In recent years, there has been a revival of interest in metabolic changes of cancer cells as it has been noticed that malignant transformation and metabolic reprogramming are closely intertwined. ...The pentose phosphate pathway (PPP) is one of the fundamental components of cellular metabolism crucial for cancer cells. This review will discuss recent findings regarding the involvement of PPP enzymes in several types of cancer, with a focus on hepatocellular carcinoma (HCC). We will pay considerable attention to the involvement of glucose-6-phosphate dehydrogenase, the rate-limiting enzyme of the PPP. Subsequently, we discuss the inhibition of the PPP as a potential therapeutic strategy against cancer, in particular, HCC.
Activation of thyroid hormone receptor β (THRβ) has shown beneficial effects on metabolic alterations, including non-alcoholic fatty liver disease (NAFLD). Here, we investigated the effect of TG68, a ...novel THRβ agonist, on fatty liver accumulation and liver injury in mice fed a high-fat diet (HFD). C57BL/6 mice fed HFD for 17 or 18 weeks, a time when all mice developed massive steatohepatitis, were then given TG68 at a dose of 9.35 or 2.8 mg/kg for 2 or 3 weeks, respectively. As a reference compound, the same treatment was adopted using equimolar doses of MGL-3196, a selective THRβ agonist currently in clinical phase III. The results showed that treatment with TG68 led to a reduction in liver weight, hepatic steatosis, serum transaminases, and circulating triglycerides. qRT-PCR analyses demonstrated activation of THRβ, as confirmed by increased
levels of
and
, and changes in lipid metabolism, as revealed by increased expression of
and
. The present results showed that this novel THRβ agonist exerts an anti-steatogenic effect coupled with amelioration of liver injury in the absence of extra-hepatic side effects, suggesting that TG68 may represent a useful tool for the treatment of NAFLD.
Background & Aims Although the growth suppressing Hippo pathway has been implicated in hepatocellular carcinoma (HCC) pathogenesis, it is unknown at which stage of hepatocarcinogenesis its ...dysregulation occurs. We investigated in rat and human preneoplastic lesions whether overexpression of the transcriptional co-activator Yes-associated protein (YAP) is an early event. Methods The experimental model used is the resistant-hepatocyte (R-H) rat model. Gene expression was determined by qRT-PCR or immunohistochemistry. Forward genetic experiments were performed in human HCC cells and in murine oval cells. Results All foci of preneoplastic hepatocytes, generated in rats 4 weeks after diethylnitrosamine (DENA) treatment, displayed YAP accumulation. This was associated with down-regulation of the β-TRCP ligase, known to mediate YAP degradation, and of microRNA-375, targeting YAP. YAP accumulation was paralleled by the up-regulation of its target genes. Increased YAP expression was also observed in human early dysplastic nodules and adenomas. Animal treatment with verteporfin (VP), which disrupts the formation of the YAP-TEAD complex, significantly reduced preneoplastic foci and oval cell proliferation. In vitro experiments confirmed that VP-mediated YAP inhibition impaired cell growth in HCC and oval cells; notably, oval cell transduction with wild type or active YAP conferred tumorigenic properties in vitro and in vivo. Conclusions These results suggest that (i) YAP overexpression is an early event in rat and human liver tumourigenesis; (ii) it is critical for the clonal expansion of carcinogen-initiated hepatocytes and oval cells, and (iii) VP-induced disruption of the YAP-TEAD interaction may provide an important approach for the treatment of YAP-overexpressing cancers.
SARS-CoV-2 infection is a world-wide public health problem. Several aspects of its pathogenesis and the related clinical consequences still need elucidation. In Italy, Sardinia has had very low ...numbers of infections. Taking advantage of the low genetic polymorphism in the Sardinian population, we analyzed clinical, genetic and immunogenetic factors, with particular attention to HLA class I and II molecules, to evaluate their influence on susceptibility to SARS-CoV-2 infection and the clinical outcome.
We recruited 619 healthy Sardinian controls and 182 SARS-CoV-2 patients. Thirty-nine patients required hospital care and 143 were without symptoms, pauci-symptomatic or with mild disease. For all participants, we collected demographic and clinical data and analyzed the HLA allele and haplotype frequencies.
Male sex and older age were more frequent in hospitalized patients, none of whom had been vaccinated during the previous seasonal flu vaccination campaignes. Compared to the group of asymptomatic or pauci-symptomatic patients, hospitalized patients also had a higher frequency of autoimmune diseases and glucose-6-phosphate-dehydrogenase (G6PDH) deficiency. None of these patients carried the beta-thalassemia trait, a relatively common finding in the Sardinian population. The extended haplotype HLA-A*02:05, B*58:01, C*07:01, DRB1*03:01 OR 0.1 (95% CI 0-0.6), Pc = 0.015 was absent in all 182 patients, while the HLA-C*04:01 allele and the three-loci haplotype HLA-A*30:02, B*14:02, C*08:02 OR 3.8 (95% CI 1.8-8.1), Pc = 0.025 were more frequently represented in patients than controls. In a comparison between in-patients and home care patients, the HLA-DRB1*08:01 allele was exclusively present in the hospitalized patients OR > 2.5 (95% CI 2.7-220.6), Pc = 0.024.
