Back to Search
Start Over
Far upstream element-binding protein 1 facilitates hepatocellular carcinoma invasion and metastasis
- Source :
- Carcinogenesis. 41:950-960
- Publication Year :
- 2019
- Publisher :
- Oxford University Press (OUP), 2019.
-
Abstract
- Objective: To identify the role of FUBP1 in hepatocellular carcinoma (HCC) progression, invasion and metastasis. Methods: The expression and clinical significance of FUBP1 in HCC was analyzed by university of California santa cruz (UCSC) Xena online bioinformatics analysis tool and TMA from 451 HCC patients who underwent surgery that removed the primary tumor. CD45-EpCam circulating tumor cell was analyzed by CellSearchTM system. Gain-of-function and loss-of-function studies for FUBP1 were performed by implementing lentivirus infection system. HCC cell proliferation, migration and long term survival were measured by CCK-8, transwell assay and clone formation test respectively. The effect of tumor cell growth in vivo was measured by using tumor xenograft mice. Results: mRNA expression level of FUBP1 is higher in HCC tumors compared to adjacent normal liver tissue. Statistical analysis shows that higher expression of FUBP1 is related with hepatitis B virus (HBV) infection background and often with microvascular invasion. Kaplan-Meier analysis revealed significantly shorter median TTR (Time to Recurrence) and overall survival (OS) in patients with high FUBP1 compared with those patients with low FUBP1. The 2-year and 5-year recurrence rate is higher, corresponding with lower OS, in patients with high FUBP1 expression than low FUBP1. Univariate and multivariate analysis revealed that FUBP expression level was an independent indicator for both TTR and OS. In addition, FUBP1 expression in tumors positively correlated with the percentage of CD45-EpCam circulating tumor cell in blood before operation. Overexpression of FUBP1 enhances HCC proliferation, invasion and metastasis. By using shRNAs to deplete FUBP1 expression, HCC cells displayed decreased cell proliferation, soft-agar growth and invasion. In contrast, FUBP1 overexpression promotes primary tumor growth and lung metastasis. qPCR and Western Blot confirmed that the FUBP1 overexpression induces upregulation of N-cadherin and Vimentin whereas inhibiting E-cadherin, important epithelial mesenchymal transition (EMT) markers. By performing gene expression profiling, we identified that FUBP1 activates the TGF-β/smad pathway through promoting the expression of THBS1 (Thrombospondin-1, TSP-1). LSKL (Peptide antagonist of Thrombospondin-1) could inhibit HCC proliferation and invasion in vitro and vivo through blocking activation of TGF-β/smad pathway mediated by THBS1. Conclusions: High level of FUBP1 in HCC predicts poor prognosis after surgery. Overexpression of FUBP1 promotes HCC proliferation, invasion and metastasis, at least partially through enriching the generation of CTCs by activates TGF-I²/smad pathway and enhancing EMT in vitro and vivo. LSKL could inhibit HCC proliferation and invasion in vitro and vivo through blocking activation of TGF-β/smad pathway mediated by THBS1. Funding: National Science and Technology Major Project (2013ZX10002011-004, 2018ZX10203204-006-002). National Key Research and Development Program (2016YFC0902400), National Natural Science Foundation of China (81572823, 81572884). Declaration of Interest: The authors declare no conflict of interest. Ethical Approval: This study was approved by the Clinical Trail Ethics Committee of Zhongshan Hospital and all other four clinical centers. Approval for research protocol and use of human subjects was obtained from the research ethics committee of Zhongshan Hospital. Informed consent was obtained from each patient.
- Subjects :
- Male
0301 basic medicine
Cancer Research
Smad Proteins
Vimentin
SMAD
Metastasis
Thrombospondin 1
Mice
Circulating tumor cell
0302 clinical medicine
Cell Movement
Neoplasm Metastasis
Far Upstream Element-Binding Protein 1
Liver Neoplasms
RNA-Binding Proteins
General Medicine
Primary tumor
DNA-Binding Proteins
Gene Expression Regulation, Neoplastic
Hepatocellular carcinoma
030220 oncology & carcinogenesis
Heterografts
Female
Regulatory Pathway
Signal transduction
Liver cancer
Signal Transduction
Carcinoma, Hepatocellular
Biology
Transforming Growth Factor beta1
03 medical and health sciences
In vivo
Cell Line, Tumor
medicine
Animals
Humans
Neoplasm Invasiveness
Epithelial–mesenchymal transition
Cell Proliferation
business.industry
medicine.disease
digestive system diseases
030104 developmental biology
Tissue Array Analysis
biology.protein
Cancer research
Peptides
business
Transforming growth factor
Subjects
Details
- ISSN :
- 14602180 and 01433334
- Volume :
- 41
- Database :
- OpenAIRE
- Journal :
- Carcinogenesis
- Accession number :
- edsair.doi.dedup.....acd42068fb43a768f722f95951ce865b