The expression of TGF-β1, Smad3, phospho-Smad3 and Smad7 is correlated with the development and invasion of nonfunctioning pituitary adenomas

Journal of Translational Medicine

Zhang Yazhuo¹  Wang Fei¹  Wu Yonggang¹  Wang Hongyun¹  Hong Lichuan¹  Cao Lei¹  Lan Xiaolei¹  Wu Youtu¹  Li Chuzhong¹  Li Zhenye¹ 

[1] Beijing Neurosurgical Institute, Capital Medical University, Beijing 100050, China

关键词: Smad7;    Smad4;    Smad3;    Smad2;    TGF-β1;    Invasion;    Nonfunctioning pituitary adenoma;   

Others  :  817630
DOI  :  10.1186/1479-5876-12-71

 received in 2014-01-03, accepted in 2014-03-12,  发布年份 2014

【 摘 要 】

Background

Transforming growth factor β (TGF-β) signaling functions as a suppressor or a promoter in tumor development, depending on the tumor stage and type. However, the role of TGF-β signaling in nonfunctioning pituitary adenomas (NFPAs) has not been explored.

Methods

TGF-β1, Smad2, phospho-Smad2 (p-Smad2), Smad3, phospho-Smad3 (p-Smad3), Smad4, and Smad7 were detected in 5 cases of normal anterior pituitaries, 29 cases of invasive NFPAs, and 21 cases of noninvasive NFPAs by real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR), Western blot, and immunohistochemical analysis.

Results

The Smad3 and p-Smad3 protein levels gradually decreased from normal anterior pituitaries, noninvasive NFPAs, to invasive NFPAs. However, there were no significant differences in Smad2 (P = 0.122) and p-Smad2 protein levels (P = 0.101) or Smad2 mRNA level (P = 0.409). In addition, the TGF-β1 mRNA level gradually decreased while the Smad7 mRNA level gradually increased from normal anterior pituitaries, noninvasive NFPAs, to invasive NFPAs. Furthermore, proliferating cell nuclear antigen (PCNA) mRNA level was markedly increased in invasive NFPAs compared to noninvasive ones (P < 0.01), and its level was negatively correlated with Smad3 mRNA level (P < 0.01).

Conclusion

The activity of TGF-β signaling may be restrained in NFPAs and is correlated with the development and invasion of NFPAs.

