Overexpression of fatty acid synthase in chemically and hormonally induced hepatocarcinogenesis of the rat

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.

[1]  崇宏 田地野.  Expression of Fatty Acid Synthase as a Prognostic Indicator in Soft Tissue Sarcomas , 2001 .

[2]  F. Dombrowski,et al.  Hepatocellular neoplasms induced by low-number pancreatic islet transplants in streptozotocin diabetic rats. , 1997, The American journal of pathology.

[3]  H. Towle,et al.  The Role of SREBP-1c in Nutritional Regulation of Lipogenic Enzyme Gene Expression* , 2002, The Journal of Biological Chemistry.

[4]  Massimo Loda,et al.  Fatty acid synthase: A metabolic oncogene in prostate cancer? , 2004, Journal of cellular biochemistry.

[5]  S. Wakil,et al.  Fatty acid synthase, a proficient multifunctional enzyme. , 1989, Biochemistry.

[6]  T. Roskams,et al.  Overexpression of fatty acid synthase is an early and common event in the development of prostate cancer , 2002, International journal of cancer.

[7]  M. Leuze,et al.  The human fatty acid synthase gene and de novo lipogenesis are coordinately regulated in human adipose tissue. , 2004, The Journal of nutrition.

[8]  L. Jacobs,et al.  Fatty acid synthesis: a potential selective target for antineoplastic therapy. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[9]  H. Adami,et al.  Excess risk of primary liver cancer in patients with diabetes mellitus. , 1996, Journal of the National Cancer Institute.

[10]  G. Ramadori,et al.  Analysis of the IGF Axis in Preneoplastic Hepatic Foci and Hepatocellular Neoplasms Developing after Low-Number Pancreatic Islet Transplantation into the Livers of Streptozotocin Diabetic Rats , 2000, Laboratory Investigation.

[11]  M. Magnuson,et al.  Hepatic Glucokinase Is Required for the Synergistic Action of ChREBP and SREBP-1c on Glycolytic and Lipogenic Gene Expression* , 2004, Journal of Biological Chemistry.

[12]  D. Heimburger,et al.  The expression of fatty acid synthase (FASE) is an early event in the development and progression of squamous cell carcinoma of the lung. , 2000, Human pathology.

[13]  Andrzej Witkowski,et al.  Structural and functional organization of the animal fatty acid synthase. , 2003, Progress in lipid research.

[14]  Stuart Smith.  The animal fatty acid synthase: one gene, one polypeptide, seven enzymes , 1994, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[15]  J. Swinnen,et al.  Fatty acid synthase drives the synthesis of phospholipids partitioning into detergent-resistant membrane microdomains. , 2003, Biochemical and biophysical research communications.

[16]  M. Schweizer,et al.  Insulin-responsive regions of the rat fatty acid synthase gene promoter. , 1994, Biochemical and biophysical research communications.

[17]  C. Townsend,et al.  Fatty acid synthase inhibition triggers apoptosis during S phase in human cancer cells. , 2003, Cancer research.

[18]  D. Mayer,et al.  Early Bioenergetic Changes in Hepatocarcinogenesis: Preneoplastic Phenotypes Mimic Responses to Insulin And Thyroid Hormone , 1997, Journal of bioenergetics and biomembranes.

[19]  R. Schneider-Stock,et al.  Apolipoprotein A-IV mRNA overexpression in early preneoplastic hepatic foci induced by low-number pancreatic islet transplants in streptozotocin-diabetic rats. , 2003, Pathology, research and practice.

[20]  T. Sugino,et al.  Fatty acid synthase is expressed mainly in adult hormone-sensitive cells or cells with high lipid metabolism and in proliferating fetal cells. , 2000, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[21]  A. Nashimoto,et al.  Fatty acid synthase is highly expressed in carcinoma, adenoma and in regenerative epithelium and intestinal metaplasia of the stomach , 2002, Histopathology.

[22]  T. Sugino,et al.  Fatty Acid Synthase Is Expressed Mainly in Adult Hormone-sensitive Cells or Cells with High Lipid Metabolism and in Proliferating Fetal Cells1 , 2000 .

[23]  R. Kurman,et al.  Fatty acid synthase expression in endometrial carcinoma , 1998, Cancer.

