POTENTIAL THERAPEUTIC USE OF TRIIODOTHYRONINE (T3) IN HEPATOCELLULAR CARCINOMA

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver with a poor prognostic outcome due to limited and ineffective therapeutic strategies. Thus, it is mandatory to develop more efficient and powerful treatments for this aggressive tumor. Recent studies have suggested the possible role of local hypothyroidism in HCC development, in both humans and rodents. Previous observations from our laboratory showed that 1-week exogenous administration of triiodothyronine (T3) induced the regression of preneoplastic hepatic nodules generated by the Resistant Hepatocyte (RH) model of rat hepatocarcinogenesis. The first aim of this study was to investigate the mechanism/s responsible for the rapid regression of preneoplastic nodules observed 1 week after T3. Transcriptomic analysis showed that a short administration of T3 caused a striking shift of the global expression profile of the aggressive preneoplastic nodules positive for the presumptive progenitor marker cytokeratin-19 (KRT-19) towards that of normal liver or of the indolent KRT-19 negative lesions. This reprogramming preceded the regression of the nodules and was associated with increased mRNA levels of genes involved in the maintenance of differentiated hepatocyte status such as Hnf4-α and Klf9. These changes were associated with the activation of the T3/Thyroid hormone receptor (TR) axis in KRT-19+ hypothyroid nodules, as shown by a striking increase of Dio1 mRNA levels. Unfortunately, the diagnosis of human HCC is too often made at late stages, when there are no effective treatments that would improve patients’ survival. Therefore, a second aim of my thesis was to determine whether T3 could exert its anti-tumoral effect also when administered to HCCs bearing rats. Remarkably, we found that 5 cycles of T3 (one week every three weeks) induced the regression of HCCs as observed both at macroscopic as well as at microscopic examination. Indeed, while the liver of all the rats not exposed to T3 displayed multiple HCCs, treatment with T3 reduced the multiplicity of the tumors and the tumor burden. Similar to what was found in preneoplastic nodules, we observed increased expression of genes involved in the maintenance of the hepatocyte differentiated status such as Klf9, Cebpα and Hnf4-α, paralleled by the loss of neoplastic markers such GST-P and KRT-19. Furthermore, we also demonstrated the ability of T3 to reactivate the T3/TR axis in fully developed HCCs. Collectively, these results suggest that T3 acts as a powerful anti-tumoral agent at early and late stages of rat HCC development, in virtue of its differentiating capacity. They also suggest that recently developed thyromimetic drugs, devoid of T3-induced adverse side effects, represent a promising tool in human HCC therapy.