Abstract
Human lung adenocarcinoma, the most prevalent form of lung cancer, is characterized by many molecular abnormalities. K-ras mutations are associated with the initiation of lung adenocarcinomas, but K-ras-independent mechanisms may also initiate lung tumors. Here, we find that the runt-related transcription factor Runx3 is essential for normal murine lung development and is a tumor suppressor that prevents lung adenocarcinoma. Runx3−/− mice, which die soon after birth, exhibit alveolar hyperplasia. Importantly, Runx3−/− bronchioli exhibit impaired differentiation, as evidenced by the accumulation of epithelial cells containing specific markers for both alveolar (that is SP-B) and bronchiolar (that is CC10) lineages. Runx3−/− epithelial cells also express Bmi1, which supports self-renewal of stem cells. Lung adenomas spontaneously develop in aging Runx3+/− mice (∼18 months after birth) and invariably exhibit reduced levels of Runx3. As K-ras mutations are very rare in these adenomas, Runx3+/− mice provide an animal model for lung tumorigenesis that recapitulates the preneoplastic stage of human lung adenocarcinoma development, which is independent of K-Ras mutation. We conclude that Runx3 is essential for lung epithelial cell differentiation, and that downregulation of Runx3 is causally linked to the preneoplastic stage of lung adenocarcinoma.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Bangsow C, Rubins N, Glusman G, Bernstein Y, Negreanu V, Goldenberg D et al. (2001). The RUNX3 gene—sequence, structure and regulated expression. Gene 279: 221–232.
Bea S, Tort F, Pinyol M, Puig X, Hernandez L, Hernandez S et al. (2001). BMI-1 gene amplification and overexpression in hematological malignancies occur mainly in mantle cell lymphomas. Cancer Res 61: 2409–2412.
Belinsky SA, Nikula KJ, Palmisano WA, Michels R, Saccomanno G, Gabrielson E et al. (1998). Aberrant methylation of p16 (INK4a) is an early event in lung cancer and a potential biomarker for early diagnosis. Proc Natl Acad Sci USA 95: 11891–11896.
Bishop AE . (2004). Pulmonary epithelial stem cells. Cell Prolif 37: 89–96.
Cardoso WV, Lu J . (2006). Regulation of early lung morphogenesis: questions, facts and controversies. Development 133: 1611–1624.
Cazorla M, Hernandez L, Fernandez PL, Fabra A, Peinado MA, Dasenbrock C et al. (1998). Ki-ras gene mutations and absence of p53 gene mutations in spontaneous and urethane-induced early lung lesions in CBA/J mice. Mol Carcinog 21: 251–260.
Chi XZ, Kim J, Lee YH, Lee JW, Lee KS, Wee H et al. (2009). Runt-related transcription factor RUNX3 is a target of MDM2-mediated ubiquitination. Cancer Res 69: 8111–8119.
Chi XZ, Yang JO, Lee KY, Ito K, Sakakura C, Li QL et al. (2005). RUNX3 suppresses gastric epithelial cell growth by inducing p21(WAF1/Cip1) expression in cooperation with transforming growth factor {beta}-activated SMAD. Mol Cell Biol 25: 8097–8107.
Collins LG, Haines C, Perkel R, Enck RE . (2007). Lung cancer: diagnosis and management. Am Fam Physician 75: 56–63.
Costa RH, Kalinichenko VV, Lim L . (2001). Transcription factors in mouse lung development and function. Am J Physiol Lung Cell Mol Physiol 280: L823–L838.
Dimri GP, Martinez JL, Jacobs JJ, Keblusek P, Itahana K, Van Lohuizen M et al. (2002). The Bmi-1 oncogene induces telomerase activity and immortalizes human mammary epithelial cells. Cancer Res 62: 4736–4745.
Dovey JS, Zacharek SJ, Kim CF, Lees JA . (2008). Bmi1 is critical for lung tumorigenesis and bronchioalveolar stem cell expansion. Proc Natl Acad Sci USA 105: 11857–11862.
Fainaru O, Woolf E, Lotem J, Yarmus M, Brenner O, Goldenberg D et al. (2004). Runx3 regulates mouse TGF-beta-mediated dendritic cell function and its absence results in airway inflammation. EMBO J 23: 969–979.
Goel A, Arnold CN, Tassone P, Chang DK, Niedzwiecki D, Dowell JM et al. (2004). Epigenetic inactivation of RUNX3 in microsatellite unstable sporadic colon cancers. Int J Cancer 112: 754–759.
Guo WH, Weng LQ, Ito K, Chen LF, Nakanishi H, Tatematsu M et al. (2002). Inhibition of growth of mouse gastric cancer cells by Runx3, a novel tumor suppressor. Oncogene 21: 8351–8355.
Inoue K, Ozaki S, Shiga T, Ito K, Masuda T, Okado N et al. (2002). Runx3 controls the axonal projection of proprioceptive dorsal root ganglion neurons. Nat Neurosci 5: 946–954.
