Threonyl-tRNA synthetase overexpression correlates with angiogenic markers and progression of human ovarian cancer

BMC Cancer

Theresa L Wellman¹  Midori Eckenstein¹  Cheung Wong²  Mercedes Rincon²  Takamaru Ashikaga²  Sharon L Mount²  Christopher S Francklyn²  Karen M Lounsbury² 

[1] Departments of Pharmacology, University of Vermont, College of Medicine, Burlington, Vermont 05405, USA

[2] The Vermont Cancer Center, University of Vermont, College of Medicine, Burlington, Vermont 05405, USA

关键词: Multivariate Cox analysis;    Database analysis;    Serous papillary ovarian cancer;    tRNA synthetase;    Angiogenesis;    Tumor microenvironment;   

Others  :  1134693
DOI  :  10.1186/1471-2407-14-620

 received in 2014-04-25, accepted in 2014-08-20,  发布年份 2014

【 摘 要 】

Background

Ovarian tumors create a dynamic microenvironment that promotes angiogenesis and reduces immune responses. Our research has revealed that threonyl-tRNA synthetase (TARS) has an extracellular angiogenic activity separate from its function in protein synthesis. The objective of this study was to test the hypothesis that TARS expression in clinical samples correlates with angiogenic markers and ovarian cancer progression.

Methods

Protein and mRNA databases were explored to correlate TARS expression with ovarian cancer. Serial sections of paraffin embedded ovarian tissues from 70 patients diagnosed with epithelial ovarian cancer and 12 control patients were assessed for expression of TARS, vascular endothelial growth factor (VEGF) and PECAM using immunohistochemistry. TARS secretion from SK-OV-3 human ovarian cancer cells was measured. Serum samples from 31 tissue-matched patients were analyzed by ELISA for TARS, CA-125, and tumor necrosis factor-α (TNF-α).

Results

There was a strong association between the tumor expression of TARS and advancing stage of epithelial ovarian cancer (p < 0.001). TARS expression and localization were also correlated with VEGF (p < 0.001). A significant proportion of samples included heavy TARS staining of infiltrating leukocytes which also correlated with stage (p = 0.017). TARS was secreted by ovarian cancer cells, and patient serum TARS was related to tumor TARS and angiogenic markers, but did not achieve significance with respect to stage. Multivariate Cox proportional hazard models revealed a surprising inverse relationship between TARS expression and mortality risk in late stage disease (p = 0.062).

Conclusions

TARS expression is increased in epithelial ovarian cancer and correlates with markers of angiogenic progression. These findings and the association of TARS with disease survival provide clinical validation that TARS is associated with angiogenesis in ovarian cancer. These results encourage further study of TARS as a regulator of the tumor microenvironment and possible target for diagnosis and/or treatment in ovarian cancer.

