BackgroundAlthough expression of MTA1 inversely correlates with the nuclear localization of ERα, the effect and molecular mechanism of ERα regulation of MTA1 remain unknown.MethodsQuantitative real-time PCR and western blot analyses were used to measure levels of MTA1. The effect on HCC cell proliferation and invasion was assessed by EdU incorporation assays and Transwell, respectively. ShRNA and dual-luciferase assays were used to investigate the regulatory relationship between MTA1 and ERα in cell lines.ResultsWe found that MTA1 gene regulation by ERα may be influenced by nuclear corepressors. The MTA1 promoter has three functional ER-element half-sites that lead to decreased MTA1 transcription and expression. ERα overexpression suppressed the proliferation and invasion of hepatocellular carcinoma cells (HCC). In addition, overexpression of MTA1 attenuated ERα-mediated suppression of the proliferation and invasion of HCC cells and tumor formation in vivo. These results suggested feedback regulation between ERα and MTA1. In summary, our results demonstrated that ERα suppressed proliferation and invasion of human HCC cells through downregulation of MTA1 transcription.ConclusionsOur study is an improved description of the mechanisms of the suppressive effect of ERα on HCCs, adding understanding to the gender disparity of HCC progression.

Acute rejection is commonly encountered for long-term survival in liver transplant (LT) recipients and may impact their long-term survival if rejection is severe or recurrent. The aim of this study is to examine the therapeutic potential of transforming growth factor (TGF-b)-overexpressing mesenchymal stem cells (MSCs) in inducing a local immunosuppression in liver grafts after transplantation. MSCs were transduced with a lentiviral vector expressing the human TGF-b1 gene; TGF-b1-overexpressing MSCs (designated as TGF/MSCs) were then transfused into the liver grafts via the portal vein of a rat LT model of acute rejection. Rejection severity was assessed by clinical and histologic analysis. The immunity suppression effects and mechanism of TGF/ MSCs were tested, focusing on their ability to induce generation of regulatory T cells (Tregs) in the liver grafts. Our findings demonstrate that transfusion of TGF/MSCs prevented rejection, reduced mortality, and improved survival of rats after LT. The therapeutic effects were associated with the immunosuppressive effects of MSCs and TGF-b1. Their reciprocal effects on Tregs induction and function resulted in more CD4 1 Foxp3 1 Helios-induced Tregs, fewer Th17 cells, and improved immunosuppressive effects in local liver grafts. Thus, TGF/MSCs can induce a local immunosuppressive effect in liver grafts after transplantation. The immunomodulatory activity of TGF-b1 modified MSCs may be a gateway to new therapeutic approaches to prevent organ rejection in clinical transplantation. STEM CELLS 2016;34:2681-2692 SIGNIFICANCE STATEMENTAcute rejection is commonly encountered for long-term survival in liver transplant recipients. Despite great improvements in systemic immunosuppressive agents, complications related to the administration of immunosuppressive therapy remain a predominant cause of posttransplantation morbidity and mortality. Thus, local and alloantigen specific immunological tolerance may be a promising approach to improved organ transplantation. Regulatory T cells (Tregs) are available to enforce graft to function as alternative immunosuppressive therapy possibly with less side effects. mesenchymal stem cells can induce the generation of Tregs, and transforming growth factor (TGF)-b enhance the induction. Our study demonstrated that systemic administration of TGF/MSCs induced a local and highly efficient suppression by producing more induced Tregs in the local liver grafts.

In this study, the antitumor consequences of using B7-1, B7-2 and 4-1BBL gene transfer have demonstrated the therapeutic potential of gene therapy approach for hepatocellular carcinoma.