Professor Sun Choi’s Joint Research Team Identifies a New Development Mechanism Behind Liver Cancer and Designs...
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- Date2021.08.06
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Professor Sun Choi’s Joint Research Team Identifies a New Development Mechanism Behind Liver Cancer and Designs Peptides with Efficacy Against Hepatocellular Carcinoma
A joint research team including Professor Sun Choi of the Department of Pharmacy as a co-corresponding author identified a mechanism underlying hepatic fibrosis and hepatoma based on the signaling activation of the tumor protein c-Src and the cell membrane protein TM4SF5. They also succeeded in designing peptides (small protein fragments) that inhibit carcinogenesis by blocking protein-protein interactions between TM4SF5 and c-Src, which efficacy was verified through animal testing. The results of this study were published in a top world-renowned academic journal, Theranostics (IF 11.556, JCR top 3.22% in the Medicine, Research & Experimental category), on July 6 (Tue), 2021.
Professor Sun Choi’s research team in collaboration with Professor Jung Weon Lee from Seoul National University College of Pharmacy conducted research on the correlation between liver diseases and the cell membrane protein TM4SF5, which transmits signals by binding to intra- and extra-cellular proteins,. In the landmark of this profitable collaboration, they also recently published an article in Cell Metabolism (IF 27.287, JCI top 1.69% in the Endocrinology & Metabolism category) identifying that, although the expression of TM4SF5 was insignificant in normal liver tissue, it increased under inflammatory metabolic disorders and inflammatory diseases to play a critical role in developing fatty liver, fatty hepatitis, and hepatoma.
In this study, the research team discovered a new mechanism for c-Src signaling, a typical tumor protein that appears in various cancer cells, to be activated by binding to the membrane protein TM4SF5. The C-terminal tail of TM4SF5 binds to the inactive form of c-Src in the cytoplasm, recruiting c-Src at the cell membrane. This complex further binds with phosphatase that activates the tumor protein. In summary, the team newly found that the tumor protein c-Src can be activated at the cell membrane through its association with the membrane protein TM4SF5, even if it does not possess the ability to remain at the membrane, for example, by binding to fat molecules.
Furthermore, through molecular modeling and point-mutation studies, the research team identified the atomic-level details of the binding process between TM4SF5 and c-Src, including the designed peptides with the ability to disrupt their binding. The team predicted that these peptide fragments, which resemble the C-terminal tail of TM4SF5, would intercept the c-Src action by competing against the actual TM4SF5, thus disrupting the binding of the two cell proteins. By conjugating with specific viral sequences, that help to infiltrate into cells, the designed peptides were confirmed to be effective in animal models. By actually injecting these peptide fragments into cells and tumor-infested laboratory mice, the team identified that both, the development of liver cancer and its metastasis to the lungs were inhibited.
The research team emphasized the significance of this study, noting that “By identifying the molecular mechanism of hepatic fibrosis and hepatoma based on the signaling activation of the tumor protein aided by and the cell membrane protein, we obtained key information to control the activation of the tumor protein by disrupting the binding between the two proteins. This study will be expected to serve as a starting point in developing of safe peptide biomedicines that can prevent the development of liver diseases, including hepatoma.”
This study was the result of a nice collaboration conducted by Professor Sun Choi at Ewha and Professor Jung Weon Lee at Seoul National University College of Pharmacy (co-corresponding authors), and participated in by Professor Yoonji Lee (co-first author) at Chung-Ang University College of Pharmacy who received bachelor’s, master’s and doctorate degrees at Ewha Womans University College of Pharmacy and served as an instructor at the University of Texas Southwestern Medical Center in the U.S.