The data emerging from our study suggest that the extended haplotype HLA-A*02:05, B*58:01, C*07:01, DRB1*03:01 has a protective effect against SARS-CoV-2 infection in the Sardinian population. Genetic factors that resulted to have a negative influence on the disease course were presence of the HLA-DRB1*08:01 allele and G6PDH deficiency, but not the beta-thalassemic trait. Absence of influenza vaccination could be a predisposing factor for more severe disease.
The signaling pathways activated by thyroid hormone receptors (THR) are of fundamental importance for organogenesis, growth and differentiation, and significantly influence energy metabolism, lipid ...utilization and glucose homeostasis. Pharmacological control of these pathways would likely impact the treatment of several human diseases characterized by altered metabolism, growth or differentiation. Not surprisingly, biomedical research has been trying for the past decades to pharmacologically target the 3,5,3'-triiodothyronine (T3)/THR axis.
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studies have provided evidence of the potential utility of the activation of the T3-dependent pathways in metabolic syndrome, non-alcoholic fatty liver disease (NAFLD), and in the treatment of hepatocellular carcinoma (HCC). Unfortunately, supra-physiological doses of the THR agonist T3 cause severe thyrotoxicosis thus hampering its therapeutic use. However, the observation that most of the desired beneficial effects of T3 are mediated by the activation of the beta isoform of THR (THRβ) in metabolically active organs has led to the synthesis of a number of THRβ-selective thyromimetics. Among these drugs, GC-1, GC-24, KB141, KB2115, and MB07344 displayed a promising therapeutic strategy for liver diseases. However, although these drugs exhibited encouraging results when tested in the treatment of experimentally-induced obesity, dyslipidemia, and HCC, significant adverse effects limited their use in clinical trials. More recently, evidence has been provided that some metabolites of thyroid hormones (TH), mono and diiodothyronines, could also play a role in the treatment of liver disease. These molecules, for a long time considered inactive byproducts of the metabolism of thyroid hormones, have now been proposed to be able to modulate and control lipid and cell energy metabolism. In this review, we will summarize the current knowledge regarding T3, its metabolites and analogs with reference to their possible clinical application in the treatment of liver disease. In particular, we will focus our attention on NAFLD, non-alcoholic steatohepatitis (NASH) and HCC. In addition, the possible therapeutic use of mono- and diiodothyronines in metabolic and/or neoplastic liver disease will be discussed.
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•Nrf2 is frequently mutated/activated at early stages of hepatocarcinogenesis.•Genetic inactivation of Nrf2 does not interfere with carcinogen-induced initiation.•Genetic inactivation ...of Nrf2 fully prevents the development of preneoplastic lesions.•Nrf2 targeting represents a promising strategy for HCC treatment.
Dysregulation of the Keap1-Nrf2 pathway has been observed in experimental and human tumors, suggesting possible roles of the pathway in cancer development. Herein, we examined whether Nrf2 (Nfe2l2) activation occurs at early steps of rat hepatocarcinogenesis, to assess critical contributions of Nrf2 to the onset of hepatocellular carcinoma (HCC).
We used wild-type (WT) and Nrf2 knockout (Nrf2KO) rats treated with a single injection of diethylnitrosamine (DENA) followed by choline-devoid methionine-deficient (CMD) diet. This experimental model causes massive fatty liver and steatohepatitis with fibrosis and enables identification of early stages of hepatocarcinogenesis.
We found that Nrf2 activation takes place in early preneoplastic lesions identified by the marker glutathione S-transferase placental form (GSTP). Nrf2 missense mutations, known to disrupt the Keap1-Nrf2 binding, were present in 65.7% of GSTP-positive foci. Nrf2KO rats were used to directly investigate whether Nrf2 is critical for initiation and/or clonal expansion of DENA-damaged hepatocytes. While Nrf2 genetic inactivation did not alter DENA-induced initiation, it led to increased liver injury and chronic compensatory hepatocyte regeneration when rats were fed a CMD diet. However, in spite of such a permissive environment, the livers of Nrf2KO rats did not display any preneoplastic lesion unlike those of WT rats.
These results demonstrate that, in a model of hepatocarcinogenesis resembling human non-alcoholic fatty liver disease: i) Nrf2 is activated at early steps of the tumorigenic process and ii) Nrf2 is mandatory for the clonal expansion of initiated cells, indicating that Nrf2 is critical in the onset of HCC.
