Functional disruption of macrophage migration inhibitory factor (MIF) suppresses proliferation of human H460 lung cancer cells by caspase-dependent apoptosis

Cancer Cell International

Dujuan Wang²  Yifeng Luo¹  Junna Hou¹  Yubiao Guo¹ 

[1] Department of Pulmonary Medicine, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China;Department of Physiopathology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China

关键词: Caspase-4;    Caspase-3;    Apoptosis;    Proliferation;    Non-small cell lung cancer;    Macrophage migration inhibitory factor (MIF);   

Others  :  794125
DOI  :  10.1186/1475-2867-13-28

 received in 2012-09-24, accepted in 2013-02-28,  发布年份 2013

【 摘 要 】

Background

Macrophage migration inhibitory factor (MIF) is important in regulating cell proliferation and apoptosis in both normal and cancerous cells, and may be important in cancer progression and metastasis. In human non-small cell lung cancer (NSCLC), the underlying mechanisms responsible for MIF-dependent regulation of cellular proliferation, and cell death remain poorly appreciated.

Methods

The human H460 lung cancer cell-line was treated with an optimally determined dose of 50 pmol/ml MIF siRNA, following which cell proliferation, cell cycle and apoptosis were analyzed. Additionally, known pathways of apoptosis including expression of Annexin-V, enhanced production of caspases-3 and −4 and expression of the Akt signaling protein were assessed in an attempt to provide insights into the signaling pathways involved in apoptosis following disruption of MIF expression.

Results

Specific siRNA sequences markedly decreased MIF expression in H460 cells by 2 to 5-fold as compared with the negative control. Moreover, MIF miRNA dampened not only cellular proliferation, but increased the frequency of apoptotic cells as assessed by cell-surface Annexin-V expression. Entry of cells into apoptosis was partly dependent on enhanced production of caspases −3 and −4 while not affecting the expression of either caspase-8 or the Akt signaling pathway.

Conclusions

In a model of NSCLC, knockdown of MIF mRNA expression dampened H460 proliferation by mechanisms partly dependent on entry of cells into apoptosis and enhanced production of caspase-3 and −4. MIF expression may thus be important in NSCLC progression. Targeting MIF may have clinical utility in the management of human lung cancer.