Ito K, Inoue KI, Bae SC, Ito Y . (2009). Runx3 expression in gastrointestinal tract epithelium: resolving the controversy. Oncogene 28: 1379–1384.
Ito K, Lim AC, Salto-Tellez M, Motoda L, Osato M, Chuang LS et al. (2008). RUNX3 attenuates beta-catenin/T cell factors in intestinal tumorigenesis. Cancer Cell 14: 226–237.
Ito K, Liu Q, Salto-Tellez M, Yano T, Tada K, Ida H et al. (2005). RUNX3, a novel tumor suppressor, is frequently inactivated in gastric cancer by protein mislocalization. Cancer Res 65: 7743–7750.
Jackson EL, Willis N, Mercer K, Bronson RT, Crowley D, Montoya R et al. (2001). Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras. Genes Dev 15: 3243–3248.
Kang GH, Lee S, Lee HJ, Hwang KS . (2004). Aberrant CpG island hypermethylation of multiple genes in prostate cancer and prostatic intraepithelial neoplasia. J Pathol 202: 233–240.
Kato N, Tamura G, Fukase M, Shibuya H, Motoyama T . (2003). Hypermethylation of the RUNX3 gene promoter in testicular yolk sac tumor of infants. Am J Pathol 163: 387–391.
Kim CF, Jackson EL, Woolfenden AE, Lawrence S, Babar I, Vogel S et al. (2005a). Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell 121: 823–835.
Kim WJ, Kim EJ, Jeong P, Quan C, Kim J, Li QL et al. (2005b). RUNX3 inactivation by point mutations and aberrant DNA methylation in bladder tumors. Cancer Res 65: 9347–9354.
Lau QC, Raja E, Salto-Tellez M, Liu Q, Ito K, Inoue M et al. (2006). RUNX3 is frequently inactivated by dual mechanisms of protein mislocalization and promoter hypermethylation in breast cancer. Cancer Res 66: 6512–6520.
Lee B, Thirunavukkarasu K, Zhou L, Pastore L, Baldini A, Hecht J et al. (1997). Missense mutations abolishing DNA binding of the osteoblast-specific transcription factor OSF2/CBFA1 in cleidocranial dysplasia. Nat Genet 16: 307–310.
Leung C, Lingbeek M, Shakhova O, Liu J, Tanger E, Saremaslani P et al. (2004). Bmi1 is essential for cerebellar development and is overexpressed in human medulloblastomas. Nature 428: 337–341.
Levanon D, Bettoun D, Harris-Cerruti C, Woolf E, Negreanu V, Eilam R et al. (2002). The Runx3 transcription factor regulates development and survival of TrkC dorsal root ganglia neurons. EMBO J 21: 3454–3463.
Li QL, Ito K, Sakakura C, Fukamachi H, Inoue K, Chi XZ et al. (2002). Causal relationship between the loss of RUNX3 expression and gastric cancer. Cell 109: 113–124.
Li QL, Kim HR, Kim WJ, Choi JK, Lee YH, Kim HM et al. (2004). Transcriptional silencing of the RUNX3 gene by CpG hypermethylation is associated with lung cancer. Biochem Biophys Res Commun 314: 223–228.
Licchesi JD, Westra WH, Hooker CM, Machida EO, Baylin SB, Herman JG . (2008). Epigenetic alteration of Wnt pathway antagonists in progressive glandular neoplasia of the lung. Carcinogenesis 29: 895–904.
Look AT . (1997). Oncogenic transcription factors in the human acute leukemias. Science 278: 1059–1064.
Lund AH, van Lohuizen M . (2002). RUNX: a trilogy of cancer genes. Cancer Cell 1: 213–215.
Malkinson AM . (1998). Molecular comparison of human and mouse pulmonary adenocarcinomas. Exp Lung Res 24: 541–555.
Minna JD, Roth JA, Gazdar AF . (2002). Focus on lung cancer. Cancer Cell 1: 49–52.
Mori M, Kaji M, Tezuka F, Takahashi T . (1998). Comparative ultrastructural study of atypical adenomatous hyperplasia and adenocarcinoma of the human lung. Ultrastruct Pathol 22: 459–466.
Mundlos S, Olsen BR . (1997). Heritable diseases of the skeleton Part I: molecular insights into skeletal development-transcription factors and signaling pathways. FASEB J 11: 125–132.
Okuda T, Fisher R, Downing JR . (1996). Molecular diagnostics in pediatric acute lymphoblastic leukemia. Mol Diagn 1: 139–151.
Osanai M, Igarashi T, Yoshida Y . (2001). Unique cellular features in atypical adenomatous hyperplasia of the lung: ultrastructural evidence of its cytodifferentiation. Ultrastruct Pathol 25: 367–373.
Otto F, Thornell AP, Crompton T, Denzel A, Gilmour KC, Rosewell IR et al. (1997). Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development. Cell 89: 765–771.
Peacock CD, Watkins DN . (2008). Cancer stem cells and the ontogeny of lung cancer. J Clin Oncol 26: 2883–2889.
