The clinical relevance functional role of ACADM in Hepatocellular Carcinoma

Abstract

Introduction

Acyl-Coenzyme A dehydrogenase (ACADM) is an enzyme responsible for degrading medium-chain fatty acids found in dairy foods and body fats. Mutations in the ACADM gene results in the accumulation of non-degraded or partially degraded medium chain fatty acids in tissues, leading to eventual liver and brain damage. Therefore, investigating the clinical relevance and functional role of ACADM in hepatocellular carcinoma (HCC) tumorigenesis can help us understand better the role of beta-oxidation genes in HCC.

Material and Methods ACADM mRNA expression in human HCC cell lines and tissues was determined by quantitative real time PCR and clinicopathological analysis was performed. Subsequent functional characterisation of ACADM in HCC was determined with cell migration, invasion and soft agar assays after the stable knockdown of ACADM in HCC cell lines.

Results and Discussions ACADM was downregulated in 64% of HCC cases examined. The overall ACADM mRNA level was significantly down-regulated in HCC tissues when compared with non-tumorous liver tissues and negatively correlated with the aggressiveness of HCC cell lines. Clinicopathological analysis revealed that ACADM under-expression was significantly correlated with bigger tumour size, venous invasion, late stage and poor differentiation in HCC. Stable knockdown clones of ACADM established in immortalized liver cell line and HCC cell lines showed elevated level of cellular triglyceride and lipid content. Functional analyses with cell migration, invasion and soft agar assays illustrated that when ACADM activity was suppressed, cells displayed increased abilities of migration, invasion and anchorage independent growth. Our findings further found that caveolin-1 (Cav1) acts as an upstream negative regulator of ACADM. In Cav1 knockdown cells, ACADM was upregulated at the transcriptional and translational levels. Cav1 and ACADM expressions showed a significant negative correlation in HCC tissues and cell lines.

Conclusion Cav1 has been reported to be a metastasis promoter in HCC. Here, we delineate a new molecular pathway in which oncogenic Cav1 downregulates ACADM leading to the dysregulation of beta-oxidation in HCC. Our findings also reveal the tight association between ACADM under-expression with the aggressive HCC clinical features suggesting targeting Cav1, negative regulator of ACADM, as a therapeutic intervention in HCC.