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Molecular Cancer
Published in: Molecular Cancer 1/2012

Open Access 01-12-2012 | Research

Deficiency of CCAAT/enhancer binding protein family DNA binding prevents malignant conversion of adenoma to carcinoma in NNK-induced lung carcinogenesis in the mouse

Authors: Shioko Kimura, Jorge Paiz, Mitsuhiro Yoneda, Taketomo Kido, Charles Vinson, Jerrold M Ward

Published in: Molecular Cancer | Issue 1/2012

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Abstract

Background

The CCAAT/enhancer binding proteins (C/EBPs) play important roles in carcinogenesis of many tumors including the lung. Since multiple C/EBPs are expressed in lung, the combinatorial expression of these C/EBPs on lung carcinogenesis is not known.

Methods

A transgenic mouse line expressing a dominant negative A-C/EBP under the promoter of lung epithelial Clara cell secretory protein (CCSP) gene in doxycycline dependent fashion was subjected to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung carcinogenesis bioassay in the presence and absence of doxycycline, and the effect of abolition of DNA binding activities of C/EBPs on lung carcinogenesis was examined.

Results

A-C/EBP expression was found not to interfere with tumor development; however, it suppressed the malignant conversion of adenoma to carcinoma during NNK-induced lung carcinogenesis. The results suggested that Ki67 may be used as a marker for lung carcinomas in mouse.

