期刊
CANCER LETTERS
卷 444, 期 -, 页码 82-93出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2018.12.010
关键词
HCC; Regorafenib resistance; Metastasis; Pin1; EMT
类别
资金
- Joint Funds for the Innovation of Science and Technology, Fujian province [2016Y9037]
- Joint Funds for Health and Education of Fujian Province [WKJ2016-2-34]
- Natural Science Foundation of Fujian Province [2016J05190]
- Nursery Research Fund Project of Fujian Medical University [2015MP035]
- Scientific Research Personnel Training Project for Health and Family Planning of Fujian Province [2016.1-34]
- Youth Research Project of Fujian Provincial Department of Education [JAT160213]
- National Institutes of Health [R01CA205153]
Hepatocellular carcinoma (HCC) is the second leading cancer death because of its high metastasis and drug resistance. Regorafenib was newly approved by FDA for HCC treatment, but its resistance is not understood. The unique isomerase Pin1 is critical for HCC development, but its role in metastasis and drug resistance is unknown. Here we generated Regorafenib-resistant HCC cells and found that they exhibited enhanced tumor invasion and metastasis in vitro and in vivo, and elevated Pin1 levels. Furthermore, Pin1 was highly overexpressed and closely related to the EMT in human HCC tissues. Depletion or overexpression of Pin1 correspondingly inhibited or promoted HCC cell migration and invasion, with altered expression of EMT-related molecules, E-cadherin and Snail. Significantly, Pin1 interacted with Gli1, a regulator of the EMT, and silencing Gli1 partly blocked Pin1-induced EMT in HCC cells. Moreover, genetic or chemical Pin1 inhibition reversed Regorafenib resistance of HCC with reducing EMT, migration, invasion and metastasis in vitro and in vivo. These results reveal a novel molecular mechanism underlying Regorafenib resistance in HCC, and also provide first evidence that Pin1 inhibitors offer an attractive strategy for treating Regorafenib-resistant HCC.
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