Research Paper Volume 10, Issue 12 pp 4120—4140

Overexpression of FoxM1 predicts poor prognosis of intrahepatic cholangiocarcinoma

Lingyun Liu 1, 2, *, , Jian Wu 1, *, , Yu Guo 3, *, , Wenxuan Xie 1, , Bin Chen 1, , Yi Zhang 1, , Shaoqiang Li 1, , Yunpeng Hua 1, , Baogang Peng 1, , Shunli Shen 1, ,

  • 1 Department of Hepatic Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzho, Guangdong 510080, China
  • 2 Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin 541000, Guangxi, China
  • 3 Department of General Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzho, Guangdong 510080, China
* Equal contribution

received: July 24, 2018 ; accepted: December 12, 2018 ; published: December 21, 2018 ;

https://doi.org/10.18632/aging.101706
How to Cite

Copyright: Liu et al. This is an open‐access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

FoxM1 is an oncoprotein that is significantly overexpressed in many malignancies including hepatocellular carcinoma, but its role in intrahepatic cholangiocarcinoma (ICC) remains unclear. This study explores the expression of FoxM1 in human ICC, its relationships with clinical outcomes, and its role in the proliferation, migration, and invasion of ICC in vitro and in vivo. The results show that FoxM1 was markedly elevated in tumor tissues versus the paired peritumoral tissues. Overexpression of FoxM1 was correlated with multiple tumor nodules, tumor size > 5 cm, positive lymph node metastasis and advanced TNM stage. Cox analysis revealed that overexpression of FoxM1 is an independent prognostic indicator for both the overall survival and disease-free survival of ICC patients after hepatectomy. Furthermore, up/downregulation of FoxM1 markedly promoted/inhibited ICC cell proliferation, migration, and invasion in vitro and in vivo. Bioinformatic analysis indicated that overexpression of FoxM1 resulted in the dysregulation of multiple signaling pathways in ICC, and selected components of some key signaling pathways such as c-Myc signaling were confirmed in vitro. In addition, overexpression of FoxM1 enhanced MMP-9 and MMP-2 protein expression in ICC cells. In conclusion, FoxM1 promotes ICC progression and is a reliable predictor of poor prognosis in ICC.

Abbreviations

ICC: intrahepatic cholangiocarcinoma; FoxM1: Forkhead Box Protein M1; OS: overall survival; DFS: disease-free survival; qRT-PCR: quantitative Real-Time PCR; IHC: immunohistochemistry; GSEA: Gene Set Enrichment Analysis; TCGA: The Cancer Genome Atlas; LNM: lymph node metastasis; TNM: tumor node metastasis; CEA: carcinoembryonic antigen; CA19-9: carbohydrate antigen 19-9; ES: enrichment Score; NES: normalized enrichment score; Nom P-value: nominal p-value; FDR q-value: false discovery rate q-value.