FOXM1 expression correlates with tumor invasion and a poor prognosis of colorectal cancer
Introduction
Colorectal cancer (CRC) is the third most common cancer in the world (Jemal et al., 2009). In 2010, it is estimated that there have been approximately 102,900 new cases of CRC and with around 51,370 deaths from CRC. Despite the current surgical techniques and chemoradiotherapy that have made significant improvements, the prognosis of patients with advanced CRC remains poor and the morbidity remains high (Shelton, 2002). In China, the 5 years survival rate of stage IV CRC patients is only 8% and almost none survive for up to 10 years. In particular, liver metastasis is the leading cause of death in patients with CRC (Shimada et al., 2009). Therefore, a fuller understanding of pathogenesis and biological features of CRC will be helpful to exploit a novel prognostic marker and therapeutic target for CRC.
FoxM1 belongs to a large family of Forkhead transcription factors that possesses a winged-helix DNA-binding domain called Forkhead box (FOX) (Wierstra and Alves, 2007). FoxM1 plays a key role in cell cycle progression where endogenous FOXM1 expression peaks at S and G2/M phases (Leung et al., 2001). FOXM1 is ubiquitously expressed in proliferating cells, but is absent in differentiated cells (Laoukili et al., 2007). Abnormal upregulation of FOXM1 has been reported to be involved in malignant transformation and tumor development (Wang et al., 2010). The over-expression of FOXM1 is found in a variety of human cancers, such as basal cell carcinomas, hepatocellular carcinoma, lung cancer, breast cancer, etc. (Teh et al., 2002, Sun et al., 2011a, Sun et al., 2011b, Gialmanidis et al., 2009, Kretschmer et al., 2011). Yoshida et al. (2007) showed that the forkhead box M1 transcription factor contributes to the development and growth of mouse colorectal cancer. Also, by screening global gene expression using cDNA expression array on 41 CRC tissue samples and 25 non-cancerous colorectal tissue samples, Uddin et al. (2011) found that FoxM1 signaling contributes to aggressiveness in a subset of CRC and that the FOXM1 gene may serve as a useful molecular biomarker and potential therapeutic target. However, the relationship of FOXM1 with prognosis of CRC is still unclear and the roles of FOXM1 in the metastatic process of CRC remain to be elucidated.
In order to evaluate the prognostic role of FOXM1 in CRC, semi-quantitative RT-PCR and immunohistochemistry was performed to determine the expression of FOXM1 mRNA and protein in a series of patients with primary CRC. Moreover, sections of adjacent normal mucosa tissues, lymph node and liver metastases tissue samples were also analyzed. Finally, small interfering RNA (siRNA) technology was used to inhibit the expression of FOXM1 in CRC cells and analyze the effect of its inhibition on invasion and metastasis of CRC cells.
Section snippets
Patients and tissue samples
Fifteen CRC tissues and corresponding tumor adjacent tissues (with 1.0–2.0 cm distance from tumor edge) excised from 2002 to 2004, respectively, were selected from the Department of Surgery of Jinling Hospital, Nanjing University (Table 1). Paraffin-embedded blocks of 112 surgically resected primary CRC tissues were also included in the present study. Histopathological analyses confirmed the malignant and adjacent normal mucosa tissues. Tumor staging was defined according to the criteria for
Results
Semi-quantitative RT-PCR assay was performed to detect the expression of FOXM1 mRNA in 15 CRC tissues and adjacent normal mucosa tissues. GAPDH was used as an internal control, and the ratio of FOXM1/GAPDH was used to reflect the relative mRNA expression level of FOXM1. As shown in Fig. 1A, the relative level of FOXM1 mRNA in CRC tissues was significantly higher than that in adjacent normal mucosa tissues (P < 0.01). Then, Western blot assay was performed to analyze the expression of FOXM1
Discussion
In the present study, we detected the expression of FOXM1 mRNA and protein expression in CRC tissues and adjacent normal mucosa tissues. It was shown that the levels of FOXM1 expression were significantly higher in CRC tissues than in adjacent normal mucosa tissues, not only at the transcriptional level, but also at the translational level. Meanwhile, we also showed that high FOXM1 expression was closely correlated with the presence of lymph node metastasis, incidence of liver metastasis and
Acknowledgements
The study was supported by grants from the Jiangsu Provincial Personnel Department “the Great of Six Talented Man Peak” Project (No. 20096C30).
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These authors contributed equally to this work.