Absence of Runx3 expression in normal gastrointestinal epithelium calls into question its tumour suppressor function

Abstract

The Runx3 transcription factor regulates cell fate decisions during embryonic development and in adults. It was previously reported that Runx3 is strongly expressed in embryonic and adult gastrointestinal tract (GIT) epithelium (Ep) and that its loss causes gastric cancer. More than 280 publications have based their research on these findings and concluded that Runx3 is indeed a tumour suppressor (TS). In stark contrast, using various measures, we found that Runx3 expression is undetectable in GIT Ep. Employing a variety of biochemical and genetic techniques, including analysis of Runx3-GFP and R26LacZ/Runx3Cre or R26tdTomato/Runx3Cre reporter strains, we readily detected Runx3 in GIT-embedded leukocytes, dorsal root ganglia, skeletal elements and hair follicles. However, none of these approaches revealed detectable Runx3 levels in GIT Ep. Moreover, our analysis of the original Runx3LacZ/LacZ mice used in the previously reported study failed to reproduce the GIT expression of Runx3. The lack of evidence for Runx3 expression in normal GIT Ep creates a serious challenge to the published data and undermines the notion that Runx3 is a TS involved in cancer pathogenesis.

The Influence of Survival Analysis on Runx3 Gene Expression in the Primary Tumor of Patients Suffering from Stomach Carcinoma

“…Recently, studies have reported that silencing a tumor suppressor gene may result in loss of its function in tumorigenesis [16]. Inactivation mechanisms of the Runx3 gene are believed to be promoter hypermethylation and homozygous deletion [16,17].…”

“…Inactivation mechanisms of the Runx3 gene are believed to be promoter hypermethylation and homozygous deletion [16,17]. Genetic variants of the Runx3 gene may also play an inactivation role.…”

Transcription Factor Runx3 Regulates Interleukin-15-Dependent Natural Killer Cell Activation

“…1A), as was also observed by Ohno et al (25). To determine the developmental stage at which Runx3 expression is acquired, we used two Runx3 knock-in (KI) mouse strains, P1-AFP (Runx3 P1-AFP/ϩ ) and P2-EGFP (Runx3 P2-EGFP/ϩ ), harboring altered GFP (AFP) or enhanced green fluorescent protein (EGFP) inserted at the P1 or P2 ATG codon, respectively (27). Analysis of compound P1/P2-GFP mice (double heterozygote Runx3 P1-AFP/ϩ; P2-EGFP/ϩ mice) showed that ϳ60% of BM NKP (Lin (Fig.…”

“…Ϫ/Ϫ , Runx3 P1-AFP/ϩ , and Runx3 P2-GFP/ϩ mice was described previously (27,28). Rag Ϫ/Ϫ ␥c Ϫ/Ϫ females were obtained from Taconic farms (stock number 004111-MM).…”

Carcinogen-Induced Skin Tumor Development Requires Leukocytic Expression of the Transcription Factor Runx3

“…Despite these profound immune anomalies, in vivo studies of wound closure, contact hypersensitivity, and epidermal apoptosis were unaltered in skins of Runx3-null mice (18). Runx3 is also highly expressed in respiratory and gastrointestinal tract leukocytes, but is absent from their epithelia (13,22,23). Significantly, Runx3-null mice spontaneously develop airway and colon inflammation (19,20,22), attesting to Runx3 involvement in leukocyte homeostasis in these tissues.…”