Journal
EUROPEAN JOURNAL OF PHARMACOLOGY
Volume 906, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.ejphar.2021.174214
Keywords
Hepatocellular carcinoma; E26 transformation specific sequence 1; Small molecular inhibitor; Matrix metalloproteinase
Categories
Funding
- Chinese Government (Wu Jieping Medical Research Foundation), China [320.6750.17212]
- Fourth Affiliated Hospital Of Harbin Medical University, Harbin, China [HYDSYXH201908]
- Haiyan Medical Research Foundation [JJZD2017-07]
- National Science and Technology, China [2017ZX10203206]
- Haiyan Science Foundation of Harbin Medical University Cancer Hospital, Harbin, China [JJZD2017-07]
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This study identified novel small molecule inhibitors of ETS-1 for HCC treatment and demonstrated that compounds similar to EI-4 can effectively inhibit the activation of ETS-1 and reduce proliferation and invasion of HCC cells. These findings provide valuable insights for developing safer and more effective molecular therapy strategies for HCC.
The transcription factor ETS-1 (E26 transformation specific sequence 1) is the key regulator for malignant tumor cell proliferation and invasion by mediating the transcription of the invasion/migration related factors, e.g. MMPs (matrix metalloproteinases). This work aims to identify the novel small molecule inhibitors of ETS-1 using a small molecule compound library and to study the inhibitors' antitumor activity against hepatocellular carcinoma (HCC). The luciferase reporter is used to examine the inhibition and activation of ETS-1's transcription factor activity in HCC cells, including a highly invasive HCC cell line, MHCC97-H, and five lines of patient-derived cells. The inhibition of the proliferation of HCC cells is examined using the MTT assay, while the invasion of HCC cells is examined using the transwell assay. The anti-tumor activity of the selected compound on HCC cells is also examined in a subcutaneous tumor model or intrahepatic tumor model in nude mice. The results show that for the first time, four compounds, EI1 similar to EI-4, can inhibit the transcription factor activation of ETS-1 and the proliferation or invasion of HCC cells. Among the four compounds, EI-4 has the best activation. The results from this paper contribute to expanding our understanding of ETS-1 and provide alternative, the safer and more effective, HCC molecular therapy strategies.
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