Macrophage migration inhibitory factor engages PI3K/Akt signalling and is a prognostic factor in metastatic melanoma

BMC Cancer

Rick F Thorne²  Xu Dong Zhang³  Peter Hersey⁴  Xin Yan Geng¹  Elham Sadeqzadeh³  Timothy J Molloy⁵  Charles E de Bock³  Camila S Oliveira³ 

[1]School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW 2308, Australia

[2]School of Environmental and Life Sciences, Faculty of Science & IT, University of Newcastle, Ourimbah, NSW 2258, Australia

[3]Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia

[4]Kolling Institute of Medical Research, University of Sydney, St. Leonards, NSW 2065, Australia

[5]The Kinghorn Cancer Centre and Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia

关键词: Proliferation;    Prognostic factor;    Metastasis;    Melanoma;    MIF;    Cell cycle;    BRAF;    Akt signalling;   

Others  :  1121228
DOI  :  10.1186/1471-2407-14-630

 received in 2014-05-08, accepted in 2014-08-20,  发布年份 2014

【 摘 要 】

Background

Macrophage migration inhibitory factor (MIF) is a widely expressed cytokine involved in a variety of cellular processes including cell cycle regulation and the control of proliferation. Overexpression of MIF has been reported in a number of cancer types and it has previously been shown that MIF is upregulated in melanocytic tumours with the highest expression levels occurring in malignant melanoma. However, the clinical significance of high MIF expression in melanoma has not been reported.

Methods

MIF expression was depleted in human melanoma cell lines using siRNA-mediated gene knockdown and effects monitored using in vitro assays of proliferation, cell cycle, apoptosis, clonogenicity and Akt signalling. In silico analyses of expression microarray data were used to correlate MIF expression levels in melanoma tumours with overall patient survival using a univariate Cox regression model.

Results

Knockdown of MIF significantly decreased proliferation, increased apoptosis and decreased anchorage-independent growth. Effects were associated with reduced numbers of cells entering S phase concomitant with decreased cyclin D1 and CDK4 expression, increased p27 expression and decreased Akt phosphorylation. Analysis of clinical outcome data showed that MIF expression levels in primary melanoma were not associated with outcome (HR = 1.091, p = 0.892) whereas higher levels of MIF in metastatic lesions were significantly associated with faster disease progression (HR = 2.946, p = 0.003 and HR = 4.600, p = 0.004, respectively in two independent studies).

Conclusions

Our in vitro analyses show that MIF functions upstream of the PI3K/Akt pathway in human melanoma cell lines. Moreover, depletion of MIF inhibited melanoma proliferation, viability and clonogenic capacity. Clinically, high MIF levels in metastatic melanoma were found to be associated with faster disease recurrence. These findings support the clinical significance of MIF signalling in melanoma and provide a strong rationale for both targeting and monitoring MIF expression in clinical melanoma.

【 授权许可】

   
2014 Oliveira et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

Figure 7.