【 授权许可】

   
2014 Wellman et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

【 参考文献 】

• [1]Vaughan S, Coward JI, Bast RC Jr, Berchuck A, Berek JS, Brenton JD, Coukos G, Crum CC, Drapkin R, Etemadmoghadam D, Friedlander M, Gabra H, Kaye SB, Lord CJ, Lengyel E, Levine DA, McNeish IA, Menon U, Mills GB, Nephew KP, Oza AM, Sood AK, Stronach EA, Walczak H, Bowtell DD, Balkwill FR: Rethinking ovarian cancer: recommendations for improving outcomes. Nat Rev 2011, 11(10):719-725.
• [2]Mucaj V, Shay JE, Simon MC: Effects of hypoxia and HIFs on cancer metabolism. Int J Hematol 2012, 95(5):464-470.
• [3]Saad AF, Hu W, Sood AK: Microenvironment and pathogenesis of epithelial ovarian cancer. Horm Cancer 2010, 1(6):277-290.
• [4]Shield K, Ackland ML, Ahmed N, Rice GE: Multicellular spheroids in ovarian cancer metastases: Biology and pathology. Gynecol Oncol 2009, 113(1):143-148.
• [5]Van Gorp T, Cadron I, Despierre E, Daemen A, Leunen K, Amant F, Timmerman D, De Moor B, Vergote I: HE4 and CA125 as a diagnostic test in ovarian cancer: prospective validation of the Risk of Ovarian Malignancy Algorithm. Br J Cancer 2011, 104(5):863-870.
• [6]Wong C, Wellman TL, Lounsbury KM: VEGF and HIF-1alpha expression are increased in advanced stages of epithelial ovarian cancer. Gynecol Oncol 2003, 91(3):513-517.
• [7]Lee S, Garner EI, Welch WR, Berkowitz RS, Mok SC: Over-expression of hypoxia-inducible factor 1 alpha in ovarian clear cell carcinoma. Gynecol Oncol 2007, 106(2):311-317.
• [8]Kulbe H, Chakravarty P, Leinster DA, Charles KA, Kwong J, Thompson RG, Coward JI, Schioppa T, Robinson SC, Gallagher WM, Galletta L, Salako MA, Smyth JF, Hagemann T, Brennan DJ, Bowtell DD, Balkwill FR, Australian Ovarian Cancer Study G: A dynamic inflammatory cytokine network in the human ovarian cancer microenvironment. Cancer Res 2012, 72(1):66-75.
• [9]Funahashi Y, Wakabayashi T, Semba T, Sonoda J, Kitoh K, Yoshimatsu K: Establishment of a quantitative mouse dorsal air sac model and its application to evaluate a new angiogenesis inhibitor. Oncol Res 1999, 11(7):319-329.
• [10]Howard OMZ, Dong HF, Yang D, Raben N, Nagaraju K, Rosen A, Casciola-Rosen L, Härtlein M, Kron M, Yang D, Yiadom K, Dwivedi S, Plotz PH, Oppenheim JJ: Histidyl-tRNA Synthetase and Asparaginyl-tRNA Synthetase, Autoantigens in Myositis, Activate Chemokine Receptors on T Lymphocytes and Immature Dendritic Cells. J Exp Med 2002, 196(6):781-791.
• [11]Sigurgeirsson B, Lindelof B, Edhag O, Allander E: Risk of cancer in patients with dermatomyositis or polymyositis. A population-based study. N Engl J Med 1992, 326(6):363-367.
• [12]Suber TL, Casciola-Rosen L, Rosen A: Mechanisms of disease: autoantigens as clues to the pathogenesis of myositis. Nat Clin Pract Rheumatol 2008, 4(4):201-209.
• [13]Williams TF, Mirando AC, Wilkinson B, Francklyn CS, Lounsbury KM: Secreted Threonyl-tRNA synthetase stimulates endothelial cell migration and angiogenesis. Nat Sci Reports 2013, 3:1317.
• [14]Barrett T, Edgar R: Gene expression omnibus: microarray data storage, submission, retrieval, and analysis. Meth in Enz 2006, 411:352-369.
• [15]Uhlen M, Oksvold P, Fagerberg L, Lundberg E, Jonasson K, Forsberg M, Zwahlen M, Kampf C, Wester K, Hober S, Wernerus H, Bjorling L, Ponten F: Towards a knowledge-based Human Protein Atlas. Nat Biotech 2010, 28(12):1248-1250.
• [16]Cassavaugh JM, Hale SA, Wellman TL, Howe AK, Wong C, Lounsbury KM: Negative regulation of HIF-1α by an FBW7-mediated degradation pathway during hypoxia. J Cell Biochem 2011, 112(12):3882-3890.
• [17]Hough CD, Sherman-Baust CA, Pizer ES, Montz FJ, Im DD, Rosenshein NB, Cho KR, Riggins GJ, Morin PJ: Large-Scale Serial Analysis of Gene Expression Reveals Genes Differentially Expressed in Ovarian Cancer. Cancer Res 2000, 60(22):6281-6287.
• [18]Moreno CS, Matyunina L, Dickerson EB, Schubert N, Bowen NJ, Logani S, Benigno BB, McDonald JF: Evidence that p53-mediated cell-cycle-arrest inhibits chemotherapeutic treatment of ovarian carcinomas. PloS one 2007, 2(5):e441.
• [19]Perets R, Wyant GA, Muto KW, Bijron JG, Poole BB, Chin KT, Chen JY, Ohman AW, Stepule CD, Kwak S, Karst AM, Hirsch MS, Setlur SR, Crum CP, Dinulescu DM, Drapkin R: Transformation of the fallopian tube secretory epithelium leads to high-grade serous ovarian cancer in Brca;Tp53;Pten models. Cancer Cell 2013, 24(6):751-765.