【 授权许可】

   
2013 Guo 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]Jemal A, Siegel R, Xu J, Ward E: Cancer statistics, 2010. CA Cancer J Clin 2010, 60(5):277-300.
• [2]Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH: Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002, 346(2):92-98.
• [3]Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH: Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006, 355(24):2542-2550.
• [4]Carney DN: Lung cancer–time to move on from chemotherapy. New Engl J Med 2002, 346(2):126-128.
• [5]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.
• [6]Bacher M, Metz CN, Calandra T, Mayer K, Chesney J, Lohoff M, Gemsa D, Donnelly T, Bucala R: An essential regulatory role for macrophage migration inhibitory factor in T-cell activation. Proc Natl Acad Sci USA 1996, 93(15):7849-7854.
• [7]Rossi AG, Haslett C, Hirani N, Greening AP, Rahman I, Metz CN, Bucala R, Donnelly SC: Human circulating eosinophils secrete macrophage migration inhibitory factor (MIF). Potential role in asthma. J Clin Invest 1998, 101(12):2869-2874.
• [8]Imamura K, Nishihira J, Suzuki M, Yasuda K, Sasaki S, Kusunoki Y, Tochimaru H, Takekoshi Y: Identification and immunohistochemical localization of macrophage migration inhibitory factor in human kidney. Biochem Mol Biol Int 1996, 40(6):1233-1242.
• [9]Nishihira J, Koyama Y, Mizue Y: Identification of macrophage migration inhibitory factor (MIF) in human vascular endothelial cells and its induction by lipopolysaccharide. Cytokine 1998, 10(3):199-205.
• [10]McClelland M, Zhao L, Carskadon S, Arenberg D: Expression of CD74, the receptor for macrophage migration inhibitory factor, in non-small cell lung cancer. Am J Pathol 2009, 174(2):638-646.
• [11]White ES, Flaherty KR, Carskadon S, Brant A, Iannettoni MD, Yee J, Orringer MB, Arenberg DA: Macrophage migration inhibitory factor and CXC chemokine expression in non-small cell lung cancer: role in angiogenesis and prognosis. Clin Cancer Res 2003, 9(2):853-860.
• [12]Kayser K, Nwoye JO, Kosjerina Z, Goldmann T, Vollmer E, Kaltner H, Andre S, Gabius HJ: Atypical adenomatous hyperplasia of lung: its incidence and analysis of clinical, glycohistochemical and structural features including newly defined growth regulators and vascularization. Lung Cancer 2003, 42(2):171-182.
• [13]Rendon BE, Roger T, Teneng I, Zhao M, Al-Abed Y, Calandra T, Mitchell RA: Regulation of human lung adenocarcinoma cell migration and invasion by macrophage migration inhibitory factor. J Biol Chem 2007, 282(41):29910-29918.
• [14]Hauck CR, Sieg DJ, Hsia DA, Loftus JC, Gaarde WA, Monia BP, Schlaepfer DD: Inhibition of focal adhesion kinase expression or activity disrupts epidermal growth factor-stimulated signaling promoting the migration of invasive human carcinoma cells. Cancer Res 2001, 61(19):7079-7090.
• [15]Chan AY, Coniglio SJ, Chuang YY, Michaelson D, Knaus UG, Philips MR, Symons M: Roles of the Rac1 and Rac3 GTPases in human tumor cell invasion. Oncogene 2005, 24(53):7821-7829.
• [16]Conroy H, Mawhinney L, Donnelly SC: Inflammation and cancer: macrophage migration inhibitory factor (MIF)–the potential missing link. QJM 2010, 103(11):831-836.
• [17]Cooke G, Armstrong ME, Donnelly SC: Macrophage migration inhibitory factor (MIF), enzymatic activity and the inflammatory response. Biofactors 2009, 35(2):165-168.
• [18]Bach JP, Rinn B, Meyer B, Dodel R, Bacher M: Role of MIF in inflammation and tumorigenesis. Oncology 2008, 75(3–4):127-133.
• [19]Bucala R, Donnelly SC: Macrophage migration inhibitory factor: a probable link between inflammation and cancer. Immunity 2007, 26(3):281-285.
• [20]Ralph JA, Ahmed AU, Santos LL, Clark AR, McMorrow J, Murphy EP, Morand EF: Identification of NURR1 as a mediator of MIF signaling during chronic arthritis: effects on glucocorticoid-induced MKP1. Am J Pathol 2010, 177(5):2366-2378.
• [21]Lehmann LE, Book M, Hartmann W, Weber SU, Schewe JC, Klaschik S, Hoeft A, Stuber F: A MIF haplotype is associated with the outcome of patients with severe sepsis: a case control study. J Transl Med 2009, 7:100. BioMed Central Full Text
• [22]Shiroeda H, Tahara T, Nakamura M, Shibata T, Nomura T, Yamada H, Hayashi R, Saito T, Yamada M, Fukuyama T, et al.: Association between functional promoter polymorphisms of macrophage migration inhibitory factor (MIF) gene and ulcerative colitis in Japan. Cytokine 2010, 51(2):173-177.
• [23]Takahashi N, Nishihira J, Sato Y, Kondo M, Ogawa H, Ohshima T, Une Y, Todo S: Involvement of macrophage migration inhibitory factor (MIF) in the mechanism of tumor cell growth. Mol Med 1998, 4(11):707-714.
• [24]Hira E, Ono T, Dhar DK, El-Assal ON, Hishikawa Y, Yamanoi A, Nagasue N: Overexpression of macrophage migration inhibitory factor induces angiogenesis and deteriorates prognosis after radical resection for hepatocellular carcinoma. Cancer 2005, 103(3):588-598.
• [25]Meyer-Siegler KL, Bellino MA, Tannenbaum M: Macrophage migration inhibitory factor evaluation compared with prostate specific antigen as a biomarker in patients with prostate carcinoma. Cancer 2002, 94(5):1449-1456.
• [26]Binsky I, Haran M, Starlets D, Gore Y, Lantner F, Harpaz N, Leng L, Goldenberg DM, Shvidel L, Berrebi A, et al.: IL-8 secreted in a macrophage migration-inhibitory factor- and CD74-dependent manner regulates B cell chronic lymphocytic leukemia survival. Proc Natl Acad Sci USA 2007, 104(33):13408-13413.
