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Decreased FOXF1 promotes hepatocellular carcinoma tumorigenesis, invasion, and stemness and is associated with poor clinical outcome

Authors Zhao Z, Wang D, Hu D, Li Y, Liu S

Received 23 August 2015

Accepted for publication 25 January 2016

Published 23 March 2016 Volume 2016:9 Pages 1743—1752


Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Norbert Ajeawung

Peer reviewer comments 3

Editor who approved publication: Professor Daniele Santini

Zhen-guo Zhao,1,2 De-qiang Wang,3 De-fei Hu,4 You-sheng Li,1 Shuang-hai Liu2

1Department of Surgery, Jinling Hospital, Nanjing Medical University, Nanjing, 2Department of General Surgery, The Affiliated Jiangyin Hospital of Southeast University Medical College, Jiangyin, 3Tumor Treatment Center, The Affiliated Hospital of Jiangsu University, Zhenjiang, 4Clinical Laboratory, The Second People’s Hospital of Huai’an, Huai’an, People’s Republic of China

Abstract: Forkhead box F1 (FOXF1), a member of the forkhead transcription factor superfamily, plays critical roles in the progression of certain types of cancers. However, the expression and function of FOXF1 in human hepatocellular carcinoma (HCC) are still unclear. Quantitative real-time reverse transcription polymerase chain reaction, Western blotting, and immunohistochemistry detected the relatively lower expression status of FOXF1 in HCC cases. Soft agar and transwell assays clearly demonstrated that FOXF1-knockdown cells showed significantly increased in vitro cell tumorigenesis and invasion, and FOXF1-overexpressing cells had significantly reduced growth and invasion potential. Our study also examined the role of FOXF1 in HCC cell stemness by sphere formation, aldehyde dehydrogenase (ALDH1) activity, and CD44/133-positive cell analysis. Enforced FOXF1 expression decreased HCC cell stemness, and the downregulation of FOXF1 promoted cancer cell stemness. The in vivo study showed that overexpressed FOXF1 inhibits nude mouse tumorigenicity with downregulation of CD44 and proliferating cell nuclear antigen. More importantly, loss of FOXF1 expression was linked to poor overall survival time by Kaplan–Meier analysis.

Keywords: hepatocellular carcinoma, FOXF1, tumorigenesis, invasion, cancer stemness, clinical outcome

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