart J, McLeod HL, Wang HL . (2005). Differential expression of the AP-1 transcription factor family members in human colorectal epithelial and neuroendocrine neoplasms. Am J Clin Pathol 124: 11–19.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the Association for International Cancer Research grant 07–0083 (to ET) and by a grant from the National Health and Medical Research Council of Australia (to AD). MP is supported by an ‘Equipe Labelisée’ grant from the French Ligue Nationale contre le Cancer

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Author notes

  1. A E Sayan and R Stanford: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester, UK

    A E Sayan, R Stanford, R Vickery, K Kulbicki, R Pal, M Kriajevska, J K Mellon & E Tulchinsky

  2. Cancer Sciences Division, School of Medicine, University of Southampton, Southampton, UK

    A E Sayan

  3. Life Technologies Inc, Woburn, MA, USA

    E Grigorenko

  4. Department of Biochemistry and Molecular Biology, Bio21 Institute, University of Melbourne, Melbourne, Victoria, Australia

    J Diesch & A S Dhillon

  5. Medical Research Council Toxicology Unit, Leicester, UK

    R Edwards & P Greaves

  6. Institue de Génétique Moleculaire de Montpellier, CNRS, Universités Montpellier I et II, UMR5535, Montpellier, France

    I Jariel-Encontre & M Piechaczyk

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  1. A E Sayan
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Correspondence to A S Dhillon or E Tulchinsky.

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Sayan, A., Stanford, R., Vickery, R. et al. Fra-1 controls motility of bladder cancer cells via transcriptional upregulation of the receptor tyrosine kinase AXL. Oncogene 31, 1493–1503 (2012). https://doi.org/10.1038/onc.2011.336

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  • DOI: https://doi.org/10.1038/onc.2011.336

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