Hsu Ping-I, Hsieh Hsiao-Ling, Lee Jihjong, Lin Li-Fang, Chen Hui-Chun, Lu Pei-Jung, Hsiao Michael
Department of Internal Medicine, Kaohsiung Veterans General Hospital and National Yang-Ming University, Taiwan.
Ann Surg Oncol. 2009 Jun;16(6):1686-94. doi: 10.1245/s10434-009-0428-2. Epub 2009 Mar 17.
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.
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.
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.
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.
RUNX3是胃上皮细胞的主要生长调节因子，参与人类和小鼠的胃癌发生过程。在本研究中，我们调查了RUNX3在肿瘤进展及人类胃癌预后中的作用。
我们通过免疫组织化学分析了95例原发性胃腺癌中RUNX3蛋白的表达程度，并将表达水平与临床病理参数相关联。我们分别通过集落形成试验、末端脱氧核苷酸转移酶（TdT）介导的脱氧尿苷三磷酸（dUTP）缺口末端标记（TUNEL）试验以及蛋白质印迹分析，检测了pFlag/RUNX3对AGS和SNU1胃癌细胞系中细胞生长、凋亡及半胱天冬酶-3表达的影响。还评估了pFlag/RUNX3对AGS侵袭和迁移能力的影响。
37例（39%）胃癌病例中RUNX3表达缺失。RUNX3在弥漫型和混合型癌症中的表达频率低于肠型癌症（分别为P < 0.001和P = 0.001）。此外，RUNX3表达缺失与淋巴结转移相关（P = 0.02），并与胃癌患者的不良生存相关（P = 0.018）。pFlag/RUNX3转染后，胃癌细胞的生长受到抑制。RUNX3的重新表达导致半胱天冬酶-3上调并促进凋亡。此外，RUNX3的重新表达在体外显著抑制了AGS细胞的侵袭和迁移。
本研究表明，RUNX3表达缺失与胃癌的淋巴结转移及不良预后高度相关。RUNX3的重新表达可能诱导凋亡，并抑制癌细胞的生长以及侵袭/迁移。这些结果表明，靶向RUNX3通路可能是治疗胃癌的一种潜在方式。
