Functional characterization of novel tumour suppressor galectin-2 in hepatocellular carcinoma

Abstract

BACKGROUND: Hepatocellular carcinoma (HCC) is the second most common cause of cancer mortality in the world. The development of HCC, hepatocarcinogenesis, is a multistep progression. However, the prognosis of HCC is predominantly poor and has a low survival rate because of its late presentation, high incidence of recurrence and metastasis resulting in limited therapeutic options. From our previous studies, tumour suppressor Deleted in liver cancer 1 (DLC1) is a crucial RhoGTP activating protein (RhoGAP) for HCC development. In our screening study, we identified galectin-2 as a downstream target protein of the DLC1 pathway. Hence, the characteristic of galectin-2 expression has triggered us to study its clinical significance and functional role in HCC in further details. MATERIAL AND METHODS: This project is divided into two main sections: 1) analysis of clinical correlation of galectin-2 expression in HCC cell lines and tissues and 2) functional characterization of galectin-2 in HCC tumourigenesis and metastasis. RESULTS: For clinical analysis of galectin-2 expression in HCC, around fifty HCC patient samples were examined. The results showed that the expression of galectin-2 was significantly underexpressed in HCC tumorous tissues when compared to the corresponding non-tumorous liver tissues. Galectin-2 expression was also directly correlated to DLC1 expression. Additionally, underexpression of galectin-2 was significantly associated with poor overall survival. In HCC cell line panel, galectin-2 was dramatically expressed in an immortalized liver cell line MIHA; in contrast, it was downregulated in both the non-metastatic and metastatic HCC cell lines. To address the functional roles of galectin-2 in HCC, the abilities of galectin-2 to regulate cell proliferation, cell migration and cell invasion were analyzed in the tetracycline inducible (Tet-on) cell line model by expressing galectin-2 in metastatic MHCC-97L cells. The results illustrated that galectin-2 significantly inhibited cell proliferation, migration and invasion in HCC metastatic cells. Furthermore, the ability of galectin-2 in suppressing tumor development was revealed in the in vivo study via subcutaneous injection in nude mice performed with galectin-2 expressing metastatic MHCC-97L cells. CONCLUSIONS: In this study, the clinical relevance of galectin-2 revealed its underexpression in HCC and its association with poorer prognosis. Functionally, galectin-2 was demonstrated to inhibit growth, motility and tumorigenesis of HCC. Further investigation for the detail underlying the interplay between DLC1 and galectin-2 will also be discussed and will be crucial in the understanding of underlying basis of HCC tumorigenesis.