1. Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
2. Institute of Pathology, Fudan University, Shanghai 200032, China
3. Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
4. Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China.
5. Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
6. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
7. Department of neurosurgery, 1st affiliated hospital of Sun Yat-sen University, Guangzhou, 510080, China
* Ping Wei, Nu Zhang and Yiqin Wang contributed equally to this work
The forkhead box M1 (FOXM1) transcription factor is one of the key genes inducing tumor invasion and metastasis by an unknown mechanism. In this study, we set out to investigate the effects of FOXM1 overexpression on metastatic human lung adenocarcinoma and the underlying mechanism. FOXM1 expression was analyzed in 78 frozen lung adenocarcinoma tissue samples using an Affymetrix microarray and a 155-paraffin-embedded lung adenocarcinoma tissue microarray with immunohistochemical detection. FOXM1 was found to be overexpressed in lung adenocarcinoma, particularly in metastatic patients, compared to non-metastatic patients. Knockdown of FOXM1 by a specific siRNA significantly suppressed EMT progression, migration and invasion of lung adenocarcinoma cells in vitro, and tumor growth and metastasis in vivo, whereas restored expression of FOXM1 had the opposite effect. FOXM1 binds directly to the SNAIL promoter through two specific binding sites and constitutively transactivates it. Collectively, our findings indicate that FOXM1 may play an important role in advancing lung adenocarcinoma progression. Aberrant FOXM1 expression directly and constitutively activates SNAIL, thereby promoting lung adenocarcinoma metastasis. Inhibition of FOXM1-SNAIL signaling may present an ideal target for future treatment.
Keywords: Lung adenocarcinoma, Invasion, Metastasis, FOXM1, SNAIL