Department of Urology, First Affiliated Hospital of Gannan Medical University, No 23, Qing Nian Road, Ganzhou 341000, People's Republic of China.
J Transl Med. 2012 Sep 24;10:200. doi: 10.1186/1479-5876-10-200.
Fork head box M1 (FoxM1) is a proliferation-associated transcription factor essential for cell cycle progression. Numerous studies have documented that FoxM1 has multiple functions in tumorigenesis and its elevated levels are frequently associated with cancer progression. The present study was conducted to investigate the expression of FoxM1 and its prognostic significance in clear cell renal cell carcinoma (ccRCC). Meanwhile, the function of FoxM1 in human ccRCC was further investigated in cell culture models.
Real-time quantitative PCR, western blot and immunohistochemistry were used to explore FoxM1 expression in ccRCC cell lines and primary ccRCC clinical specimens. FoxM1 expression was knocked down by small interfering RNA (siRNA) in Caki-1 and 786-O cells; proliferation, colony formation, cell cycle, migration, invasion, and angiogenesis were assayed.
FoxM1 expression was up-regulated in the majority of the ccRCC clinical tissue specimens at both mRNA and protein levels. Clinic pathological analysis showed that FoxM1 expression was significantly correlated with primary tumor stage (P <0.001), lymph node metastasis (P = 0.01), distant metastasis (P = 0.01), TNM stage (P < 0.001) and histological grade (P = 0.003). The Kaplan-Meier survival curves revealed that high FoxM1 expression was associated with poor prognosis in ccRCC patients (P < 0.001). FoxM1 expression was an independent prognostic marker of overall ccRCC patient survival in a multivariate analysis (P = 0.008). Experimentally, we found that down-regulation of FoxM1 inhibited cell proliferation and induced cell cycle arrest with reduced expression of cyclin B1, cyclin D1, and Cdk2, and increased expression of p21 and p27. Also, down-regulation of FoxM1 reduced expression and activity of matrix metalloproteinase-2 (MMP-2), MMP-9 and vascular endothelial growth factor (VEGF), resulting in the inhibition of migration, invasion, and angiogenesis.
These results suggest that FoxM1 expression is likely to play important roles in ccRCC development and progression, and that FoxM1 is a prognostic biomarker and a promising therapeutic target for ccRCC.
叉头框 M1（FoxM1）是细胞周期进展所必需的增殖相关转录因子。大量研究表明，FoxM1 在肿瘤发生中有多种功能，其水平升高常与癌症进展相关。本研究旨在探讨 FoxM1 在透明细胞肾细胞癌（ccRCC）中的表达及其预后意义。同时，在细胞培养模型中进一步研究了 FoxM1 在人 ccRCC 中的功能。
采用实时定量 PCR、Western blot 和免疫组织化学方法检测 ccRCC 细胞系和原发性 ccRCC 临床标本中 FoxM1 的表达。用小干扰 RNA（siRNA）敲低 Caki-1 和 786-O 细胞中的 FoxM1 表达；检测增殖、集落形成、细胞周期、迁移、侵袭和血管生成。
FoxM1 在大多数 ccRCC 临床组织标本中的 mRNA 和蛋白水平均上调。临床病理分析表明，FoxM1 表达与原发肿瘤分期（P<0.001）、淋巴结转移（P=0.01）、远处转移（P=0.01）、TNM 分期（P<0.001）和组织学分级（P=0.003）显著相关。Kaplan-Meier 生存曲线显示，FoxM1 高表达与 ccRCC 患者预后不良相关（P<0.001）。多因素分析显示，FoxM1 表达是 ccRCC 患者总生存的独立预后标志物（P=0.008）。实验发现，下调 FoxM1 表达抑制细胞增殖，诱导细胞周期阻滞，下调细胞周期蛋白 B1、D1 和 Cdk2，上调 p21 和 p27。下调 FoxM1 表达还降低了基质金属蛋白酶-2（MMP-2）、MMP-9 和血管内皮生长因子（VEGF）的表达和活性，从而抑制迁移、侵袭和血管生成。
这些结果表明，FoxM1 表达可能在 ccRCC 的发生和发展中起重要作用，FoxM1 是 ccRCC 的预后标志物和有前途的治疗靶点。
