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Prospero-related homeobox 1 drives angiogenesis of hepatocellular carcinoma through selectively activating interleukin-8 expression
- Source :
- Hepatology (Baltimore, Md.). 66(6)
- Publication Year :
- 2017
-
Abstract
- Angiogenesis has been proven to play an important role in the progression of hepatocellular carcinoma (HCC). However, the molecular mechanism underlying HCC angiogenesis is not well understood. In this study, Prospero-related homeobox 1 (PROX1) was identified as a novel proangiogenic factor in HCC cell lines and tissues. A strong positive correlation was found between the levels of PROX1 and microvessel density in HCC tissues. Knockdown of PROX1 expression in HCC cells significantly inhibited the in vitro capillary tube formation by human vascular endothelial cells and in vivo angiogenesis of HCC, while overexpression of PROX1 in HCC cells induced the opposite effects. PROX1 and nuclear factor κB p65 expression levels were positively correlated in both HCC tissues and cell lines. PROX1 enhances the nuclear accumulation of p65 and stabilizes p65 by recruiting ubiquitin-specific protease 7 to prevent p65 ubiquitination. Consequently, PROX1 activated nuclear factor κB signaling and selectively promoted expression of the proangiogenic interleukin-8 (IL-8) by epigenetically stimulating the IL-8 promoter. Finally, progression of high PROX1 expression HCC in tumor xenograft mice could be effectively contained by an anti-IL-8 monoclonal antibody. Conclusions We have identified PROX1 as a crucial promoter of HCC angiogenesis; our study provides an insight into PROX1's function in HCC progression and the potential therapeutic application of anti-IL-8 antibody in high PROX1 expression HCC patients. (Hepatology 2017;66:1894-1909).
- Subjects :
- 0301 basic medicine
Transcriptional Activation
Pathology
medicine.medical_specialty
Carcinoma, Hepatocellular
Angiogenesis
Mice, Nude
Biology
Neovascularization
Ubiquitin-Specific Peptidase 7
03 medical and health sciences
Mice
Random Allocation
0302 clinical medicine
Liver Neoplasms, Experimental
medicine
Animals
Humans
Interleukin 8
Molecular Targeted Therapy
neoplasms
Homeodomain Proteins
Gene knockdown
Hepatology
Neovascularization, Pathologic
Protein Stability
Tumor Suppressor Proteins
Interleukin-8
Liver Neoplasms
Transcription Factor RelA
Antibodies, Monoclonal
medicine.disease
Xenograft Model Antitumor Assays
digestive system diseases
In vitro
030104 developmental biology
Cell culture
030220 oncology & carcinogenesis
Hepatocellular carcinoma
Cancer research
Homeobox
medicine.symptom
Subjects
Details
- ISSN :
- 15273350
- Volume :
- 66
- Issue :
- 6
- Database :
- OpenAIRE
- Journal :
- Hepatology (Baltimore, Md.)
- Accession number :
- edsair.doi.dedup.....525a610ee8d82d0959e5ea18b1ab2203