Dysregulation of the Keap1-Nrf2 molecular pathway has been observed in human tumors. In a nutritional model of hepatocarcinogenesis, the protein Nrf2 is frequently mutated/activated at early steps of the tumorigenic process. Herein, we show that Nrf2 is mandatory for the development of preneoplastic lesions. These results suggest that Nrf2 has a critical role in the onset of hepatocellular carcinoma.
Studies on gene and/or microRNA (miRNA) dysregulation in the early stages of hepatocarcinogenesis are hampered by the difficulty of diagnosing early lesions in humans. Experimental models ...recapitulating human hepatocellular carcinoma (HCC) are then used to perform this analysis. We performed miRNA and gene expression profiling to characterize the molecular events involved in the multistep process of hepatocarcinogenesis in the resistant‐hepatocyte rat model. A high percentage of dysregulated miRNAs/genes in HCC were similarly altered in early preneoplastic lesions positive for the stem/progenitor cell marker cytokeratin‐19, indicating that several HCC‐associated alterations occur from the very beginning of the carcinogenic process. Our analysis also identified miRNA/gene‐target networks aberrantly activated at the initial stage of hepatocarcinogenesis. Activation of the nuclear factor erythroid related factor 2 (NRF2) pathway and up‐regulation of the miR‐200 family were among the most prominent changes. The relevance of these alterations in the development of HCC was confirmed by the observation that NRF2 silencing impaired while miR‐200a overexpression promoted HCC cell proliferation in vitro. Moreover, T3‐induced in vivo inhibition of the NRF2 pathway accompanied the regression of cytokeratin‐19‐positive nodules, suggesting that activation of this transcription factor contributes to the onset and progression of preneoplastic lesions towards malignancy. The finding that 78% of genes and 57% of dysregulated miRNAs in rat HCC have been previously associated with human HCC as well underlines the translational value of our results. Conclusion: This study indicates that most of the molecular changes found in HCC occur in the very early stages of hepatocarcinogenesis. Among these, the NRF2 pathway plays a relevant role and may represent a new therapeutic target. (Hepatology 2014;58:228–241)
Metabolic changes are associated with cancer, but whether they are just bystander effects of deregulated oncogenic signaling pathways or characterize early phases of tumorigenesis remains unclear. ...Here we show in a rat model of hepatocarcinogenesis that early preneoplastic foci and nodules that progress towards hepatocellular carcinoma (HCC) are characterized both by inhibition of oxidative phosphorylation (OXPHOS) and by enhanced glucose utilization to fuel the pentose phosphate pathway (PPP). These changes respectively require increased expression of the mitochondrial chaperone TRAP1 and of the transcription factor NRF2 that induces the expression of the rate-limiting PPP enzyme glucose-6-phosphate dehydrogenase (G6PD), following miR-1 inhibition. Such metabolic rewiring exclusively identifies a subset of aggressive cytokeratin-19 positive preneoplastic hepatocytes and not slowly growing lesions. No such metabolic changes were observed during non-neoplastic liver regeneration occurring after two/third partial hepatectomy. TRAP1 silencing inhibited the colony forming ability of HCC cells while NRF2 silencing decreased G6PD expression and concomitantly increased miR-1; conversely, transfection with miR-1 mimic abolished G6PD expression. Finally, in human HCC patients increased G6PD expression levels correlates with grading, metastasis and poor prognosis. Our results demonstrate that the metabolic deregulation orchestrated by TRAP1 and NRF2 is an early event restricted to the more aggressive preneoplastic lesions.
Several lines of evidence suggest that the thyroid hormone signaling pathway is altered in patients with NAFLD and that pharmacological strategies to target the thyroid hormone/thyroid hormone ...nuclear receptor axis (TH/THR) in the liver may exert beneficial effects. In this study, we investigated the effect of TG68, a novel THRβ agonist, on rat hepatic fat accumulation and NAFLD-associated hepatocarcinogenesis.
Male rats given a single dose of diethylnitrosamine (DEN) and fed a high fat diet (HFD) were co-treated with different doses of TG68. Systemic and hepatic metabolic parameters, immunohistochemistry and hepatic gene expression were determined to assess the effect of TG68 on THRβ activation.
Irrespectively of the dose, treatment with TG68 led to a significant reduction in liver weight, hepatic steatosis, circulating triglycerides, cholesterol and blood glucose. Importantly, a short exposure to TG68 caused regression of DEN-induced preneoplastic lesions associated with a differentiation program, as evidenced by a loss of neoplastic markers and reacquisition of markers of differentiated hepatocytes. Finally, while an equimolar dose of the THRβ agonist Resmetirom reduced hepatic fat accumulation, it did not exert any antitumorigenic effect.
The use of this novel thyromimetic represents a promising therapeutic strategy for the treatment of NAFLD-associated hepatocarcinogenesis.
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