Runx3 is required for the differentiation of lung epithelial cells and suppression of lung cancer.
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 ( approximately 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.
Lee
K-S
KS
Department of Biochemistry, Chungbuk National University, Cheongju, South Korea. klee-2005@chungbuk.ac.kr
Lee
Y-S
YS
Lee
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JM
Ito
K
K
Cinghu
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Kim
J-H
JH
Jang
J-W
JW
Li
Y-H
YH
Goh
Y-M
YM
Chi
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XZ
Wee
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Lee
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Hosoya
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Chung
J-H
JH
Jang
J-J
JJ
Kundu
J K
JK
Surh
Y-J
YJ
Kim
W-J
WJ
Ito
Y
Y
Jung
H-S
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Bae
S-C
SC
D000230:Adenocarcinoma / Q000209:etiology / Q000473:pathology; D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D050677:Core Binding Factor Alpha 3 Subunit / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D004847:Epithelial Cells / Q000166:cytology; D006801:Humans; D008168:Lung / Q000166:cytology*; D008175:Lung Neoplasms / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000032:analysis / Q000502:physiology; D063150:Polycomb Repressive Complex 1; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000502:physiology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D037701:Pulmonary Surfactant-Associated Protein B / Q000032:analysis; D012097:Repressor Proteins / Q000032:analysis / Q000502:physiology; D014520:Urethane / Q000633:toxicity; D014598:Uteroglobin / Q000032:analysis
C489421:Bmi1 protein, mouse; D050677:Core Binding Factor Alpha 3 Subunit; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D037701:Pulmonary Surfactant-Associated Protein B; D012097:Repressor Proteins; C493729:Runx3 protein, human; C493730:Runx3 protein, mouse; C556389:SCGB1A1 protein, human; C556390:Scgb1a1 protein, mouse; D014520:Urethane; D014598:Uteroglobin; D063150:Polycomb Repressive Complex 1; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)