• [27]Legendre H, Decaestecker C, Nagy N, Hendlisz A, Schuring MP, Salmon I, Gabius HJ, Pector JC, Kiss R: Prognostic values of galectin-3 and the macrophage migration inhibitory factor (MIF) in human colorectal cancers. Mod Pathol 2003, 16(5):491-504.
• [28]Khan N, Cromer CJ, Campa M, Patz EF Jr: Clinical utility of serum amyloid A and macrophage migration inhibitory factor as serum biomarkers for the detection of nonsmall cell lung carcinoma. Cancer 2004, 101(2):379-384.
• [29]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.
• [30]Lai KN, Leung JC, Metz CN, Lai FM, Bucala R, Lan HY: Role for macrophage migration inhibitory factor in acute respiratory distress syndrome. J Pathol 2003, 199(4):496-508.
• [31]Donnelly SC, Bucala R: Macrophage migration inhibitory factor: a regulator of glucocorticoid activity with a critical role in inflammatory disease. Mol Med Today 1997, 3(11):502-507.
• [32]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.
• [33]Jung H, Seong HA, Ha H: Critical role of cysteine residue 81 of macrophage migration inhibitory factor (MIF) in MIF-induced inhibition of p53 activity. J Biol Chem 2008, 283(29):20383-20396.
• [34]Kyriakis JM: Thinking outside the box about Ras. J Biol Chem 2009, 284(17):10993-10994.
• [35]White ES, Strom SR, Wys NL, Arenberg DA: Non-small cell lung cancer cells induce monocytes to increase expression of angiogenic activity. J Immunol 2001, 166(12):7549-7555.
• [36]Arenberg DA, Polverini PJ, Kunkel SL, Shanafelt A, Hesselgesser J, Horuk R, Strieter RM: The role of CXC chemokines in the regulation of angiogenesis in non-small cell lung cancer. J Leukoc Biol 1997, 62(5):554-562.
• [37]Arenberg D, Luckhardt TR, Carskadon S, Zhao L, Amin MA, Koch AE: Macrophage migration inhibitory factor promotes tumor growth in the context of lung injury and repair. Am J Respir Crit Care Med 2010, 182(8):1030-1037.
• [38]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.
• [39]Shun CT, Lin JT, Huang SP, Lin MT, Wu MS: Expression of macrophage migration inhibitory factor is associated with enhanced angiogenesis and advanced stage in gastric carcinomas. World J Gastroenterol 2005, 11(24):3767-3771.
• [40]Beswick EJ, Pinchuk IV, Minch K, Suarez G, Sierra JC, Yamaoka Y, Reyes VE: The Helicobacter pylori urease B subunit binds to CD74 on gastric epithelial cells and induces NF-kappaB activation and interleukin-8 production. Infect Immun 2006, 74(2):1148-1155.
• [41]Gamez-Pozo A, Sanchez-Navarro I, Calvo E, Agullo-Ortuno MT, Lopez-Vacas R, Diaz E, Camafeita E, Nistal M, Madero R, Espinosa E, et al.: PTRF/cavin-1 and MIF proteins are identified as non-small cell lung cancer biomarkers by label-free proteomics. PLoS One 2012, 7(3):e33752.
• [42]Calandra T, Roger T: Macrophage migration inhibitory factor: a regulator of innate immunity. Nat Rev Immunol 2003, 3(10):791-800.
• [43]Kamimura A, Kamachi M, Nishihira J, Ogura S, Isobe H, Dosaka-Akita H, Ogata A, Shindoh M, Ohbuchi T, Kawakami Y: Intracellular distribution of macrophage migration inhibitory factor predicts the prognosis of patients with adenocarcinoma of the lung. Cancer 2000, 89(2):334-341.
• [44]Mitchell RA: Mechanisms and effectors of MIF-dependent promotion of tumorigenesis. Cell Signal 2004, 16(1):13-19.
• [45]Lue H, Kapurniotu A, Fingerle-Rowson G, Roger T, Leng L, Thiele M, Calandra T, Bucala R, Bernhagen J: Rapid and transient activation of the ERK MAPK signalling pathway by macrophage migration inhibitory factor (MIF) and dependence on JAB1/CSN5 and Src kinase activity. Cell Signal 2006, 18(5):688-703.
• [46]Hudson JD, Shoaibi MA, Maestro R, Carnero A, Hannon GJ, Beach DH: A proinflammatory cytokine inhibits p53 tumor suppressor activity. J Exp Med 1999, 190(10):1375-1382.
• [47]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.
• [48]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.
• [49]Amin MA, Volpert OV, Woods JM, Kumar P, Harlow LA, Koch AE: Migration inhibitory factor mediates angiogenesis via mitogen-activated protein kinase and phosphatidylinositol kinase. Circ Res 2003, 93(4):321-329.
• [50]Chesney J, Metz C, Bacher M, Peng T, Meinhardt A, Bucala R: An essential role for macrophage migration inhibitory factor (MIF) in angiogenesis and the growth of a murine lymphoma. Mol Med 1999, 5(3):181-191.
• [51]Xu X, Wang B, Ye C, Yao C, Lin Y, Huang X, Zhang Y, Wang S: Overexpression of macrophage migration inhibitory factor induces angiogenesis in human breast cancer. Cancer Lett 2008, 261(2):147-157.
• [52]Rao RV, Hermel E, Castro-Obregon S, del Rio G, Ellerby LM, Ellerby HM, Bredesen DE: Coupling endoplasmic reticulum stress to the cell death program. Mechanism of caspase activation. J Biol Chem 2001, 276(36):33869-33874.
• [53]Oyadomari S, Araki E, Mori M: Endoplasmic reticulum stress-mediated apoptosis in pancreatic beta-cells. Apoptosis 2002, 7(4):335-345.
• [54]Nakagawa T, Yuan J: Cross-talk between two cysteine protease families. Activation of caspase-12 by calpain in apoptosis. J Cell Biol 2000, 150(4):887-894.
• [55]Hitomi J, Katayama T, Eguchi Y, Kudo T, Taniguchi M, Koyama Y, Manabe T, Yamagishi S, Bando Y, Imaizumi K, et al.: Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis and Abeta-induced cell death. J Cell Biol 2004, 165(3):347-356.
• [56]Li Z, Zhang T, Dai H, Liu G, Wang H, Sun Y, Zhang Y, Ge Z: Endoplasmic reticulum stress is involved in myocardial apoptosis of streptozocin-induced diabetic rats. J Endocrinol 2008, 196(3):565-572.
• [57]MacFarlane M: TRAIL-induced signalling and apoptosis. Toxicol Lett 2003, 139(2–3):89-97.