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.
Highlights
As a common hepatic malignancy derived from seconddegree bile tracts, intrahepatic cholangiocarcinoma (ICC) constitutes 5-10% of human primary liver cancers [1]
QRT-PCR and Western blotting analysis showed that the mRNA and protein expression levels of Forkhead Box Protein M1 (FoxM1) were significantly higher in ICC cancer tissues than in the matched peritumoral tissues (Fig. 1A, B)
The results showed that FoxM1 was mainly expressed in the cell membrane and cytoplasm of tumor cells
Summary
As a common hepatic malignancy derived from seconddegree bile tracts, ICC constitutes 5-10% of human primary liver cancers [1]. The incidence of and mortality due to ICC has rapidly increased in recent decades, with geographic variations [2]. Due to the insidious onset and highly invasive biological behavior of ICC, patients with ICC often have advanced clinical stage at diagnosis and have missed the opportunity for radical surgery [3]. Early tumor recurrence and metastasis is common in ICC patients after surgery [4]. The www.aging‐us.com current 3-year and 5-year overall survival rates of patients with ICC are only 31% and 18%, respectively [5].
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