Petersen I, Petersen S . (2001). Towards a genetic-based classification of human lung cancer. Anal Cell Pathol 22: 111–121.
Reddy R, Buckley S, Doerken M, Barsky L, Weinberg K, Anderson KD et al. (2004). Isolation of a putative progenitor subpopulation of alveolar epithelial type 2 cells. Am J Physiol Lung Cell Mol Physiol 286: L658–L667.
Sato K, Tomizawa Y, Iijima H, Saito R, Ishizuka T, Nakajima T et al. (2006). Epigenetic inactivation of the RUNX3 gene in lung cancer. Oncol Rep 15: 129–135.
Taniuchi I, Sunshine MJ, Festenstein R, Littman DR . (2002). Evidence for distinct CD4 silencer functions at different stages of thymocyte differentiation. Mol Cell 10: 1083–1096.
Tozawa T, Tamura G, Honda T, Nawata S, Kimura W, Makino N et al. (2004). Promoter hypermethylation of DAP-kinase is associated with poor survival in primary biliary tract carcinoma patients. Cancer Sci 95: 736–740.
Tuveson DA, Shaw AT, Willis NA, Silver DP, Jackson EL, Chang S et al. (2004). Endogenous oncogenic K-ras(G12D) stimulates proliferation and widespread neoplastic and developmental defects. Cancer Cell 5: 375–387.
Valk-Lingbeek ME, Bruggeman SW, van Lohuizen M . (2004). Stem cells and cancer; the polycomb connection. Cell 118: 409–418.
Vonlanthen S, Heighway J, Altermatt HJ, Gugger M, Kappeler A, Borner MM et al. (2001). The bmi-1 oncoprotein is differentially expressed in non-small cell lung cancer and correlates with INK4A-ARF locus expression. Br J Cancer 84: 1372–1376.
Weisenberger DJ, Siegmund KD, Campan M, Young J, Long TI, Faasse MA et al. (2006). CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat Genet 38: 787–793.
Westra WH, Baas IO, Hruban RH, Askin FB, Wilson K, Offerhaus GJ et al. (1996). K-ras oncogene activation in atypical alveolar hyperplasias of the human lung. Cancer Res 56: 2224–2228.
Wistuba II, Gazdar AF . (2006). Lung cancer preneoplasia. Annu Rev Pathol 1: 331–348.
Woolf E, Xiao C, Fainaru O, Lotem J, Rosen D, Negreanu V et al. (2003). Runx3 and Runx1 are required for CD8T cell development during thymopoiesis. Proc Natl Acad Sci USA 100: 7731–7736.
Wuenschell CW, Sunday ME, Singh G, Minoo P, Slavkin HC, Warburton D . (1996). Embryonic mouse lung epithelial progenitor cells co-express immunohistochemical markers of diverse mature cell lineages. J Histochem Cytochem 44: 113–123.
Xiao WH, Liu WW . (2004). Hemizygous deletion and hypermethylation of RUNX3 gene in hepatocellular carcinoma. World J Gastroenterol 10: 376–380.
Yano T, Ito K, Fukamachi H, Chi XZ, Wee HJ, Inoue K et al. (2006). The RUNX3 tumor suppressor upregulates Bim in gastric epithelial cells undergoing transforming growth factor beta-induced apoptosis. Mol Cell Biol 26: 4474–4488.
Zochbauer-Muller S, Minna JD . (2000). The biology of lung cancer including potential clinical applications. Chest Surg Clin N Am 10: 691–708.
Acknowledgements
This work was supported by research grants from the Korea Science and Engineering Foundation (R16-2003–002–01001–02006 to S-C Bae and R13-2003–013–05001–0 to H-S Jung) and a grant from the Basic Research Promotion Fund of the Korea Research Foundation (KRF-2005–217-E00002 to K-S Lee).
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies the paper on the Oncogene website
Rights and permissions
About this article
Cite this article
Lee, KS., Lee, YS., Lee, JM. et al. Runx3 is required for the differentiation of lung epithelial cells and suppression of lung cancer. Oncogene 29, 3349–3361 (2010). https://doi.org/10.1038/onc.2010.79
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/onc.2010.79
Keywords
This article is cited by
-
RUNX3 regulates the susceptibility against EGFR-targeted non-small cell lung cancer therapy using 47Sc-conjugated cetuximab
BMC Cancer (2023)
-
Runt-related transcription factors in human carcinogenesis: a friend or foe?
Journal of Cancer Research and Clinical Oncology (2023)
-
MicroRNA-19a Inhibition Directly and Indirectly Ameliorates Th2 Airway Inflammation in Asthma by Targeting RUNX3
Inflammation (2023)
-
RUNX3-dependent oxidative epithelial-to-mesenchymal transition in methamphetamine-induced chronic lung injury
Cell Stress and Chaperones (2020)
-
Runx3 plays a critical role in restriction-point and defense against cellular transformation
Oncogene (2017)