【 参考文献 】

• [1]Bloom BR, Bennett B: Mechanism of a reaction in vitro associated with delayed-type hypersensitivity. Science 1966, 153(3731):80-82.
• [2]David JR: Delayed hypersensitivity in vitro: its mediation by cell-free substances formed by lymphoid cell-antigen interaction. Proc Natl Acad Sci U S A 1966, 56(1):72-77.
• [3]Baugh JA, Bucala R: Macrophage migration inhibitory factor. Crit Care Med 2002, 30(1 Supp):S27-S35.
• [4]Calandra T, Roger T: Macrophage migration inhibitory factor: a regulator of innate immunity. Nat Rev Immunol 2003, 3(10):791-800.
• [5]Bando H, Matsumoto G, Bando M, Muta M, Ogawa T, Funata N, Nishihira J, Koike M, Toi M: Expression of macrophage migration inhibitory factor in human breast cancer: association with nodal spread. Jpn J Cancer Res 2002, 93(4):389-396.
• [6]Tomiyasu M, Yoshino I, Suemitsu R, Okamoto T, Sugimachi K: Quantification of macrophage migration inhibitory factor mRNA expression in non-small cell lung cancer tissues and its clinical significance. Clin Cancer Res 2002, 8(12):3755-3760.
• [7]He XX, Yang J, Ding YW, Liu W, Shen QY, Xia HH: Increased epithelial and serum expression of macrophage migration inhibitory factor (MIF) in gastric cancer: potential role of MIF in gastric carcinogenesis. Gut 2006, 55(6):797-802.
• [8]Dumitru CA, Gholaman H, Trellakis S, Bruderek K, Dominas N, Gu X, Bankfalvi A, Whiteside TL, Lang S, Brandau S: Tumor-derived macrophage migration inhibitory factor modulates the biology of head and neck cancer cells via neutrophil activation. Int J Cancer 2011, 129(4):859-869.
• [9]Baron N, Deuster O, Noelker C, Stuer C, Strik H, Schaller C, Dodel R, Meyer B, Bacher M: Role of macrophage migration inhibitory factor in primary glioblastoma multiforme cells. J Neurosci Res 2011, 89(5):711-717.
• [10]Liao B, Zhong BL, Li Z, Tian XY, Li Y, Li B: Macrophage migration inhibitory factor contributes angiogenesis by up-regulating IL-8 and correlates with poor prognosis of patients with primary nasopharyngeal carcinoma. J Surg Oncol 2010, 102(7):844-851.
• [11]Calandra T, Bernhagen J, Mitchell RA, Bucala R: The macrophage is an important and previously unrecognized source of macrophage migration inhibitory factor. J Exp Med 1994, 179(6):1895-1902.
• [12]Flieger O, Engling A, Bucala R, Lue H, Nickel W, Bernhagen J: Regulated secretion of macrophage migration inhibitory factor is mediated by a non-classical pathway involving an ABC transporter. FEBS Lett 2003, 551(1–3):78-86.
• [13]Swope MD, Lolis E: Macrophage migration inhibitory factor: cytokine, hormone, or enzyme? Rev Physiol Biochem Pharmacol 1999, 139:1-32.
• [14]Bifulco C, McDaniel K, Leng L, Bucala R: Tumor growth-promoting properties of macrophage migration inhibitory factor. Curr Pharm Des 2008, 14(36):3790-3801.
• [15]Yasasever V, Camlica H, Duranyildiz D, Oguz H, Tas F, Dalay N: Macrophage migration inhibitory factor in cancer. Cancer Invest 2007, 25(8):715-719.
• [16]Leng L, Metz CN, Fang Y, Xu J, Donnelly S, Baugh J, Delohery T, Chen Y, Mitchell RA, Bucala R: MIF signal transduction initiated by binding to CD74. J Exp Med 2003, 197(11):1467-1476.
• [17]Starlets D, Gore Y, Binsky I, Haran M, Harpaz N, Shvidel L, Becker-Herman S, Berrebi A, Shachar I: Cell-surface CD74 initiates a signaling cascade leading to cell proliferation and survival. Blood 2006, 107(12):4807-4816.
• [18]Shi X, Leng L, Wang T, Wang W, Du X, Li J, McDonald C, Chen Z, Murphy JW, Lolis E, Noble P, Knudson W, Bucala R: CD44 is the signaling component of the macrophage migration inhibitory factor-CD74 receptor complex. Immunity 2006, 25(4):595-606.
• [19]Bernhagen J, Krohn R, Lue H, Gregory JL, Zernecke A, Koenen RR, Dewor M, Georgiev I, Schober A, Leng L, Kooistra T, Fingerle-Rowson G, Ghezzi P, Kleemann R, McColl SR, Bucala R, Hickey MJ, Weber C: MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment. Nat Med 2007, 13(5):587-596.
