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.

Relationship Between 18F-FDG Accumulation and Lactate Dehydrogenase A Expression in Lung Adenocarcinomas

“…The glycolytic enzyme LDHA, which converts pyruvate to lactate, ensures efficient glycolytic metabolism and plays an important role in the development, invasion, and metastasis of malignancies (20)(21)(22). Therefore, we evaluated whether LDHA knockdown or LDH inhibitor oxamate decreases 18 F-FDG uptake and how it may affect cellular growth and proliferation.…”

“…Upregulation of LDHA ensures efficient glycolytic metabolism for tumor cells and reduces oxygen dependency (20). We and others have demonstrated that LDHA plays an important role in the development, invasion, and metastasis of malignant tumors (21,22). However, the relationship between 18 F-FDG accumulation and LDHA expression, and its possible mechanism, is not clear.…”

Inhibition of LDH-A by oxamate induces G2/M arrest, apoptosis and increases radiosensitivity in nasopharyngeal carcinoma cells

“…Recently, an increasing number of studies indicate that LDH-A plays an essential role in tumor maintenance, growth and progression (7)(8)(9)(10). Furthermore, relevant studies have demonstrated that inhibition of LDH-A induces oxidative stress and suppresses tumor growth in a variety of cancer cell lines (9,(11)(12)(13). Regarding NPC, LDH-A was reported to be highly expressed in head and neck cancer cells and was found to be associated with local relapse, worse survival and distant metastasis (14).…”

Silencing LDHA inhibits proliferation, induces apoptosis and increases chemosensitivity to temozolomide in glioma cells

“…In renal cell carcinoma, knocking down LDHA resulted in potential anticancer effects (14). Although the abnormal expression of LDHA has been reported in several cancers (10)(11)(12)(13)(14)(15), little is known about the expression pattern of LDHA and its underlying roles in GBM. Previous reports using data from the Oncomine database showed that the mRNA levels of LDHA were up-regulated in GBM compared to matched tissues (16); these finding prompted us to examine the underlying role of LDHA in glioma malignancy.…”

“…In oesophageal squamous cell carcinoma (ESCC), knocking down LDHA inhibited cell growth and migration in vitro, as well as tumorigenesis in vivo (11). In hepatocellular carcinoma (HCC), LDHA knockdown resulted in a significant reduction in metastatic potential in a xenograft mouse model (12). In pancreatic cancer, when LDHA was overexpressed, tumor growth was increased (13).…”