• [20]Erickson BK, Conner MG, Landen CN Jr: The role of the fallopian tube in the origin of ovarian cancer. Am J of Obst and Gynecol 2013, 209(5):409-414.
• [21]Suh KS, Park SW, Castro A, Patel H, Blake P, Liang M, Goy A: Ovarian cancer biomarkers for molecular biosensors and translational medicine. Expt Rev of Mol Diag 2010, 10(8):1069-1083.
• [22]Michalaki V, Syrigos K, Charles P, Waxman J: Serum levels of IL-6 and TNF-alpha correlate with clinicopathological features and patient survival in patients with prostate cancer. Br J Cancer 2004, 90(12):2312-2316.
• [23]Yadavalli SS, Ibba M: Quality control in aminoacyl-tRNA synthesis its role in translational fidelity. Adv Protein Chem Struc Biol 2012, 86:1-43.
• [24]Sampath P, Mazumder B, Seshadri V, Gerber CA, Chavatte L, Kinter M, Ting SM, Dignam JD, Kim S, Driscoll DM, Fox PL: Noncanonical function of glutamyl-prolyl-tRNA synthetase: gene-specific silencing of translation. Cell 2004, 119(2):195-208.
• [25]Park SG, Ewalt KL, Kim S: Functional expansion of aminoacyl-tRNA synthetases and their interacting factors: new perspectives on housekeepers. Trends Biochem Sci 2005, 30(10):569-574.
• [26]Greenberg Y, King M, Kiosses WB, Ewalt K, Yang X, Schimmel P, Reader JS, Tzima E: The novel fragment of tyrosyl tRNA synthetase, mini-TyrRS, is secreted to induce an angiogenic response in endothelial cells. Faseb J 2008, 22(5):1597-1605.
• [27]Wakasugi K, Slike BM, Hood J, Otani A, Ewalt KL, Friedlander M, Cheresh DA, Schimmel P: A human aminoacyl-tRNA synthetase as a regulator of angiogenesis. PNAS 2002, 99(1):173-177.
• [28]Kim S, You S, Hwang D: Aminoacyl-tRNA synthetases and tumorigenesis: more than housekeeping. Nat Rev Cancer 2011, 11(10):708-718.
• [29]Fukui H, Hanaoka R, Kawahara A: Noncanonical Activity of Seryl-tRNA Synthetase Is Involved in Vascular Development. Circ Res 2009, 104(11):1253-1259.
• [30]Park MC, Kang T, Jin D, Han JM, Kim SB, Park YJ, Cho K, Park YW, Guo M, He W, Yang X-L, Schimmel P, Kim S: Secreted human glycyl-tRNA synthetase implicated in defense against ERK-activated tumorigenesis. PNAS 2012, 109(11):E640-E647.
• [31]Cassavaugh J, Lounsbury KM: Hypoxia-mediated biological control. J Cell Biochem 2011, 112(3):735-744.
• [32]Schmitt J, Matei D: Targeting angiogenesis in ovarian cancer. Cancer Treat Rev 2012, 38(4):272-283.
• [33]Mathivanan S, Fahner CJ, Reid GE, Simpson RJ: ExoCarta 2012: database of exosomal proteins, RNA and lipids. Nucl Acids Res 2012, 40(D1):D1241-D1244.
• [34]Liang B, Peng P, Chen S, Li L, Zhang M, Cao D, Yang J, Li H, Gui T, Li X, Shen K: Characterization and proteomic analysis of ovarian cancer-derived exosomes. J Proteom 2013, 80:171-182.
• [35]Leclerc P, Jibard N, Meng X, Schweizer-Groyer G, Fortin D, Rajkowski K, Kang K, Catelli MG, Baulieu EE, Cadepond F: Quantification of the nucleocytoplasmic distribution of wild type and modified proteins using confocal microscopy: interaction between 90-kDa heat shock protein (Hsp90 alpha) and glucocorticosteroid receptor (GR). Exp Cell Res 1998, 242(1):255-264.
• [36]Hamaguchi E, Takamura T, Shimizu A, Nagai Y: Tumor necrosis factor-alpha and troglitazone regulate plasminogen activator inhibitor type 1 production through extracellular signal-regulated kinase- and nuclear factor-kappaB-dependent pathways in cultured human umbilical vein endothelial cells. JPET 2003, 307(3):987-994.
• [37]Tahir SA, Yang G, Goltsov AA, Watanabe M, Tabata K, Addai J, el Fattah MA, Kadmon D, Thompson TC: Tumor cell-secreted caveolin-1 has proangiogenic activities in prostate cancer. Cancer Res 2008, 68(3):731-739.
• [38]Buschow SI, van Balkom BW, Aalberts M, Heck AJ, Wauben M, Stoorvogel W: MHC class II-associated proteins in B-cell exosomes and potential functional implications for exosome biogenesis. Immunol Cell Biol 2010, 88(8):851-856.
• [39]Townsend KN, Spowart JE, Huwait H, Eshragh S, West NR, Elrick MA, Kalloger SE, Anglesio M, Watson PH, Huntsman DG, Lum JJ: Markers of T cell infiltration and function associate with favorable outcome in vascularized high-grade serous ovarian carcinoma. PloS one 2013, 8(12):e82406.