• [20]Schwartz V, Lue H, Kraemer S, Korbiel J, Krohn R, Ohl K, Bucala R, Weber C, Bernhagen J: A functional heteromeric MIF receptor formed by CD74 and CXCR4. FEBS Lett 2009, 583(17):2749-2757.
• [21]Ren Y, Chan HM, Li Z, Lin C, Nicholls J, Chen CF, Lee PY, Lui V, Bacher M, Tam PK: Upregulation of macrophage migration inhibitory factor contributes to induced N-Myc expression by the activation of ERK signaling pathway and increased expression of interleukin-8 and VEGF in neuroblastoma. Oncogene 2004, 23(23):4146-4154.
• [22]Lue H, Thiele M, Franz J, Dahl E, Speckgens S, Leng L, Fingerle-Rowson G, Bucala R, Luscher B, Bernhagen J: Macrophage migration inhibitory factor (MIF) promotes cell survival by activation of the Akt pathway and role for CSN5/JAB1 in the control of autocrine MIF activity. Oncogene 2007, 26(35):5046-5059.
• [23]Li GQ, Xie J, Lei XY, Zhang L: Macrophage migration inhibitory factor regulates proliferation of gastric cancer cells via the PI3K/Akt pathway. World J Gastroenterol 2009, 15(44):5541-5548.
• [24]Rumpler G, Becker B, Hafner C, McClelland M, Stolz W, Landthaler M, Schmitt R, Bosserhoff A, Vogt T: Identification of differentially expressed genes in models of melanoma progression by cDNA array analysis: SPARC, MIF and a novel cathepsin protease characterize aggressive phenotypes. Exp Dermatol 2003, 12(6):761-771.
• [25]Shimizu T, Abe R, Nakamura H, Ohkawara A, Suzuki M, Nishihira J: High expression of macrophage migration inhibitory factor in human melanoma cells and its role in tumor cell growth and angiogenesis. Biochem Biophys Res Commun 1999, 264(3):751-758.
• [26]Repp AC, Mayhew ES, Apte S, Niederkorn JY: Human uveal melanoma cells produce macrophage migration-inhibitory factor to prevent lysis by NK cells. J Immunol 2000, 165(2):710-715.
• [27]Culp WD, Tsagozis P, Burgio M, Russell P, Pisa P, Garland D: Interference of macrophage migration inhibitory factor expression in a mouse melanoma inhibits tumor establishment by up-regulating thrombospondin-1. Mol Cancer Res 2007, 5(12):1225-1231.
• [28]Thomas WD, Smith MJ, Si Z, Hersey P: Expression of the co-stimulatory molecule CD40 on melanoma cells. Int J Cancer 1996, 68(6):795-801.
• [29]Zhang XD, Franco A, Myers K, Gray C, Nguyen T, Hersey P: Relation of TNF-related apoptosis-inducing ligand (TRAIL) receptor and FLICE-inhibitory protein expression to TRAIL-induced apoptosis of melanoma. Cancer Res 1999, 59(11):2747-2753.
• [30]Sadeqzadeh E, de Bock CE, Zhang XD, Shipman KL, Scott NM, Song C, Yeadon T, Oliveira CS, Jin B, Hersey P, Boyd AW, Burns GF, Thorne RF: Dual processing of FAT1 cadherin protein by human melanoma cells generates distinct protein products. J Biol Chem 2011, 286(32):28181-28191.
• [31]Thorne RF, Ralston KJ, de Bock CE, Mhaidat NM, Zhang XD, Boyd AW, Burns GF: Palmitoylation of CD36/FAT regulates the rate of its post-transcriptional processing in the endoplasmic reticulum. Biochim Biophys Acta 2010, 1803(11):1298-1307.
• [32]de Bock CE, Ardjmand A, Molloy TJ, Bone SM, Johnstone D, Campbell DM, Shipman KL, Yeadon TM, Holst J, Spanevello MD, Nelmes G, Catchpoole DR, Lincz LF, Boyd AW, Burns GF, Thorne RF: The Fat1 cadherin is overexpressed and an independent prognostic factor for survival in paired diagnosis-relapse samples of precursor B-cell acute lymphoblastic leukemia. Leukemia 2012, 26(5):918-926.
• [33]Guo Y, Hou J, Luo Y, Wang D: Functional disruption of macrophage migration inhibitory factor (MIF) suppresses proliferation of human H460 lung cancer cells by caspase-dependent apoptosis. Cancer Cell Int 2013, 13(1):28.
• [34]Madhunapantula SV, Robertson GP: The PTEN-AKT3 signaling cascade as a therapeutic target in melanoma. Pigment Cell Melanoma Res 2009, 22(4):400-419.
• [35]Madhunapantula SV, Robertson GP: Therapeutic Implications of Targeting AKT Signaling in Melanoma. Enzyme Res 2011, 2011:327923.
