Acyclic retinoid (ACR) is a promising drug under clinical trials for preventing recurrence of hepatocellular carcinoma (HCC). The objective of the present study was to gain insights into molecular basis of the anti-tumorigenic action of ACR from a metabolic point of view. To achieve this, comprehensive cationic and lipophilic liver metabolic profiling was performed in mouse diethylnitrosamine (DEN)-induced hepatic tumorigenesis model using both capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS) and liquid chromatograph time-of-flight mass spectrometry (LC-TOFMS). ACR significantly counteracted against acceleration of lipogenesis below but not glucose metabolism in DEN-treated mice liver, suggesting an important role of lipid metabolic reprogramming in the initiation step of hepatic tumorigenesis. Knowledge-based pathway analysis suggested that inhibition of linoleic acid metabolites such as arachidonic acid, a pro-inflammatory precursor, played a crucial role in the prevention by ACR of DEN-induced chronic inflammation-mediated tumorigenesis of the liver. As a molecular mechanism of ACR's effect to prevent the aberrant lipogenesis, microarray analysis identified that a key transcription regulator of both embryogenesis and tumorigenesis, COUP-TFII (COUP transcription factor 2), also known as NR2F2, was associated with the metabolic effect of ACR in human HCC cells. Our study provided potential therapeutic targets for the chemoprevention of HCC as well as new insights into the mechanisms underlying prevention of hepatic tumorigenesis.
- Received August 25, 2015.
- Revision received December 15, 2015.
- Accepted December 31, 2015.
- Copyright © 2016, American Association for Cancer Research.