Conclusions

The DNA binding of C/EBP family members can be used as a potential molecular target for lung cancer therapy.
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Literature
1.
Johnson PF: Molecular stop signs: regulation of cell-cycle arrest by C/EBP transcription factors. J Cell Sci. 2005, 118: 2545-2555. 10.1242/jcs.02459CrossRefPubMed
2.
3.
Nerlov C: The C/EBP family of transcription factors: a paradigm for interaction between gene expression and proliferation control. Trends Cell Biol. 2007, 17: 318-324. 10.1016/j.tcb.2007.07.004CrossRefPubMed
4.
Vinson C, Myakishev M, Acharya A, Mir AA, Moll JR, Bonovich M: Classification of human B-ZIP proteins based on dimerization properties. Mol Cell Biol. 2002, 22: 6321-6335. 10.1128/MCB.22.18.6321-6335.2002PubMedCentralCrossRefPubMed
5.
Newman JR, Keating AE: Comprehensive identification of human bZIP interactions with coiled-coil arrays. Science. 2003, 300: 2097-2101. 10.1126/science.1084648CrossRefPubMed
6.
Gery S, Tanosaki S, Bose S, Bose N, Vadgama J, Koeffler HP: Down-regulation and growth inhibitory role of C/EBPalpha in breast cancer. Clin Cancer Res. 2005, 11: 3184-3190. 10.1158/1078-0432.CCR-04-2625CrossRefPubMed
7.
Halmos B, Huettner CS, Kocher O, Ferenczi K, Karp DD, Tenen DG: Down-regulation and antiproliferative role of C/EBPalpha in lung cancer. Cancer Res. 2002, 62: 528-534.PubMed
8.
Loomis KD, Zhu S, Yoon K, Johnson PF, Smart RC: Genetic ablation of CCAAT/enhancer binding protein alpha in epidermis reveals its role in suppression of epithelial tumorigenesis. Cancer Res. 2007, 67: 6768-6776. 10.1158/0008-5472.CAN-07-0139PubMedCentralCrossRefPubMed
9.
Pabst T, Mueller BU, Zhang P, Radomska HS, Narravula S, Schnittger S, Behre G, Hiddemann W, Tenen DG: Dominant-negative mutations of CEBPA, encoding CCAAT/enhancer binding protein-alpha (C/EBPalpha), in acute myeloid leukemia. Nat Genet. 2001, 27: 263-270. 10.1038/85820CrossRefPubMed
10.
Gombart AF, Hofmann WK, Kawano S, Takeuchi S, Krug U, Kwok SH, Larsen RJ, Asou H, Miller CW, Hoelzer D, Koeffler HP: Mutations in the gene encoding the transcription factor CCAAT/enhancer binding protein alpha in myelodysplastic syndromes and acute myeloid leukemias. Blood. 2002, 99: 1332-1340. 10.1182/blood.V99.4.1332CrossRefPubMed
11.
Truong BT, Lee YJ, Lodie TA, Park DJ, Perrotti D, Watanabe N, Koeffler HP, Nakajima H, Tenen DG, Kogan SC: CCAAT/Enhancer binding proteins repress the leukemic phenotype of acute myeloid leukemia. Blood. 2003, 101: 1141-1148. 10.1182/blood-2002-05-1374CrossRefPubMed
12.
Shim M, Powers KL, Ewing SJ, Zhu S, Smart RC: Diminished expression of C/EBPalpha in skin carcinomas is linked to oncogenic Ras and reexpression of C/EBPalpha in carcinoma cells inhibits proliferation. Cancer Res. 2005, 65: 861-867.PubMed
13.
Zahnow CA, Younes P, Laucirica R, Rosen JM: Overexpression of C/EBPbeta-LIP, a naturally occurring, dominant-negative transcription factor, in human breast cancer. J Natl Cancer Inst. 1997, 89: 1887-1891. 10.1093/jnci/89.24.1887CrossRefPubMed
14.
Raught B, Gingras AC, James A, Medina D, Sonenberg N, Rosen JM: Expression of a translationally regulated, dominant-negative CCAAT/enhancer-binding protein beta isoform and up-regulation of the eukaryotic translation initiation factor 2alpha are correlated with neoplastic transformation of mammary epithelial cells. Cancer Res. 1996, 56: 4382-4386.PubMed
15.
Cao Z, Umek RM, McKnight SL: Regulated expression of three C/EBP isoforms during adipose conversion of 3T3-L1 cells. Genes Dev. 1991, 5: 1538-1552. 10.1101/gad.5.9.1538CrossRefPubMed
16.
Berg T, Didon L, Nord M: Ectopic expression of C/EBPalpha in the lung epithelium disrupts late lung development. Am J Physiol Lung Cell Mol Physiol. 2006, 291: L683-L693. 10.1152/ajplung.00497.2005CrossRefPubMed
17.
Cassel TN, Nord M: C/EBP transcription factors in the lung epithelium. Am J Physiol Lung Cell Mol Physiol. 2003, 285: L773-L781.CrossRefPubMed
18.
Tomita T, Kido T, Kurotani R, Iemura S, Sterneck E, Natsume T, Vinson C, Kimura S: CAATT/enhancer-binding proteins alpha and delta interact with NKX2-1 to synergistically activate mouse secretoglobin 3A2 gene expression. J Biol Chem. 2008, 283: 25617-25627. 10.1074/jbc.M805140200PubMedCentralCrossRefPubMed
19.
Tada Y, Brena RM, Hackanson B, Morrison C, Otterson GA, Plass C: Epigenetic modulation of tumor suppressor CCAAT/enhancer binding protein alpha activity in lung cancer. J Natl Cancer Inst. 2006, 98: 396-406. 10.1093/jnci/djj093CrossRefPubMed
20.
Armstrong DA, Phelps LN, Vincenti MP: CCAAT enhancer binding protein-beta regulates matrix metalloproteinase-1 expression in interleukin-1beta-stimulated A549 lung carcinoma cells. Mol Cancer Res. 2009, 7: 1517-1524. 10.1158/1541-7786.MCR-09-0082CrossRefPubMed
