The Role of Galectin-1 in Fibrosis-promoted Liver Cancer Progression

The objective of this proposal is to dissect the role of galectin-1 (Gal-1), a b-galactoside binding lectin, in fibrosis-promoted hepatocarcinogenesis and to investigate whether targeting Gal-1 suppresses fibrosis-promoted liver cancer progression. Liver cancer is the second leading cause of cancer death in Taiwan. Most cases of liver cancer are hepatocellular carcinoma (HCC) and develop with severe liver fibrosis (cirrhosis) which limits the therapeutic options. This is because the fibrotic livers lost their functions and many treatments such as liver resection will cause complications and death. The fibrotic livers provide the microenvironment that increases HCC cell malignancy and promotes cancer progression. However, it is unclear how fibrosis promotes liver cancer progression and whether normalizing fibrotic microenvironment affects tumor malignancy. Our preliminary results demonstrated that Gal-1 regulated the activation of hepatic stellate cells to myofibroblasts, a critical step in liver fibrosis, and that loss of Gal-1 inhibited thioacetamide-induced liver fibrosis in mice. Knockdown of Gal-1 in hepatic myofibroblasts (HMFs) suppresses HMF conditioned medium induced migration, invasion and stemness of HCC cells. Therefore, it is hypothesized that targeting Gal-1 may normalize the fibrotic microenvironment and inhibit fibrosis-promoted cancer progression. In this study, an orthotropic tumor model and Gal-1 null mice will be used to dissect the effect of Gal-1 in tumor progression under the fibrotic microenvironment. In addition, a three dimension (3D) co-culture system that mimics the tumor-myofibroblasts interactions will be used to study the underlying mechanisms. Four specific aims are proposed to verify our hypothesis. Aim 1: To investigate the effect of Gal-1 on fibrosis-promoted liver cancer progression using Gal-1 null mice and orthotropic tumor models. Aim 2. To investigate the role of Gal-1 in hepatic myofibroblast-promoted cancer cell invasion and stemness using three-dimensional (3D) co-culture systems. Aim 3. To examine whether Gal-1 mediated MCP-1/CCL2 production regulates the paracrine effect of hepatic myofibroblast on cancer cell invasion and stemness. Aim 4: To investigate the therapeutic effect of Gal-1 small hairpin (sh)RNA on fibrosis-enhanced liver cancer. Since several Gal-1 inhibitors for fibrotic diseases have been investigated in clinical trials, it is believed that targeting Gal-1 will not only benefit the therapy of liver fibrosis but also liver cancer.