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Biosci Rep. 2018 May 8;38(3). pii: BSR20171264. doi: 10.1042/BSR20171264. Print 2018 Jun 29.

Regorafenib inhibits tumor progression through suppression of ERK/NF-κB activation in hepatocellular carcinoma bearing mice.

Weng MC1,2, Wang MH2, Tsai JJ3, Kuo YC4,5, Liu YC6, Hsu FT7,8,9,10, Wang HE11.

Author information

1
Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taiwan.
2
Division of Isotope Application, Institute of Nuclear Energy Research, Atomic Energy Council, Taiwan.
3
Division of Gastroenterology, Department of Medicine, National Yang-Ming University Hospital, Yilan, Taiwan.
4
Radiation Oncology, Show Chwan Memorial Hospital, Changhua, Taiwan.
5
Department of Radiological Technology, China Medical University, Taichung, Taiwan.
6
Department of Radiation Oncology, National Yang-Ming University Hospital, Yilan, Taiwan.
7
Department of Radiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan hewang@ym.edu.tw sakiro920@tmu.edu.tw.
8
Department of Medical Imaging, Taipei Medical University Hospital, Taipei, Taiwan.
9
Research Center of Translational Imaging, College of Medicine, Taipei Medical University, Taipei, Taiwan.
10
Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
11
Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taiwan hewang@ym.edu.tw sakiro920@tmu.edu.tw.

Abstract

Regorafenib has been demonstrated in our previous study to trigger apoptosis through suppression of extracellular signal-regulated kinase (ERK)/nuclear factor-κB (NF-κB) activation in hepatocellular carcinoma (HCC) SK-Hep1 cells in vitro However, the effect of regorafenib on NF-κB-modulated tumor progression in HCC in vivo is ambiguous. The aim of the present study is to investigate the effect of regorafenib on NF-κB-modulated tumor progression in HCC bearing mouse model. pGL4.50 luciferase reporter vector transfected SK-Hep1 (SK-Hep1/luc2) and Hep3B 2.1-7 tumor bearing mice were established and used for the present study. Mice were treated with vehicle or regorafenib (20 mg/kg/day by gavage) for 14 days. Effects of regorafenib on tumor growth and protein expression together with toxicity of regorafenib were evaluated with digital caliper and bioluminescence imaging (BLI), ex vivo Western blotting immunohistochemistry (IHC) staining, and measurement of body weight and pathological examination of liver tissue, respectively, in SK-Hep1/luc2 and Hep3B 2.1-7 tumor bearing mice. The results indicated regorafenib significantly reduced tumor growth and expression of phosphorylated ERK, NF-κB p65 (Ser536), phosphorylated AKT, and tumor progression-associated proteins. In addition, we found regorafenib induced both extrinsic and intrinsic apoptotic pathways. Body weight and liver morphology were not affected by regorafenib treatment. Our findings present the mechanism of tumor progression inhibition by regorafenib is linked to suppression of ERK/NF-κB signaling in SK-Hep1/luc2 and Hep3B 2.1-7 tumor bearing mice.

KEYWORDS:

Bioluminescence imaging; Regorafenib; apoptosis; hepatocellular carcinoma; nuclear factor kappaB

PMID:
29535278
PMCID:
PMC5938429
DOI:
10.1042/BSR20171264
[Indexed for MEDLINE]
Free PMC Article

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