Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan.
Int J Cancer. 2012 Nov 15;131(10):2284-93. doi: 10.1002/ijc.27525. Epub 2012 Apr 17.
Runt-related transcription factor 2 (RUNX2) belongs to the RUNX family of heterodimeric transcription factors, and is mainly associated with osteogenesis. Previous in vitro studies demonstrated that RUNX2 increased the cell proliferation of mouse and rat colon carcinoma cells but the status of RUNX2 has remained unknown in human colon carcinoma. Therefore, we examined clinical significance and biological functions of RUNX2 in colon carcinoma. RUNX2 immunoreactivity was examined in 157 colon carcinoma tissues using immunohistochemistry. RUNX2 immunoreactivity was evaluated as percentage of positive carcinoma cells [i.e., labeling index (LI)]. We used SW480 and DLD-1 human colon carcinoma cells, expressing estrogen receptor-β (ER) in subsequent in vitro studies. RUNX2 immunoreactivity was detected in colon carcinoma cells, and the median value of RUNX2 LI was 67%. RUNX2 LI was significantly associated with Dukes' stage, liver metastasis and ERβ status. In addition, RUNX2 LI was significantly associated with adverse clinical outcome of the colon carcinoma patients, and turned out an independent prognostic factor following multivariate analysis. Results of in vitro studies demonstrated that both SW480 and DLD-1 cells transfected with small interfering RNA against RUNX2 significantly decreased their cell proliferation, migration and invasive properties. In addition, RUNX2 mRNA level was significantly decreased by ER antagonist in these two cells. These findings all suggest that RUNX2 is a potent prognostic factor in human colon carcinoma patients through the promotion of cell proliferation and invasion properties, and is at least partly upregulated by estrogen signals through ERβ of carcinoma cells.
RUNX2 属于 RUNX 家族异二聚体转录因子，主要与成骨作用有关。之前的体外研究表明，RUNX2 可增加小鼠和大鼠结肠癌细胞的增殖，但在人结肠癌细胞中 RUNX2 的状态仍不清楚。因此，我们研究了 RUNX2 在结肠癌细胞中的临床意义和生物学功能。采用免疫组织化学法检测 157 例结肠癌组织中 RUNX2 的免疫反应性。用阳性癌细胞的百分比[即标记指数（LI）]来评估 RUNX2 免疫反应性。在随后的体外研究中，我们使用表达雌激素受体-β（ER）的 SW480 和 DLD-1 人结肠癌细胞。在结肠癌细胞中检测到 RUNX2 免疫反应性，RUNX2 LI 的中位数为 67%。RUNX2 LI 与 Dukes 分期、肝转移和 ERβ 状态显著相关。此外，RUNX2 LI 与结肠癌患者的不良临床结局显著相关，且在多变量分析中是独立的预后因素。体外研究结果表明，转染针对 RUNX2 的小干扰 RNA 的 SW480 和 DLD-1 细胞的增殖、迁移和侵袭特性均显著降低。此外，这两种细胞中的 ER 拮抗剂可显著降低 RUNX2 mRNA 水平。这些发现均表明，RUNX2 通过促进细胞增殖和侵袭特性成为人结肠癌患者强有力的预后因素，并且至少部分通过 ERβ 上调癌细胞中的雌激素信号。
