Background. Tumor recurrence is a major complication following liver transplantation (LT) as treatment for hepatocellular carcinoma (HCC). Immunosuppression is an important risk factor for HCC recurrence, but conceivably may depend on the type of immunosuppressive medication. Mycophenolic acid (MPA) is a currently widely used immunosuppressant. This study investigated the effects of MPA on HCC. Methods. Three human HCC cell lines and organoids from mouse primary liver tumor were used as experimental models. MTT, Alamar Blue assay, cell cycle analysis, colony formation, and [3H]-thymidine assays were performed. An LT database was used for retrospective analysis of the effect of mycophenolate mofetil, the prodrug of MPA, on HCC recurrence. Results. With clinically achievable concentrations, MPA effectively inhibited HCC cell proliferation and single-cell colony-forming unit. In short-term experiments, MPA effectively elicited S phase arrest in HCC cell lines. In addition, the initiation and growth of liver tumor organoids were effectively inhibited by MPA. Most importantly, the use of mycophenolate mofetil in patients with HCC-related LT was significantly associated with less tumor recurrence and improved patient survival. Conclusions. MPA can specifically counteract HCC growth in vitro and tumor recurrence in LT patients. These results warrant prospective clinical trials into the role of MPA-mediated immunosuppression following LT of patients with HCC.
Bibliographical noteFunding Information:
5Laboratory of Medical Genetics, Biomolecular Research Center, Wijaya Kusuma University, Surabaya, Indonesia. 6Center for Drug Design, University of Minnesota, Minneapolis, MN. K.C. and J.S. contributed equally to this work. The authors declare no conflicts of interest. This work was supported by the Central Universities deriving from the Northwest Minzu University (No. 31920180124), Zhejiang Provincial Natural Science Foundation of China (No. LY18H160066), Science Foundation of Zhejiang Sci-Tech University (grant 17042057-Y), and Ministry of Science and Technology Assistance Project (grant KY201501005).
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