Effect of HBx-mediated RXR alpha repression on DNMT3a in hepatocellular carcinoma and underlying mechanism

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Effect of HBx-mediated RXR alpha repression on DNMT3a in hepatocellular carcinoma and underlying mechanism

Basic Medicine | 更新时间：2026-01-09

- Effect of HBx-mediated RXR alpha repression on DNMT3a in hepatocellular carcinoma and underlying mechanism
- Journal of Third Military Medical University Vol. 39, Issue 24, Pages: 2374-2379(2017)
- 作者机构：
  
  1.400030 重庆，重庆市肿瘤研究所/医院/癌症中心药学部
  2.400038 重庆，第三军医大学西南医院全军肝胆外科研究所
  3.102218 北京，北京清华长庚医院肝胆胰中心
- 作者简介：
- 基金信息：
  
  the General Program of Natural Science Foundation of China(81372272)
- DOI：10.16016/j.1000-5404.201709085
  CLC： R373.21; R730.23; R735.7
- Received：12 September 2017，
  
  Revised：2017-10-10，
  
  Published：30 December 2017
- 稿件说明：
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Xia WANG, Jun YAN. Effect of HBx-mediated RXR alpha repression on DNMT3a in hepatocellular carcinoma and underlying mechanism[J]. Journal of Third Military Medical University, 2017, 39(24): 2374-2379.
DOI：

Xia WANG, Jun YAN. Effect of HBx-mediated RXR alpha repression on DNMT3a in hepatocellular carcinoma and underlying mechanism[J]. Journal of Third Military Medical University, 2017, 39(24): 2374-2379. DOI： 10.16016/j.1000-5404.201709085.

摘要

目的

2

探讨维甲酸X受体α(retinoid X receptor α

RXRα)在乙肝病毒X蛋白(hepatitis B virus X protein

HBx)上调肝细胞癌DNA甲基转移酶3a(DNA methyltransferases 3a

DNMT3a)表达中的作用及机制。

方法

2

采用RT-PCR和Western blot检测12例正常肝组织、56例HBV阳性的肝细胞癌和癌旁组织中DNMT3a、RXRα的基因和蛋白表达变化；在培养的SMMC-7721细胞中，转染HBx基因和RXRα基因，观察对其DNMT3a表达的影响；在转染HBx基因的SMMC-7721细胞中，分别加入信号通路阻断剂，观察何种信号通路在HBx调节RXRα的表达中发挥作用。

结果

2

与正常肝组织相比，肝癌组织与癌旁组织中DNMT3a的基因和蛋白表达量显著升高(

P

＜0.01)，肝癌组织与癌旁组织中RXRα的基因和蛋白表达量显著降低(

P

＜0.01)；在SMMC-7721细胞中，HBx的过表达使RXRα的蛋白表达量显著降低(

P

＜0.01)，DNMT3a的蛋白表达量显著升高(

P

＜0.01)，而RXRα与HBx共转染，则可降低HBx升高的DNMT3a蛋白表达量(

P

＜0.01)；MKK/MEK抑制剂PD98059和p38 MAPK抑制剂SB203580可显著升高HBx下调的RXRα基因和蛋白表达(

P

＜0.01)。

结论

2

HBV产生的HBx蛋白可能通过MAPK信号通路，降低RXRα表达，引起促癌基因DNMT3a蛋白含量增加。

Abstract

Objective

2

To explore the role and mechanism of retinoic acid receptor alpha (RXRα) in the regulation of DNA methyltransferases 3a (DNMT3a) expression induced by hepatitis B virus X protein (HBx) in hepatocellular carcinoma.

Methods

2

The gene and protein expression levels of DNMT3a and RXRα were detected by RT-PCR and Western blot assay respectively in normal liver tissues of 12 healthy individual

and HBV positive hepatocellular carcinoma and paired paracancerous tissues of 56 patients. The expression of DNMT3a was measured after HBx gene and/or RXRα gene were transfected in SMMC-7721 cells. The MKK/MEK blocker PD98059 and p38 MAPK blocker SB203580 were added to observe the role of signal pathways in the regulation of RXRα in SMMC-7721 cells transfected with HBx gene.

Results

2

Compared with normal liver tissues

the expression of DNMT3a at mRNA and protein levels was significantly increased in hepatocellular carcinoma tissues and adjacent tissues (

P

<

0.01)

but the levels of RXRα were significantly decreased (

P

<

0.01). Overexpression of HBx gene inhibited the level of RXRα protein and raised the level of DNMT3a protein

while RXRα co-transfected with HBx decreased the expression of DNMT3a induced by HBx (

P

<

0.01). MKK/MEK inhibitor PD98059 and p38 MAPK inhibitor SB203580 both significantly increased the expression of RXRα which was down-regulated by HBx gene (

P

<

0.01).

Conclusion

2

HBx encoded by HBV genome may reduce the expression of RXRα and increase the content of DNMT3a through the MAPK signaling pathway.

关键词

Keywords

references

CHEN S, DONG Z, YANG P, et al. Hepatitis B virus X protein stimulates high mobility group box 1 secretion and enhances hepatocellular carcinoma metastasis[J]. Cancer Lett, 2017, 394: 22-32. DOI: 10.1016/j.canlet.2017.02.011.

COUGOT D, NEUVEUT C, BUENDIA M A. HBV induced carcinogenesis[J]. J Clin Virol, 2005, 34(Suppl 1): S75-S78. DOI: 10.1016/s1386-6532(05)80014-9.

