Reversal of sorafenib resistance in hepatocellular carcinoma: epigenetically regulated disruption of 14-3-3η/hypoxia-inducible factor-1α
| Autor: | Ye Yang, Yi Dai, Lei Li, Liang Ju, Yunwei Xia, Ming Jin, Yuan Li, Wenqi Shan, Guangming Huang, Lihua Yang, Ruonan Jiao, Jianping Zhang, Qiu Yongxin, Hanyu Yang, Qinqiang Liu |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Sorafenib Cancer Research Cell signaling Immunology Protein degradation lcsh:RC254-282 Article 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Cancer stem cell microRNA medicine lcsh:QH573-671 neoplasms lcsh:Cytology business.industry Oncogenes Cell Biology lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens medicine.disease digestive system diseases Recurrent Hepatocellular Carcinoma 030104 developmental biology Hypoxia-inducible factors 030220 oncology & carcinogenesis Hepatocellular carcinoma Cancer research business Cell signalling medicine.drug |
| Zdroj: | Cell Death Discovery Cell Death Discovery, Vol 5, Iss 1, Pp 1-11 (2019) |
| ISSN: | 2058-7716 |
| DOI: | 10.1038/s41420-019-0200-8 |
| Popis: | 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 14-3-3η maintained sorafenib resistance in HCC. An analysis of the underlying molecular mechanisms revealed that 14-3-3η stabilizes hypoxia-inducible factor 1α (HIF-1α) 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 14-3-3η and thereby inhibits 14-3-3η/HIF-1α/CSC properties. In HCC patients, significant negative correlations were found between the expression of miR-16 and 14-3-3η, HIF-1α, or CSC properties. Further analysis showed that low miR-16 expression but high 14-3-3η expression can prognosticate sorafenib resistance and poor survival. Collectively, our present study indicated that miR-16/14-3-3η 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. |
| Databáze: | OpenAIRE |
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