Knockdown of lactate dehydrogenase A suppresses tumor growth and metastasis of human hepatocellular carcinoma

Abstract

In previous studies, lactate dehydrogenase A (LDHA) was identified as one of the leading genes that promote the proliferative and tumorigenic potential of malignancies. However, less definitive evidence was reported in hepatocellular carcinoma (HCC) cells. Furthermore, the role of LDHA in promoting metastasis of HCC, and its possible mechanism, is not clear. In this study, RNA interference (RNAi) mediated by lentiviral vectors (which induce strong down-regulation of gene expression) was used to analyze the role of LDHA in tumor growth and metastasis in HCC. We performed transient and stable RNAi knockdowns of LDHA in HCCLM3 cells, a line that over-expresses LDHA and has a high metastatic potential. Our studies reveal that previously unidentified effects of LHDA may mediate tumor growth and metastasic effects in HCC. First, HCC cell lines over-express LDHA. Second, LDHA inhibition results in increased apoptosis via production of reactive oxygen species in HCCLM3 cells. Thus, LDHA knockdown resulted in significant reduction in metastatic potential in a xenograft mouse model. Furthermore, we found that FAK, MMP-2, VEGF and E-cadherin proteins contribute to inhibitory effects on metastasis in HCC cells. These studies have important implications for understanding the mechanisms by which LDHA promotes tumor growth and metastasis.