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Oncogene. 2019 May;38(21):4061-4074. doi: 10.1038/s41388-019-0704-y. Epub 2019 Jan 29.

Lymphoid enhancer-binding factor-1 promotes stemness and poor differentiation of hepatocellular carcinoma by directly activating the NOTCH pathway.

Fang S1,2,3, Liu M4, Li L5, Zhang FF1,2, Li Y1,2, Yan Q1,2, Cui YZ1,2, Zhu YH5, Yuan YF5, Guan XY6,7,8.

Author information

1
Department of Clinical Oncology, The University of Hong Kong, Hong Kong, China.
2
State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China.
3
The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China.
4
Key Laboratory of Protein Modification and Degradation School of Basic Medical Sciences, Guangzhou Medical University, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China.
5
State Key Laboratory of Oncology in Southern China, Sun Yat-Sen University Cancer Center, Guangzhou, China.
6
Department of Clinical Oncology, The University of Hong Kong, Hong Kong, China. xyguan@hku.hk.
7
State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China. xyguan@hku.hk.
8
State Key Laboratory of Oncology in Southern China, Sun Yat-Sen University Cancer Center, Guangzhou, China. xyguan@hku.hk.

Abstract

The poorly differentiated hepatocellular carcinoma (HCC) cells are usually characterized by immature hepatic progenitor cell-like properties, such as enhanced self-renewal ability, resistance to chemotherapeutic drugs, and a loss of mature hepatocyte proteins. However, the molecular mechanisms governing this process still remain unclear. In this study, we found the lymphoid enhancer-binding factor-1 (LEF1), a transcriptional factor, was frequently overexpressed in HCCs, which was significantly associated with poor prognosis and tumor cell differentiation. Functional studies have found that LEF1 enhanced cell growth, foci formation, colony formation in soft agar, and tumor formation in nude mice. Different from its canonical roles in the WNT signaling pathway, we found that LEF1 could activate the critical members (e.g., NOTCH1 and NOTCH2) of the NOTCH signaling pathway through directly binding to their promoter regions. Further studies have found that LEF1 could enhance the self-renewal ability, drug resistance, dedifferentiation, and invasion of HCC cells. The oncogenic functions and the effects of LEF1 on cancer stemness could be effectively inhibited by NOTCH inhibitor. Further characterization of LEF1 may lead to the development of novel therapeutic strategies for HCC treatment.

PMID:
30696957
DOI:
10.1038/s41388-019-0704-y

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