Oncogene FOXK1 enhances invasion of colorectal carcinoma by inducing epithelial-mesenchymal transition.

Yao Wu,Yuexin Ren,Ying Peng,Qingzhen Nan,Jinjun Zhao,Aimin Li,Side Liu,Jide Wang,Pei Zhang,Ye Chen,Ruyi Xie,Mengnan Zhang,Meiyan Wu,Yang Bai,Wenjing Zhang

doi:10.18632/oncotarget.9457

Abstract

Transcriptional factor FOXK1 is a member of the FOX family, involved in the cell growth and metabolism. The higher expression of FOXK1 leads to a variety of diseases and may play an important role in the development of various tumors. However, the role of FOXK1 in the progression of colorectal cancer (CRC) remains unknown. We demonstrated that FOXK1 was overexpressed in 16 types of solid tumor tissues via tissue multi-array (TMA). We found that FOXK1 induced elevated expressions and transactivities of five major oncogenes in CRC. Moreover, the elevated expression of FOXK1 was showed to be correlated with tumor progression and was a significant predictor of overall survival in CRC patients. Furthermore, it was showed that the depletion of FOXK1 expression could inhibit the migratory and invasive abilities of CRC cells. In contrast, ectopic expression of FOXK1 elicited the opposite effects on these phenotypes in vitro. FOXK1 promoted tumor metastasis through EMT program induction. In addition, TGF-β1 induced FOXK1 expression in a time-dependent pattern and the knockdown of FOXK1 inhibited TGF-β1-induced EMT. In vivo, higher expression of FOXK1 promotes CRC cell invasion and metastasis, and induces EMT in CRC as well. Alltogether, it was concluded that the higher expression of FOXK1 could indicate a poor prognosis in CRC patients since that FOXK1 induces EMT and promotes CRC cell invasion in vitro and in vivo.

Highlights

The forkhead box (Fox) gene family is a group of highly conserved transcription factors that are expressed in diverse species, including yeast and humans. [1,2,3] Many FOX protein members have been documented to play critical roles in embryonic development [4] as well as organogenesis [5] and are involved in the regulation of a variety of physiological processes [6, 7], such as metabolic processes [8], cell signaling [9], and the cell cycle [10]
We found that Forkhead box k1 (FOXK1) is highly expressed in 16 types of solid tumor tissues and that increased FOXK1 expression significantly correlated with progression, metastasis, and poor outcome in patients with colorectal cancer (CRC)
We confirmed FOXK1 expression by immunohistochemistry in excised tissues of colon or rectal in 93 CRC patients, who were from Surgery of Nanfang Hospital, Southern Medical University

Summary

Introduction

The forkhead box (Fox) gene family is a group of highly conserved transcription factors that are expressed in diverse species, including yeast and humans. [1,2,3] Many FOX protein members have been documented to play critical roles in embryonic development [4] as well as organogenesis [5] and are involved in the regulation of a variety of physiological processes [6, 7], such as metabolic processes [8], cell signaling [9], and the cell cycle [10]. The forkhead box (Fox) gene family is a group of highly conserved transcription factors that are expressed in diverse species, including yeast and humans. [1,2,3] Many FOX protein members have been documented to play critical roles in embryonic development [4] as well as organogenesis [5] and are involved in the regulation of a variety of physiological processes [6, 7], such as metabolic processes [8], cell signaling [9], and the cell cycle [10]. Forkhead box k1 (FOXK1) is a transcription factor that belongs to the forkhead family consisting of the winged-helix DNA-binding domain and the N-terminal and C-terminal transcriptional domains [14]. The data indicate a role for human FOXK1 in regulating the developmental process as well as the potential involvement of FOXK1 in tumorigenesis [17, 18]

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Results

Conclusion