Andrea Perra

 

Department of Biomedical Sciences

Telephone: +39 0706758346

E-mail: andreaperra@omeca.it

Personal webpage: here

Principal areas of expertise: Molecular pathology; Oncology; Liver pathology

 

 


Analysis of thyroid hormone receptors effects on proliferation, metabolism and neoplastic transformation of hepatocytes

Our main research interest concerns the study of the thyroid hormone receptors pathway during liver regeneration/proliferation and in inflammatory and neoplastic diseases. Our previous studies have shown that, in a rat models of HCC, the thyroid hormone (T3) mediated activation of nuclear thyroid hormone receptors (THR) strongly accelerates the remodelling of preneoplastic lesions. This effect occurs in spite of the strong mitogenic effect of T3 on hepatocytes and and in the absence of increased apoptosis. Based on the finding that the nuclear receptors of T3 are involved in differentiation and metamorphosis, we hypothesize that the mitogenic activity of T3 is associated/followed by a process of hepatocyte differentiation. Recently, we have also demonstrated that, similarly to what observed in preneoplastic lesions, fully developed hepatocellular carcinomas (HCC) induced in rats T3, showed an inhibition of the T3/THR intra-cellular pathway and the  administration of T3 was associated with the regression of the vast majority of neoplastic lesion. Moreover, we have demonstrated that also the majority of human HCCs showed a down regulation of the T3/THR pathway. Since the possible use of T3 as an anti-tumoral agent is hampered by its  cardiovascular and metabolic side effects, our research has been focused also on the development of thyroid hormone analogs devoid of the cardiac effects of T3.

Another human disease in which an altered T3/THR pathway has been postulate, is the non alcoholic fatty liver disease (NAFLD). Subject affected by this syndrome show triglyceride accumulation in the liver, that could induce a chronic inflammatory response known ad non alcoholic steato-hepatitis (NASH). Patients with NASH have an increased risk of cirrhosis, and acute liver failure and neoplastic transformation. Since the T3/THR pathway is a master regulator of liver metabolism, we have investigated the effect of T3 administration on NAFLD, using a nutritional model of steatosis in rats. The results clearly indicated that T3 administration was able to revert steatosis and induce regression of preneoplastic lesions induced by the protocol. Since NAFLD is going to became the most prevalent risch factor for chronic liver disease, a therapeutic strategy based on the reactivation of the T3/THR pathway may have a strong impact on human health. Our research has a strong translational prospective because our experimental models share important immunohistochemical and molecular features with the corresponding human disease and we have a growing bio-bank of human samples on which we validate the experimental results.

Within these general lines of research, specific projects are:

  1. To define the role of THR and their synthetic agonists in the several steps of multistage carcinogenesis;
  2. To identify the role of transcription factors/microRNAs in the regulation of THR expression;
  3. Define the molecular mechanisms through which THR activation induces regression of preneoplastic and neoplastic lesions;
  4. Define the role of the T3/THR pathway in human NAFLD;
  5. To Identify and characterize genes that differentially regulated by T3 and their synthetic analogs.

Key publications:

  1. Kowalik MA, Columbano A, Perra A. Thyroid Hormones, Thyromimetics and Their Metabolites in the Treatment of Liver Disease. Front Endocrinol (Lausanne). 2018 Jul 10;9:382.
  2. Kowalik MA, Columbano A, Perra A. Emerging Role of the Pentose Phosphate Pathway in Hepatocellular Carcinoma. Front Oncol. 2017 May 11;7:87.
  3. Perra A, Plateroti M, Columbano A. T3/TRs axis in hepatocellular carcinoma: new concepts for an old pair. Endocr Relat Cancer. 2016 Aug;23(8):R353-69.
  4. Kowalik MA, Perra A, Ledda-Columbano GM, Ippolito G, Piacentini M, Columbano A, Falasca L. Induction of autophagy promotes the growth of early preneoplastic rat liver nodules. Oncotarget. 2016 Feb 2;7(5):5788-99.
  5. Kowalik MA, Sulas P, Ledda-Columbano GM, Giordano S, Columbano A, Perra A. Cytokeratin-19 positivity is acquired along cancer progression and does not predict cell origin in rat hepatocarcinogenesis. Oncotarget. 2015 Nov 17;6(36):38749-63.
  6. Zavattari P, Perra A, Menegon S, Kowalik MA, Petrelli A, Angioni MM, Follenzi A, Quagliata L, Ledda-Columbano GM, Terracciano L, Giordano S, Columbano A. Nrf2, but not β-catenin, mutation represents an early event in rat hepatocarcinogenesis. Hepatology. 2015 Sep;62(3):851-62.
  7. Perra A, Kowalik MA, Ghiso E, Ledda-Columbano GM, Di Tommaso L, Angioni MM, Raschioni C, Testore E, Roncalli M, Giordano S, Columbano A. YAP activation is an early event and a potential therapeutic target in liver cancer development. J Hepatol. 2014 Nov;61(5):1088-96.
  8. Petrelli A, Perra A, Cora D, Sulas P, Menegon S, Manca C, Migliore C, Kowalik MA, Ledda-Columbano GM, Giordano S, Columbano A. MicroRNA/gene profiling unveils early molecular changes and nuclear factor erythroid related factor 2 (NRF2) activation in a rat model recapitulating human hepatocellular carcinoma (HCC). Hepatology. 2014 Jan;59(1):228-41.
  9. Frau C, Loi R, Petrelli A, Perra A, Menegon S, Kowalik MA, Pinna S, Leoni VP, Fornari F, Gramantieri L, Ledda-Columbano GM, Giordano S, Columbano A. Local hypothyroidism favors the progression of preneoplastic lesions to hepatocellular carcinoma in rats. Hepatology. 2015 Jan;61(1):249-59.
  10. Szydlowska M, Pibiri M, Perra A, Puliga E, Mattu S, Ledda-Columbano GM, Columbano A, Leoni VP. The Thyromimetic KB2115 (Eprotirome) Induces Rat Hepatocyte Proliferation. Gene Expr. 2017 Jul 7;17(3):207-218.

 

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