Journal
CELLULAR ONCOLOGY
Volume 43, Issue 6, Pages 1129-1145Publisher
SPRINGER
DOI: 10.1007/s13402-020-00546-0
Keywords
HBV-associated HCC; Bufalin; HBV X protein; Androgen receptor; Cell cycle-related kinase; HBx transgenic mice
Categories
Funding
- National Natural Science Foundation of China [81774240, 81874436, 81673935, 81673938, 81672789, 81603589, 81774256, 81673767]
- Natural Science Foundation of Heilongjiang Province [H2017013]
- Chenguang Program from Shanghai Education Development Foundation
- Shanghai Municipal Education Commission [15CG48]
- Shanghai Rising-star Program [17QA1403900]
- Training plan of outstanding young medical talents, Shanghai Municipal Health Bureau [2017YQ021]
- Chinese Medicine Association [QNRC2-C14]
- Training Plan for Excellent Academic Leaders of Shanghai Health System [2017BR007]
- Science Research Project of Thirteen Five-year Plan [2018ZX10725504]
- Shanghai science and Technology Commission [16401970600]
- Shanghai Shuguang Hospital [SGXZ-201904]
- Chinese medicine preponderant disease breeding project [zybz-2017004]
Ask authors/readers for more resources
Purpose Hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC), which has a male predominance, lacks effective therapeutic options. Previously, the cardiac glycoside analogue bufalin has been found to inhibit HBV infection and HCC development. As yet, however, its molecular role in HBV-associated HCC has remained obscure. Methods Colony formation and soft agar assays, xenograft and orthotopic mouse models and HBV X protein (HBx) transgenic mice with exposure to diethylnitrosamine were used to evaluate the effect of bufalin on HBV-associated HCC growth and tumorigenicity. HBx-induced oncogenic signaling regulated by bufalin was assessed using PCR array, chromatin immunoprecipitation, site-directed mutagenesis, luciferase reporter, transcription and protein expression assays. Synergistic HCC therapeutic effects were examined using combinations of bufalin and sorafenib. Results We found that bufalin exerted a more profound effect on inhibiting the proliferation of HBV-associated HCC cells than of non HBV-associated HCC cells. Bufalin significantly inhibited HBx-induced malignant transfromation in vitro and tumorigenicity in vivo. Androgen receptor (AR) signaling was found to be a target of bufalin resistance to HBV-associated hepatocarcinogenesis. We also found that bufalin induced both AR dephosphorylation and cell cycle-related kinase (CCRK) degradation to inhibit beta-catenin/TCF signaling, which subsequently led to cell cycle arrest via cyclin D1 down-regulation and p21 up-regulation, resulting in HCC regression. Furthermore, we found that bufalin reduced > 60% diethylnitrosamine-induced hepatocarcinogenesis in HBx transgenic mice, and improved the sensitivity of refractory HBV-associated HCC cells to sorafenib treatment. Conclusion Our results indicate that bufalin acts as a potential anti-HCC therapeutic candidate to block HBx-induced AR/CCRK/beta-catenin signaling by targeting AR and CCRK, which may provide a novel strategy for the treatment of HBV-associated HCC.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available