【 授权许可】

   
2014 Zhenye et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

【 参考文献 】

• [1]Daly AF, Rixhon M, Adam C, Dempegioti A, Tichomirowa MA, Beckers A: High prevalence of pituitary adenomas: a cross-sectional study in the province of Liege, Belgium. J Clin Endocrinol Metab 2006, 91:4769-4775.
• [2]Fernandez A, Karavitaki N, Wass JA: Prevalence of pituitary adenomas: a community-based, cross-sectional study in Banbury (Oxfordshire, UK). Clin Endocrinol (Oxf) 2010, 72:377-382.
• [3]Figarella-Branger D, Trouillas J: The new WHO classification of human pituitary tumors: comments. Acta Neuropathol 2006, 111:71-72.
• [4]Buchfelder M: Management of aggressive pituitary adenomas: current treatment strategies. Pituitary 2009, 12:256-260.
• [5]Katznelson L, Alexander JM, Klibanski A: Clinical review 45: clinically nonfunctioning pituitary adenomas. J Clin Endocrinol Metab 1993, 76:1089-1094.
• [6]Colao A, Di Somma C, Pivonello R, Faggiano A, Lombardi G, Savastano S: Medical therapy for clinically non-functioning pituitary adenomas. Endocr Relat Cancer 2008, 15:905-915.
• [7]Herman V, Fagin J, Gonsky R, Kovacs K, Melmed S: Clonal origin of pituitary adenomas. J Clin Endocrinol Metab 1990, 71:1427-1433.
• [8]Gurlek A, Karavitaki N, Ansorge O, Wass JA: What are the markers of aggressiveness in prolactinomas? Changes in cell biology, extracellular matrix components, angiogenesis and genetics. Eur J Endocrinol 2007, 156:143-153.
• [9]Melmed S: Pathogenesis of pituitary tumors. Nat Rev Endocrinol 2011, 7:257-266.
• [10]Wakefield LM, Roberts AB: TGF-beta signaling: positive and negative effects on tumorigenesis. Curr Opin Genet Dev 2002, 12:22-29.
• [11]Massague J: TGFbeta in cancer. Cell 2008, 134:215-230.
• [12]Heldin CH, Miyazono K, ten Dijke P: TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature 1997, 390:465-471.
• [13]Nakao A, Afrakhte M, Moren A, Nakayama T, Christian JL, Heuchel R, Itoh S, Kawabata M, Heldin NE, Heldin CH, ten Dijke P: Identification of Smad7, a TGFbeta-inducible antagonist of TGF-beta signalling. Nature 1997, 389:631-635.
• [14]Massague J: TGFbeta signalling in context. Nat Rev Mol Cell Biol 2012, 13:616-630.
• [15]Wu Y, Li Q, Zhou X, Yu J, Mu Y, Munker S, Xu C, Shen Z, Mullenbach R, Liu Y, Li L, Gretz N, Zieker D, Weng H: Decreased levels of active SMAD2 correlate with poor prognosis in gastric cancer. PLoS One 2012, 7:e35684.
• [16]Bruna A, Darken RS, Rojo F, Ocana A, Penuelas S, Arias A, Paris R, Tortosa A, Mora J, Baselga J, Seoane J: High TGFbeta-Smad activity confers poor prognosis in glioma patients and promotes cell proliferation depending on the methylation of the PDGF-B gene. Cancer Cell 2007, 11:147-160.
• [17]Johnson MD, Shaw AK, O'Connell MJ, Sim FJ, Moses HL: Analysis of transforming growth factor beta receptor expression and signaling in higher grade meningiomas. J Neurooncol 2011, 103:277-285.
• [18]de Kruijf EM, Dekker TJ, Hawinkels LJ, Putter H, Smit VT, Kroep JR, Kuppen PJ, van de Velde CJ, ten Dijke P, Tollenaar RA, Mesker WE: The prognostic role of TGF-beta signaling pathway in breast cancer patients. Ann Oncol 2013, 24:384-390.
• [19]Wilson CB: A decade of pituitary microsurgery. The Herbert Olivecrona lecture. J Neurosurg 1984, 61:814-833.
• [20]Knosp E, Steiner E, Kitz K, Matula C: Pituitary adenomas with invasion of the cavernous sinus space: a magnetic resonance imaging classification compared with surgical findings. Neurosurgery 1993, 33:610-617. discussion 617–618
• [21]Schmittgen TD, Livak KJ: Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc 2008, 3:1101-1108.
• [22]Zhou W, Song Y, Xu H, Zhou K, Zhang W, Chen J, Qin M, Yi H, Gustafsson JA, Yang H, Fan X: In nonfunctional pituitary adenomas, estrogen receptors and slug contribute to development of invasiveness. J Clin Endocrinol Metab 2011, 96:E1237-E1245.
• [23]ten Dijke P, Hill CS: New insights into TGF-beta-Smad signalling. Trends Biochem Sci 2004, 29:265-273.
• [24]Ten Dijke P, Goumans MJ, Itoh F, Itoh S: Regulation of cell proliferation by Smad proteins. J Cell Physiol 2002, 191:1-16.
• [25]Li MO, Wan YY, Sanjabi S, Robertson AK, Flavell RA: Transforming growth factor-beta regulation of immune responses. Annu Rev Immunol 2006, 24:99-146.
• [26]Wolfraim LA, Fernandez TM, Mamura M, Fuller WL, Kumar R, Cole DE, Byfield S, Felici A, Flanders KC, Walz TM, Roberts AB, Aplan PD, Balis FM, Letterio JJ: Loss of Smad3 in acute T-cell lymphoblastic leukemia. N Engl J Med 2004, 351:552-559.
• [27]Sodir NM, Chen X, Park R, Nickel AE, Conti PS, Moats R, Bading JR, Shibata D, Laird PW: Smad3 deficiency promotes tumorigenesis in the distal colon of ApcMin/+ mice. Cancer Res 2006, 66:8430-8438.
• [28]Kleeff J, Ishiwata T, Maruyama H, Friess H, Truong P, Buchler MW, Falb D, Korc M: The TGF-beta signaling inhibitor Smad7 enhances tumorigenicity in pancreatic cancer. Oncogene 1999, 18:5363-5372.
• [29]Halder SK, Rachakonda G, Deane NG, Datta PK: Smad7 induces hepatic metastasis in colorectal cancer. Br J Cancer 2008, 99:957-965.
• [30]Hahn SA, Schutte M, Hoque AT, Moskaluk CA, da Costa LT, Rozenblum E, Weinstein CL, Fischer A, Yeo CJ, Hruban RH, Kern SE: DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science 1996, 271:350-353.
• [31]Wang LH, Kim SH, Lee JH, Choi YL, Kim YC, Park TS, Hong YC, Wu CF, Shin YK: Inactivation of SMAD4 tumor suppressor gene during gastric carcinoma progression. Clin Cancer Res 2007, 13:102-110.
• [32]Natsugoe S, Xiangming C, Matsumoto M, Okumura H, Nakashima S, Sakita H, Ishigami S, Baba M, Takao S, Aikou T: Smad4 and transforming growth factor beta1 expression in patients with squamous cell carcinoma of the esophagus. Clin Cancer Res 2002, 8:1838-1842.
• [33]Bierie B, Moses HL: TGF-beta and cancer. Cytokine Growth Factor Rev 2006, 17:29-40.
• [34]Recouvreux MV, Camilletti MA, Rifkin DB, Becu-Villalobos D, Diaz-Torga G: Thrombospondin-1 (TSP-1) analogs ABT-510 and ABT-898 inhibit prolactinoma growth and recover active pituitary transforming growth factor-beta1 (TGF-beta1). Endocrinology 2012, 153:3861-3871.
• [35]Bravo R, Frank R, Blundell PA, Macdonald-Bravo H: Cyclin/PCNA is the auxiliary protein of DNA polymerase-delta. Nature 1987, 326:515-517.
• [36]Hsu DW, Hakim F, Biller BM, de la Monte S, Zervas NT, Klibanski A, Hedley-Whyte ET: Significance of proliferating cell nuclear antigen index in predicting pituitary adenoma recurrence. J Neurosurg 1993, 78:753-761.
• [37]Recouvreux MV, Guida MC, Rifkin DB, Becu-Villalobos D, Diaz-Torga G: Active and total transforming growth factor-beta1 are differentially regulated by dopamine and estradiol in the pituitary. Endocrinology 2011, 152:2722-2730.