• [36]Stahl JM, Sharma A, Cheung M, Zimmerman M, Cheng JQ, Bosenberg MW, Kester M, Sandirasegarane L, Robertson GP: Deregulated Akt3 activity promotes development of malignant melanoma. Cancer Res 2004, 64(19):7002-7010.
• [37]Smith AP, Hoek K, Becker D: Whole-genome expression profiling of the melanoma progression pathway reveals marked molecular differences between nevi/melanoma in situ and advanced-stage melanomas. Cancer Biol Ther 2005, 4(9):1018-1029.
• [38]Xu L, Shen SS, Hoshida Y, Subramanian A, Ross K, Brunet JP, Wagner SN, Ramaswamy S, Mesirov JP, Hynes RO: Gene expression changes in an animal melanoma model correlate with aggressiveness of human melanoma metastases. Mol Cancer Res 2008, 6(5):760-769.
• [39]Bogunovic D, O’Neill DW, Belitskaya-Levy I, Vacic V, Yu YL, Adams S, Darvishian F, Berman R, Shapiro R, Pavlick AC, Lonardi S, Zavadil J, Osman I, Bhardwaj N: Immune profile and mitotic index of metastatic melanoma lesions enhance clinical staging in predicting patient survival. Proc Natl Acad Sci U S A 2009, 106(48):20429-20434.
• [40]Denz A, Pilarsky C, Muth D, Ruckert F, Saeger HD, Grutzmann R: Inhibition of MIF leads to cell cycle arrest and apoptosis in pancreatic cancer cells. J Surg Res 2010, 160(1):29-34.
• [41]Liu L, Ji C, Chen J, Li Y, Fu X, Xie Y, Gu S, Mao Y: A global genomic view of MIF knockdown-mediated cell cycle arrest. Cell Cycle 2008, 7(11):1678-1692.
• [42]Soengas MS, Lowe SW: Apoptosis and melanoma chemoresistance. Oncogene 2003, 22(20):3138-3151.
• [43]Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, et al.: Mutations of the BRAF gene in human cancer. Nature 2002, 417(6892):949-954.
• [44]Dhomen N, Marais R: BRAF signaling and targeted therapies in melanoma. Hematol Oncol Clin North Am 2009, 23(3):529-545. ix
• [45]Smalley KS: Understanding melanoma signaling networks as the basis for molecular targeted therapy. J Invest Dermatol 2010, 130(1):28-37.
• [46]Tsai J, Lee JT, Wang W, Zhang J, Cho H, Mamo S, Bremer R, Gillette S, Kong J, Haass NK, Sproesser K, Li L, Smalley KS, Fong D, Zhu YL, Marimuthu A, Nguyen H, Lam B, Liu J, Cheung I, Rice J, Suzuki Y, Luu C, Settachatgul C, Shellooe R, Cantwell J, Kim SH, Schlessinger J, Zhang KY, West BL, et al.: Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity. Proc Natl Acad Sci U S A 2008, 105(8):3041-3046.
• [47]Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, O’Dwyer PJ, Lee RJ, Grippo JF, Nolop K, Chapman PB: Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 2010, 363(9):809-819.
• [48]Vultur A, Villanueva J, Herlyn M: BRAF inhibitor unveils its potential against advanced melanoma. Cancer Cell 2010, 18(4):301-302.
• [49]Solit D, Rosen N: Oncogenic RAF: a brief history of time. Pigment Cell Melanoma Res 2010, 23(6):760-762.
• [50]Sosman JA, Kim KB, Schuchter L, Gonzalez R, Pavlick AC, Weber JS, McArthur GA, Hutson TE, Moschos SJ, Flaherty KT, Hersey P, Kefford R, Lawrence D, Puzanov I, Lewis KD, Amaravadi RK, Chmielowski B, Lawrence HJ, Shyr Y, Ye F, Li J, Nolop KB, Lee RJ, Joe AK, Ribas A: Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med 2012, 366(8):707-714.
• [51]Ascierto PA, Minor D, Ribas A, Lebbe C, O’Hagan A, Arya N, Guckert M, Schadendorf D, Kefford RF, Grob JJ, Hamid O, Amaravadi R, Simeone E, Wilhelm T, Kim KB, Long GV, Martin AM, Mazumdar J, Goodman VL, Trefzer U: Phase II Trial (BREAK-2) of the BRAF Inhibitor Dabrafenib (GSK2118436) in Patients With Metastatic Melanoma. J Clin Oncol 2013, 31(26):3205-3211.
• [52]Jiang CC, Lai F, Tay KH, Croft A, Rizos H, Becker TM, Yang F, Liu H, Thorne RF, Hersey P, Zhang XD: Apoptosis of human melanoma cells induced by inhibition of B-RAFV600E involves preferential splicing of bimS. Cell Death Dis 2010, 1:e69.
• [53]Jiang CC, Lai F, Thorne RF, Yang F, Liu H, Hersey P, Zhang XD: MEK-independent survival of B-RAFV600E melanoma cells selected for resistance to apoptosis induced by the RAF inhibitor PLX4720. Clin Cancer Res 2011, 17(4):721-730.
