Reversal of sorafenib resistance in hepatocellular carcinoma: epigenetically regulated disruption of 14-3-3η/hypoxia-inducible factor-1α

被引：34

作者：

Qiu, Yongxin ^{[1
,2
]}

Shan, Wenqi ^{[1
,3
]}

Yang, Ye ^{[1
,3
]}

Jin, Ming ^{[1
,3
]}

Dai, Yi ^{[1
,2
]}

Yang, Hanyu ^{[1
,3
]}

Jiao, Ruonan ^{[1
,2
]}

Xia, Yunwei ^{[1
,2
]}

Liu, Qinqiang ^{[2
]}

Ju, Liang ^{[2
]}

Huang, Guangming ^{[1
,2
]}

Zhang, Jianping ^{[1
,2
]}

Yang, Lihua ^{[1
,2
]}

Li, Lei ^{[1
,3
]}

Li, Yuan ^{[1
,3
]}

机构：

[1] Nanjing Med Univ, Sch Publ Hlth, Collaborat Innovat Ctr Canc Personalized Med, Jiangsu Key Lab Canc Biomarkers Prevent & Treatme, Nanjing 211166, Jiangsu, Peoples R China

[2] Nanjing Med Univ, Affiliated Hosp 2, Dept Med, Ctr Digest Dis, Nanjing 210011, Jiangsu, Peoples R China

[3] Nanjing Med Univ, Sch Publ Hlth, Minist Educ, Key Lab Modern Toxicol, Nanjing 211166, Jiangsu, Peoples R China

来源：

CELL DEATH DISCOVERY | 2019年 / 5卷 / 1期

基金：

中国国家自然科学基金;

关键词：

CANCER STEM-CELLS; GROWTH-FACTOR-BETA; ARSENIC TRIOXIDE; MESENCHYMAL TRANSITION; METASTASIS; INHIBITION; AKT; ANGIOGENESIS; MICRORNA-491; ATTENUATION;

D O I：

10.1038/s41420-019-0200-8

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Sorafenib resistance is one of the main obstacles to the treatment of advanced/recurrent hepatocellular carcinoma (HCC). Here, sorafenib-resistant HCC cells and xenografts in nude mice were used as experimental models. A cohort of patients with advanced recurrent HCC who were receiving sorafenib therapy was used to assess the clinical significance of this therapy. Our data showed that 14-3-3 eta maintained sorafenib resistance in HCC. An analysis of the underlying molecular mechanisms revealed that 14-3-3 eta stabilizes hypoxia-inducible factor 1 alpha (HIF-1 alpha) through the inhibition of ubiquitin-dependent proteasome protein degradation, which leads to the maintenance of cancer stem cell (CSC) properties. We further found that microRNA-16 (miR-16) is a competent miRNA that reverses sorafenib resistance by targeting the 3'-UTR of 14-3-3 eta and thereby inhibits 14-3-3./HIF-1 alpha/CSC properties. In HCC patients, significant negative correlations were found between the expression of miR-16 and 14-3-3 eta, HIF-1 alpha, or CSC properties. Further analysis showed that low miR-16 expression but high 14-3-3 eta expression can prognosticate sorafenib resistance and poor survival. Collectively, our present study indicated that miR-16/14-3-3 eta is involved in sorafenib resistance in HCC and that these two factors could be potential therapeutic targets and biomarkers for predicting the response to sorafenib treatment.

引用

页数：11

共 54 条

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