21.
Oh WJ, Rishi V, Orosz A, Gerdes MJ, Vinson C: Inhibition of CCAAT/enhancer binding protein family DNA binding in mouse epidermis prevents and regresses papillomas. Cancer Res. 2007, 67: 1867-1876. 10.1158/0008-5472.CAN-06-2746CrossRefPubMed
22.
Kido T, Tomita T, Okamoto M, Cai Y, Matsumoto Y, Vinson C, Maru Y, Kimura S: FOXA1 plays a role in regulating secretoglobin 1a1 expression in the absence of CCAAT/enhancer binding protein activities in lung in vivo. Am J Physiol Lung Cell Mol Physiol. 2011, 300: L441-L452. 10.1152/ajplung.00435.2009PubMedCentralCrossRefPubMed
23.
Hecht SS, Morse MA, Amin S, Stoner GD, Jordan KG, Choi CI, Chung FL: Rapid single-dose model for lung tumor induction in A/J mice by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and the effect of diet. Carcinogenesis. 1989, 10: 1901-1904. 10.1093/carcin/10.10.1901CrossRefPubMed
24.
Gialeli C, Theocharis AD, Karamanos NK: Roles of matrix metalloproteinases in cancer progression and their pharmacological targeting. FEBS J. 2011, 278: 16-27. 10.1111/j.1742-4658.2010.07919.xCrossRefPubMed
25.
Rucci N, Sanita P, Angelucci A: Roles of metalloproteases in metastatic niche. Curr Mol Medicine. 2011, 11: 609-622. 10.2174/156652411797536705.CrossRef
26.
Allen TD, Rodriguez EM, Jones KD, Bishop JM: Activated Notch1 induces lung adenomas in mice and cooperates with Myc in the generation of lung adenocarcinoma. Cancer Res. 2011, 71: 6010-6018. 10.1158/0008-5472.CAN-11-0595PubMedCentralCrossRefPubMed
27.
Rehm S, Ward JM, ten Have-Opbroek AA, Anderson LM, Singh G, Katyal SL, Rice JM: Mouse papillary lung tumors transplacentally induced by N-nitrosoethylurea: evidence for alveolar type II cell origin by comparative light microscopic, ultrastructural, and immunohistochemical studies. Cancer Res. 1988, 48: 148-160.PubMed
28.
Renne R, Brix A, Harkema J, Herbert R, Kittel B, Lewis D, March T, Nagano K, Pino M, Rittinghausen S, Rosenbruch M, Tellier P, Wohrmann T: Proliferative and nonproliferative lesions of the rat and mouse respiratory tract. Toxicol Pathol. 2009, 37: 5S-73S. 10.1177/0192623309353423CrossRefPubMed
29.
Aune G, Stunes AK, Tingulstad S, Salvesen O, Syversen U, Torp SH: The proliferation markers Ki-67/MIB-1, phosphohistone H3, and survivin may contribute in the identification of aggressive ovarian carcinomas. Internatl J Clinic Experi Pathol. 2011, 4: 444-453.
30.
Vincent-Salomon A, Hajage D, Rouquette A, Cedenot A, Gruel N, Alran S, Sastre-Garau X, Sigal-Zafrani B, Fourquet A, Kirova Y: High Ki67 expression is a risk marker of invasive relapse for classical lobular carcinoma in situ patients. Breast. 2012, 21: 380-383. 10.1016/j.breast.2012.03.005CrossRefPubMed
31.
Zhang L, Hu S, Korteweg C, Chen Z, Qiu Y, Su M, Gu J: Expression of immunoglobulin G in esophageal squamous cell carcinomas and its association with tumor grade and Ki67. Hum Pathol. 2012, 43: 423-434. 10.1016/j.humpath.2011.05.020CrossRefPubMed
32.
Agrawal S, Hofmann WK, Tidow N, Ehrich M, van den Boom D, Koschmieder S, Berdel WE, Serve H, Muller-Tidow C: The C/EBPdelta tumor suppressor is silenced by hypermethylation in acute myeloid leukemia. Blood. 2007, 109: 3895-3905. 10.1182/blood-2006-08-040147CrossRefPubMed
33.
Balamurugan K, Wang JM, Tsai HH, Sharan S, Anver M, Leighty R, Sterneck E: The tumour suppressor C/EBPdelta inhibits FBXW7 expression and promotes mammary tumour metastasis. EMBO J. 2010, 29: 4106-4117. 10.1038/emboj.2010.280PubMedCentralCrossRefPubMed
34.
Fainaru O, Adini I, Benny O, Bazinet L, Pravda E, D'Amato R, Folkman J: Doxycycline induces membrane expression of VE-cadherin on endothelial cells and prevents vascular hyperpermeability. FASEB J: official publication of the Federation of American Societies for Experimental Biology. 2008, 22: 3728-3735. 10.1096/fj.08-110494.CrossRef
35.
Nikitin AY, Alcaraz A, Anver MR, Bronson RT, Cardiff RD, Dixon D, Fraire AE, Gabrielson EW, Gunning WT, Haines DC, Kaufman MH, Linnoila RI, Maronpot RR, Rabson AS, Reddick RL, Rehm S, Rozengurt N, Schuller HM, Shmidt EN, Travis WD, Ward JM, Jacks T: Classification of proliferative pulmonary lesions of the mouse: recommendations of the mouse models of human cancers consortium. Cancer Res. 2004, 64: 2307-2316. 10.1158/0008-5472.CAN-03-3376CrossRefPubMed
Metadata
Title
Deficiency of CCAAT/enhancer binding protein family DNA binding prevents malignant conversion of adenoma to carcinoma in NNK-induced lung carcinogenesis in the mouse
Authors
Shioko Kimura
Jorge Paiz
Mitsuhiro Yoneda
Taketomo Kido
Charles Vinson
Jerrold M Ward
Publication date
01-12-2012
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2012
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/1476-4598-11-90

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