Sirolimus and MMF are insufficient immunosuppressants for regulation of the proliferation of CD133+EpCAM+ cell populations in HCC cell lines.

Abstract

Studies on effective immunosuppressive strategies for the management of patients undergoing a liver transplantation (LT) due to hepatocellular carcinoma (HCC) are limited. In the present study, immunosuppressive candidates predicted to exhibit beneficial immunosuppressive and tumor-suppressive effects in patients with HCC were assessed using Huh7 and HEP3B HCC cells, which have high proportions of CD133+EpCAM+ cancer stem cell (CSC) populations. The immunosuppressants assessed were sirolimus, tacrolimus, cyclosporine A and mycophenolate mofetil (MMF), and their activities were assessed on CSCs. Sirolimus and MMF reduced the proliferation of Huh7 and HEP3B cells; however, the proportion of CD133+EpCAM+ was notably increased in treated Huh7 cells. Sirolimus treatment alone resulted in G0-G1 cell cycle arrest at all doses in all Huh7 and CD133-EpCAM- populations; however, CD133+EpCAM+ populations showed only slight G1 arrest at higher doses only. In contrast, S-phase arrest was induced at all doses in the Huh7, CD133-EpCAM- and CD133+EpCAM+ populations by MMF. Sirolimus and MMF effectively reduced the proliferation of Huh7 and HEP3B cells, but did not exert a notable effect on the CD133+EpCAM+ cells. Therefore, therapeutic strategies utilizing Sirolimus and MMF should be further studied in vivo for regulation of CSC populations in order to reduce HCC recurrence rates.