WANG X, OISHI N, SHIMAKAMI T, et al. Hepatitis B virus X protein induces hepatic stem cell-like features in hepatocellular carcinoma by activating KDM5B[J]. World J Gastroenterol, 2017, 23(18): 3252-3261. DOI: 10.3748/wjg.v23.i18.3252.

XU Y, QI Y, LUO J, et al. Hepatitis B virus X protein stimulates proliferation, wound closure and inhibits apoptosis of HuH-7 cells via CDC42[J ] . Int J Mol Sci, 2017, 18(3): 586. DOI: 10.3390/ijms18030586.

LUPBERGER J, HILDT E. HEPATITIS B virus-induced oncogenesis[J]. World J Gastroenterol, 2007, 13(1): 74-81. DOI: 10.3748/wjg.v13.i1.74.

WEI X, TAN C, TANG C, et al. Epigenetic repression of miR-132 expression by the hepatitis B virus x protein in hepatitis B virus-related hepatocellular carcinoma[J]. Cell Signal, 2013, 25(5): 1037-1043. DOI: 10.1016/j.cellsig.2013.01.019.

LIVINGSTON C M, RAMAKRISHNAN D, STRUBIN M, et al. Identifying and characterizing interplay between hepatitis B virus X protein and Smc5/6[J]. Viruses, 2017, 9(4): e69.

KONG F, YOU H, TANG R, et al. The regulation of proteins associated with the cytoskeleton by hepatitis B virus X protein during hepatocarcinogenesis[J]. Oncol Lett, 2017, 13(4): 2514-2520. DOI: 10.3892/ol.2017.5757.

YU L, CHEN S, LUO N, et al. The C-terminus domain of the hepatitis B virus x protein stimulates the proliferation of mouse foetal hepatic progenitor cells, although it is not required for the formation of spheroids[J]. Int J Mol Med, 2017, 40(2): 400-410. DOI: 10.3892/ijmm.2017.3026.

HOU Z, XU X, FU X, et al. HBx-related long non-coding RNA MALAT1 promotes cell metastasis via up-regulating LTBP3 in hepatocellular carcinoma[J ] . Am J Cancer Res, 2017, 7(4): 845-856.

ARZUMANYAN A, FRIEDMAN T, KOTEI E, et al. Epigenetic repression of E-cadherin expression by hepatitis B virus x antigen in liver cancer[J]. Oncogene, 2012, 31(5): 563-572. DOI: 10.1038/onc.2011.255.

YAN J, LU Q, DONG J, et al. Hepatitis B virus X protein suppresses caveolin-1 expression in hepatocellular carcinoma by regulating DNA methylation[J]. BMC Cancer, 2012, 12: 353. DOI: 10.1186/1471-2407-12-353.

CORTELLINO S, XU J, SANNAI M, et al. Thymine DNA glycosylase is essential for active DNA demethylation by linked deamination-base excision repair[J]. Cell, 2011, 146(1): 67-79. DOI: 10.1016/j.cell.2011.06.020.

汤钊猷.原发性肝癌[M].上海:上海科学技术出版社, 1981.

TANG Z Y. Primary liver cancer[M]. Shanghai: Shanghai Science and Technique Publishing House, 1981.

GAO Q, WANG K, CHEN K, et al. HBx protein-mediated ATOH1 downregulation suppresses ARID2 expression and promotes hepatocellular carcinoma[J]. Cancer Sci, 2017, 108(7): 1328-1337. DOI: 10.1111/cas.13277.

KIM Y J, JUNG J K, LEE S Y, et al. Hepatitis B virus X protein overcomes stres s-induced premature senescence by repressing p16(INK4a) expression via DNA methylation[J ] . Cancer Lett, 2010, 288(2): 226-235. DOI: 10.1016/j.canlet.2009.07.007.

PARK I Y, SOHN B H, YU E, et al. Aberrant epigenetic modifications in hepatocarcinogenesis induced by hepatitis B virus X protein[J]. Gastroenterology, 2007, 132(4): 1476-1494. DOI: 10.1053/j.gastro.2007.01.034.

ZHU R, ZHANG J S, ZHU Y Z, et al. HBx-induced androgen receptor expression in HBV-associated hepatocarcinoma is independent of the methylation status of its promoter[J]. Histol Histopathol, 2011, 26(1): 23-35. DOI: 10.14670/HH-26.23.

SHIRAKAMI Y, SAKAI H, SHIMIZU M. Retinoid roles in blocking hepatocellular carcinoma[J]. Hepatobiliary Surg Nutr, 2015, 4(4): 222-228. DOI: 10.3978/j.issn.2304-3881.2015.05.01.

LI J, CHANRION M, SAWEY E, et al. Reciprocal interaction of Wnt and RXR-α pathways in hepatocyte development and hepatocellular carcinoma[J]. PLoS ONE, 2015, 10(3): e0118480. DOI: 10.1371/journal.pone.0118480.

MATSUSHIMA-NISHIWAKI R, OKUNO M, ADACHI S, et al. Phosphorylation of retinoid X receptor alpha at serine 260 impairs its metabolism and function in human hepatocellular carcinoma[J]. Cancer Res, 2001, 61(20): 7675-7682.

SHIMIZU M, TAKAI K, MORIWAKI H. Strategy and mechanism for the prevention of hepatocellular carcinoma: phosphorylated retinoid X receptor alpha is a critical target for hepatocellular carcinoma chemoprevention[J]. Cancer Sci, 2009, 100(3): 369-374. DOI: 10.1111/j.1349-7006.2008.01045.x.

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