Fatty acid synthase (FAS) is the key
enzyme of de novo
fatty acid synthesis and has been shown to be involved in
carcinogenesis of numerous human
malignancies, including breast, colorectal, and prostate
carcinomas, often associated with a worse prognosis. Although FAS is mainly expressed in the liver, an implication of FAS in hepatocarcinogenesis, has not yet been investigated. FAS expression is stimulated by
insulin and
glucose, and
insulin is also the primary trigger of hepatocarcinogenesis in an endocrine experimental model, which is induced by low-number
transplantation of islets of Langerhans into the livers of diabetic rats. We therefore investigated, whether FAS is implicated in hepatocarcinogenesis in this model and in comparison to chemically induced hepatocarcinogenesis after
N-nitrosomorpholine (NNM) treatment in diabetic and normoglycemic rats. Preneoplastic clear-cell foci of altered hepatocytes (FAH), harvested after
laser-microdissection of kryostat sections, showed an overexpression of FAS
messenger RNA in gene expression profiles, done by array-hybridization, and in quantitative RT-PCR (Light-Cycler). Virtually, all (96-98%) of the subsequently investigated FAH and the glycogenotic
hepatocellular adenomas and
carcinomas showed an additional strong FAS
protein overexpression. In the NNM-model, FAS
protein was also overexpressed in the vast majority (87%) of glycogenotic FAH and
neoplasms, in particular in the diabetic animals. Also two spontaneous glycogenotic FAH in control animals displayed strong FAS overexpression. Basophilic lesions and
neoplasms, which occasionally develop out of the primary clear-cell FAH at later stages of
carcinogenesis, however, lost FAS overexpression. In conclusion, FAS overexpression is an early phenonemon in spontaneous, hormonally and chemically induced rat hepatocarcinogenesis, demonstrable in early clear-cell (glycogenotic) FAH and hepatocellular
neoplasms. FAS overexpression can be attributed to the local
hyperinsulinemia in the
transplantation model and belongs to cellular and metabolic alterations in the chemical model, which are induced by an insulinomimetic but yet unknown mechanism.