[24]  Q. Su,et al.  Human hepatic preneoplasia: phenotypes and proliferation kinetics of foci and nodules of altered hepatocytes and their relationship to liver cell dysplasia , 1997, Virchows Archiv.

[25]  R. Schneider-Stock,et al.  Insulin Receptor, Insulin Receptor Substrate-1, Raf-1, and Mek-1 during Hormonal Hepatocarcinogenesis by Intrahepatic Pancreatic Islet Transplantation in Diabetic Rats , 2004, Cancer Research.

[26]  P. Bannasch,et al.  Dose and time dependence of the cellular phenotype in rat hepatic preneoplasia and neoplasia induced in stop experiments by oral exposure to N-nitrosomorpholine. , 1994, Carcinogenesis.

[27]  W. Grizzle,et al.  Fatty acid synthase expression is increased in neoplastic lesions of the oral tongue , 1999, Head & neck.

[28]  L. Witters,et al.  Enzymes of the fatty acid synthesis pathway are highly expressed in in situ breast carcinoma. , 1997, Clinical cancer research : an official journal of the American Association for Cancer Research.

[29]  J. Nelson,et al.  Increased fatty acid synthase as a therapeutic target in androgen‐independent prostate cancer progression , 2001, The Prostate.

[30]  G. Wolf.  Nutritional and hormonal regulation of fatty acid synthase. , 2009, Nutrition reviews.

[31]  F. Kuhajda.  Fatty-acid synthase and human cancer: new perspectives on its role in tumor biology. , 2000, Nutrition.

[32]  S. Chirala,et al.  Fatty acid synthesis is essential in embryonic development: Fatty acid synthase null mutants and most of the heterozygotes die in utero , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[33]  P. Visca,et al.  Immunohistochemical expression of human erythrocyte glucose transporter and fatty acid synthase in infiltrating breast carcinomas and adjacent typical/atypical hyperplastic or normal breast tissue. , 2001, American journal of clinical pathology.

[34]  T. Gansler,et al.  Increased expression of fatty acid synthase (OA-519) in ovarian neoplasms predicts shorter survival. , 1997, Human pathology.

[35]  F. Marandino,et al.  Immunohistochemical expression of fatty acid synthase, apoptotic-regulating genes, proliferating factors, and ras protein product in colorectal adenomas, carcinomas, and adjacent nonneoplastic mucosa. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[36]  Manabu T. Nakamura,et al.  Involvement of a Unique Carbohydrate-responsive Factor in the Glucose Regulation of Rat Liver Fatty-acid Synthase Gene Transcription* , 2001, The Journal of Biological Chemistry.

[37]  A. Rashid,et al.  Elevated expression of fatty acid synthase and fatty acid synthetic activity in colorectal neoplasia. , 1997, The American journal of pathology.

[38]  C. Mathieu,et al.  Spontaneous reestablishment of self-tolerance in BB/Pfd rats. , 1994, Transplantation.

[39]  J. Kalbfleisch,et al.  Immunohistochemical detection of a fatty acid synthase (OA-519) as a predictor of progression of prostate cancer. , 1996, Human pathology.

[40]  J. Swinnen,et al.  Advances in Brief Role of the Phosphatidylinositol 3-Kinase / PTEN / Akt Kinase Pathway in the Overexpression of Fatty Acid Synthase in LNCaP Prostate Cancer Cells 1 , 2002 .

[41]  P. Visca,et al.  Expression of fatty acid synthase (FAS) as a predictor of recurrence in stage I breast carcinoma patients , 1996, Cancer.

[42]  P. Bannasch.  Pathogenesis of hepatocellular carcinoma: sequential cellular, molecular, and metabolic changes. , 1996, Progress in liver diseases.

[43]  C. la Vecchia,et al.  A case-control study of diabetes mellitus and cancer risk. , 1994, British Journal of Cancer.

[44]  F. Dombrowski,et al.  Altered liver acini induced in diabetic rats by portal vein islet isografts resemble preneoplastic hepatic foci in their enzymic pattern. , 1996, The American journal of pathology.

[45]  P. Morin,et al.  Activation of fatty acid synthesis during neoplastic transformation: role of mitogen-activated protein kinase and phosphatidylinositol 3-kinase. , 2002, Experimental cell research.

[46]  A W Partin,et al.  OA-519 (fatty acid synthase) as an independent predictor of pathologic state in adenocarcinoma of the prostate. , 1995, Urology.