• [54]Platz A, Egyhazi S, Ringborg U, Hansson J: Human cutaneous melanoma; a review of NRAS and BRAF mutation frequencies in relation to histogenetic subclass and body site. Mol Oncol 2008, 1(4):395-405.
• [55]Palmieri G, Capone M, Ascierto ML, Gentilcore G, Stroncek DF, Casula M, Sini MC, Palla M, Mozzillo N, Ascierto PA: Main roads to melanoma. J Transl Med 2009, 7:86.
• [56]Bennett DC: How to make a melanoma: what do we know of the primary clonal events? Pigment Cell Melanoma Res 2008, 21(1):27-38.
• [57]Whiteman DC, Zhou XP, Cummings MC, Pavey S, Hayward NK, Eng C: Nuclear PTEN expression and clinicopathologic features in a population-based series of primary cutaneous melanoma. Int J Cancer 2002, 99(1):63-67.
• [58]Reifenberger J, Wolter M, Bostrom J, Buschges R, Schulte KW, Megahed M, Ruzicka T, Reifenberger G: Allelic losses on chromosome arm 10q and mutation of the PTEN (MMAC1) tumour suppressor gene in primary and metastatic malignant melanomas. Virchows Arch 2000, 436(5):487-493.
• [59]Mirmohammadsadegh A, Marini A, Nambiar S, Hassan M, Tannapfel A, Ruzicka T, Hengge UR: Epigenetic silencing of the PTEN gene in melanoma. Cancer Res 2006, 66(13):6546-6552.
• [60]Lahtz C, Stranzenbach R, Fiedler E, Helmbold P, Dammann RH: Methylation of PTEN as a prognostic factor in malignant melanoma of the skin. J Invest Dermatol 2010, 130(2):620-622.
• [61]Curtin JA, Stark MS, Pinkel D, Hayward NK, Bastian BC: PI3-kinase subunits are infrequent somatic targets in melanoma. J Invest Dermatol 2006, 126(7):1660-1663.
• [62]Curtin JA, Busam K, Pinkel D, Bastian BC: Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol 2006, 24(26):4340-4346.
• [63]Manning BD, Cantley LC: AKT/PKB signaling: navigating downstream. Cell 2007, 129(7):1261-1274.
• [64]Liang J, Zubovitz J, Petrocelli T, Kotchetkov R, Connor MK, Han K, Lee JH, Ciarallo S, Catzavelos C, Beniston R, Franssen E, Slingerland JM: PKB/Akt phosphorylates p27, impairs nuclear import of p27 and opposes p27-mediated G1 arrest. Nat Med 2002, 8(10):1153-1160.
• [65]Shin I, Yakes FM, Rojo F, Shin NY, Bakin AV, Baselga J, Arteaga CL: PKB/Akt mediates cell-cycle progression by phosphorylation of p27(Kip1) at threonine 157 and modulation of its cellular localization. Nat Med 2002, 8(10):1145-1152.
• [66]Viglietto G, Motti ML, Bruni P, Melillo RM, D’Alessio A, Califano D, Vinci F, Chiappetta G, Tsichlis P, Bellacosa A, Fusco A, Santoro M: Cytoplasmic relocalization and inhibition of the cyclin-dependent kinase inhibitor p27(Kip1) by PKB/Akt-mediated phosphorylation in breast cancer. Nat Med 2002, 8(10):1136-1144.
• [67]Diehl JA, Cheng M, Roussel MF, Sherr CJ: Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization. Genes Dev 1998, 12(22):3499-3511.
• [68]Welcker M, Singer J, Loeb KR, Grim J, Bloecher A, Gurien-West M, Clurman BE, Roberts JM: Multisite phosphorylation by Cdk2 and GSK3 controls cyclin E degradation. Mol Cell 2003, 12(2):381-392.
• [69]Miracco C, De Nisi MC, Arcuri F, Cosci E, Pacenti L, Toscano M, Lalinga AV, Biagioli M, Rubegni P, Vatti R, Maellaro E, Del Bello B, Massi D, Luzi P, Tosi P: Macrophage migration inhibitory factor protein and mRNA expression in cutaneous melanocytic tumours. Int J Oncol 2006, 28(2):345-352.
• [70]Hagemann T, Wilson J, Kulbe H, Li NF, Leinster DA, Charles K, Klemm F, Pukrop T, Binder C, Balkwill FR: Macrophages induce invasiveness of epithelial cancer cells via NF-kappa B and JNK. J Immunol 2005, 175(2):1197-1205.
• [71]Chen P, Huang Y, Bong R, Ding Y, Song N, Wang X, Song X, Luo Y: Tumor-associated macrophages promote angiogenesis and melanoma growth via adrenomedullin in a paracrine and autocrine manner. Clin Cancer Res 2011, 17(23):7230-7239.
• [72]Clemente CG, Mihm MC Jr, Bufalino R, Zurrida S, Collini P, Cascinelli N: Prognostic value of tumor infiltrating lymphocytes in the vertical growth phase of primary cutaneous melanoma. Cancer 1996, 77(7):1303-1310.