THYROID HORMONE AND METABOLIC REPROGRAMMING IN HEPATOCELLULAR CARCINOMA

Hepatocellular carcinoma is the fourth leading cause of cancer-related death worldwide. Despite new molecular-targeted therapies have been approved, the benefits that can be obtained from the current therapies remain still disappointing. Thus it is mandatory to find more efficient and powerful therapeutic solutions for this aggressive tumor. Recent studies reveal a condition of local hypothyroidism characterizing HCC from pre-neoplastic lesions till fully developed HCCs. Accordingly, a short treatment with thyroid hormone (T3) caused the regression of pre-neoplastic lesions in a rat model of hepatocarcinogenesis. Moreover, several recent studies have shown the capacity of T3 of inducing mitochondrial metabolism, suggesting a role of T3 in modulating Warburg phenomenon. Based on these evidences and our preliminary results, we hypothesized that T3 may interfere on HCC development through a reversion of the metabolic reprogramming of pre- and neoplastic hepatocytes. The first aim of the present study was to investigate whether the observed T3-dependent regression of pre-neoplastic nodules is due to its capacity to revert the Warburg phenotype of pre-neoplastic hepatocytes. Transcriptomic analysis showed that a short T3 administration caused a shift of the metabolic profile of the aggressive pre-neoplastic nodules towards that of the normal liver. This effect preceded the regression of the nodules and was associated to global reduction of G6PD expression and restoration of SDH activity. Since the diagnosis of human HCC is often made at late stages, we investigated whether T3 could exert its anti-tumorigenic effect also on fully developed HCCs and if this effect was associated to a reversion of the metabolic reprogramming of cancer cells. First of all, we found that HCCs, despite down-regulation of the T3/TR axis were able to respond to a brief treatment with T3 and showed evidence of a return to a normal metabolic profile. Moreover, treating HCCs-bearing rats with repeated cycles of T3, we observed a significant decrease of tumor burden accompanied by a restoration of a normal metabolic profile. This was evaluated by analysis of several enzymes involved in glycolysis, pentose phosphate pathway and mitochondrial respiration known to be altered in HCCs. Finally, we wondered whether following withdrawal of T3 the anti-tumorigenic effect of this hormone could be maintained. Interestingly, 4 weeks after T3 withdrawal, rats previously treated with T3 did not show any increase of tumor burden. Taken together, these results suggest that T3 exerts an important anti-tumoral effect at early and late stages of HCC development and one of the mechanisms responsible for this effect could be its capacity to revert the metabolic reprogramming characterizing these lesions. They also suggest that recently developed T3 analogs, devoid of T3 negative side effects, might represent a promising tool in human HCC therapy.