Abstract
Gastric cancer (GC) is a major cause of cancer mortality. GC studies that aim to identify relevant oncogenes and tumor suppressor genes (TSGs) are essential for devising effective new therapies. A decade ago, RUNX3, a gene that resides on human chromosome 1p36.1, was claimed to be a major TSG in GC. Since then, hundreds of studies involving thousands of GC patients have attempted to verify and extend the RUNX3 TSG paradigm. However, RUNX3 is not recognized as TSG and not listed in the “Cancer Gene Census” website. To be a TSG that protects normal cells against malignancy, the gene must be expressed in the normal tissue from which the cancer arose and its loss or inactivation should contribute to cancer development. This review summarizes compelling body of evidence challenging the RUNX3-TSG paradigm. Studies show unequivocally that RUNX3 is not expressed in normal gastric epithelium and that it fails to fulfill all other premises of a TSG. RUNX3 mutations and 1p36 deletions are not frequent in GC and RUNX3 is not associated with familial GC or with increased risk of GC. Accordingly, Runx3-/- mice do not develop tumors. RUNX3 promoter methylation, which has been reported to be a frequent event in GC, is not relevant to its alleged TSG function, since the gene is already silent in normal gastric epithelium. In sharp contrast, overexpression of RUNX3 was found in several types of human cancers, including GC, and the 1p36.1 region is amplified in B-cell lymphoma. Thus, it is possible that RUNX3 actually promotes cancer development rather than being a TSG. The true targets for GC therapy are discussed below. Those are genes frequently lost or amplified in GC and are well known for their tumor suppressive or oncogenic activity, respectively.
Highlights
Gastric cancer (GC) is highly prevalent in China and other Far East countries, constituting a major cause of worldwide cancer mortality [1,2]
RUNX3 promoter methylation, which has been reported to be a frequent event in GC, is not relevant to its alleged tumor suppressor genes (TSGs) function, since the gene is already silent in normal gastric epithelium
Taking into consideration the reservations pointed out above concerning the specificity of RUNX3 IHC staining in gastric tissue and the contradicting results concerning RUNX3 expression in normal gastric epithelium, the inevitable conclusion is that, as in mouse gastrointestinal tract (GIT), RUNX3 is not expressed in normal human gastric epithelium and that the reported cytoplasmic retention of RUNX3 in normal gastric epithelium and GC cells reflects an IHC artifact
Summary
GC is highly prevalent in China and other Far East countries, constituting a major cause of worldwide cancer mortality [1,2]. A decade ago, Li et al suggested that the transcription factor (TF) RUNX3 functions as a novel TSG that plays a major role in GC [10] This suggestion was based on their finding of high expression level of Runx in normal mouse gastrointestinal tract (GIT), gastric hyperplasia in Runx3−/− newborn mice, detection of a RUNX3 point mutation in a single GC patient, loss of RUNX3 heterozygosity (LOH) in 30% of GC patients, RUNX3 promoter DNA hyper-. Hundreds of studies involving thousands of GC patients have attempted to verify and extend the RUNX3 TSG paradigm suggested by Li et al in GC and/or in other GIT cancers [11] Many of these studies (references included in Table S1 of [12]) focused on the issue of RUNX3 promoter DNA hypermethylation, but have not tested whether RUNX3 was expressed in normal GIT and what are the consequences of this hypermethylation on RUNX3 expression in GIT. Of note, chasing the wrong gene is counter-productive and interferes with efforts to discover the correct gene
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
