Runx3 is required for the differentiation of lung epithelial cells and suppression of lung cancer

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. Runx3À/À mice, which die soon after birth, exhibit alveolar hyperplasia. Importantly, Runx3À/À 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. Runx3À/À epithelial cells also express Bmi1, which supports self-renewal of stem cells. Lung adenomas spontaneously develop in aging Runx3 þ /À mice (B18 months after birth) and invariably exhibit reduced levels of Runx3. As K-ras mutations are very rare in these adenomas, Runx3 þ /À 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.

Lung tissue regeneration after induced injury in Runx3 KO mice

“…Runx3 KO mice show alveolar hyperplasia at PN1 (Lee et al 2010). The intra-alveolar septum structure and wellexpanded alveoli have been observed in WT mice (Fig.…”

“…Runx3 heterozygous FVB mice were generated by interbreeding with Runx3 heterozygous C57BL/6 mice, followed by backcrossing with FVB mice for >10 generations. The animals were maintained under pathogen-free conditions and monitored daily (Lee et al 2010). In this experiment, lungs were extracted from WT and Runx3 KO mice at post-natal day 1 (PN1).…”

“…RUNX1 and RUNX2 play pivotal roles in hematopoiesis, osteoblast differentiation, and bone ossification (Okuda et al 1996;Otto et al 1997), whereas RUNX3 is closely involved in neurogenesis Levanon et al 2002) and thymopoiesis (Taniuchi et al 2002;Woolf et al 2003) and functions as a tumor suppressor (Bae and Lee 2006;Chi et al 2009;Guo et al 2002;Ito et al 2008;Kim et al 2005;Li et al 2002). Runx3 is essential for normal murine lung development and Runx3 knockout (KO) mice, which die soon after birth, exhibit alveolar hyperplasia (Lee et al 2010). Moreover, the intra-alveolar septum structure is not observed in the Runx3 KO mouse (Lee et al 2010).…”

“…Runx3 is essential for normal murine lung development and Runx3 knockout (KO) mice, which die soon after birth, exhibit alveolar hyperplasia (Lee et al 2010). Moreover, the intra-alveolar septum structure is not observed in the Runx3 KO mouse (Lee et al 2010). In order to understand the relationship between wound healing and the lung defect in Runx3 KO mice, we have examined the localization of various wound-healing markers after physical injury by laser.…”

Molecular Detection of Lung Cancer Stem Cells

“…RUNX3 is an essential transcription factor in the late phase of pulmonary development. It is necessary for the control of the differentiation and proliferation of the bronchiolar epithelium [23]. Its subregulation by hyper-methylation has been observed in pulmonary adenocarcinomas [24,25] and has even been proposed as an early event in the development of pulmonary carcinomas by inhibiting the differentiation of progenitor cells [23].…”