Loss of RUNX3 expression correlates with differentiation, nodal metastasis, and poor prognosis of gastric cancer.
BACKGROUND
RUNX3 is a major growth regulator of gastric epithelial cells that is involved in gastric tumorigenesis in both humans and mice. In this study, we investigated the involvement of RUNX3 in tumor progression, and in the prognosis of human gastric cancer.


METHODS
We analyzed the extent of RUNX3 protein expression by immunohistochemistry in 95 primary gastric adenocarcinomas, and correlated expression levels with clinicopathological parameters. We examined the effects of pFlag/RUNX3 on cell growth, apoptosis, and caspase-3 expression in AGS and SNU1 gastric cancer cell lines by colony-forming assay, terminal deoxynucleotidyl transferase (TdT)-mediate deoxyuridine triphosphatase (dUTP) nick-end labeling (TUNEL) assay, and Western blot analysis, respectively. The pFlag/RUNX3 effects on AGS invasion and migration potentials were also evaluated.


RESULTS
RUNX3 expression was lost in 37 (39%) cases of gastric cancer. The expression of RUNX3 in diffuse- and mixed-type cancers was less frequent than expression in intestinal-type cancer (P < 0.001 and P = 0.001, respectively). In addition, the loss of RUNX3 expression was associated with lymph node metastasis (P = 0.02), and correlated with poor gastric cancer survival (P = 0.018). The growth of gastric cancer cells was suppressed after pFlag/RUNX3 transfection. The re-expression of RUNX3 resulted in the upregulation of caspase-3 and promoted apoptosis. Furthermore, Re-expression of RUNX3 induced significant inhibitions of AGS cell invasion and migration in vitro.


CONCLUSIONS
This work shows that loss of RUNX3 expression is highly associated with lymph node metastasis and poor prognosis of gastric cancer. The re-expression of RUNX3 may induce apoptosis and inhibit the growth as well as invasion/migration of cancer cells. These results indicate that the targeting of the RUNX3 pathway could represent a potential modality for treating gastric cancer.
Hsu
Ping-I
PI
Department of Internal Medicine, Kaohsiung Veterans General Hospital and National Yang-Ming University, Taiwan. pjlu2190@mail.ncku.edu.tw
Hsieh
Hsiao-Ling
HL
Lee
Jihjong
J
Lin
Li-Fang
LF
Chen
Hui-Chun
HC
Lu
Pei-Jung
PJ
Hsiao
Michael
M
D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D017209:Apoptosis; D053148:Caspase 3 / Q000096:biosynthesis; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D050677:Core Binding Factor Alpha 3 Subunit / Q000096:biosynthesis / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D011379:Prognosis; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism
D050677:Core Binding Factor Alpha 3 Subunit; C493729:Runx3 protein, human; D053148:Caspase 3