Carcinome hépatocellulaire

Résumé

Le carcinome hépatocellulaire (CHC) ou hépatocarcinome (en anglais, hepatocellular carcinoma ou HCC) est un cancer primitif du foie. C'est le type de cancer du foie primaire le plus fréquent chez les adultes et la cause de décès la plus fréquente chez les personnes atteintes de cirrhose. Ce cancer survient dans le cadre d'une inflammation chronique du foie et est plus étroitement liée à une hépatite virale chronique (hépatite B ou C) ou à une exposition à des toxines comme l'alcool ou l'aflatoxine. Certaines maladies, comme l'hémochromatose et le déficit en alpha 1-antitrypsine, augmentent considérablement le risque de développer un CHC. Le syndrome métabolique et la NASH sont également de plus en plus reconnus comme des facteurs de risque de CHC. Comme pour tout cancer, le traitement et le pronostic du CHC varient en fonction des particularités de l'histologie tumorale, de la taille, de la propagation du cancer et de l'état de santé général. La grande majorité du CHC se trouve en

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Emerging functions of the nuclear receptor LRH-1 in liver physiology and pathology

Hadrien Charles Edouard Demagny, Kristina Schoonjans, Yu Sun

Nuclear receptors play pleiotropic roles in cell differentiation, development, proliferation, and metabolic processes to govern liver physiology and pathology. The nuclear receptor, liver receptor homolog-1 (LRH-1, NR5A2), originally identified in the liver as a regulator of bile acid and cholesterol homeostasis, was recently recognized to coordinate a multitude of other hepatic metabolic processes, including glucose and lipid processing, methyl group sensing, and cellular stress responses. In this review, we summarize the physiological and pathophysiological functions of LRH-1 in the liver, as well as the molecular mechanisms underlying these processes. This review also focuses on the recent advances highlighting LRH-1 as an attractive target for liver-associated diseases, such as non-alcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC).

2021

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The identification of cellular pathways capable of limiting ischemia/reperfusion (I/R) injury remains a frontier in medicine, and its clinical relevance is urgent. Histidine triad nucleotide binding protein 1 (HINT1) is a tumor suppressor that influences apoptosis. Because apoptotic pathways are a feature of I/R injury, we asked whether Hint1 influences hepatic I/R injury. Hint1(-/-) and C57BL/6 mice were subjected to 70% liver ischemia followed by reperfusion for 3 or 24 hours or to a sham operation. The serum aminotransferase levels, histological lesions, apoptosis, reactive oxygen species, and expression of B cell lymphoma 2-associated X protein (Bax), heme oxygenase 1 (HO-1), interleukin-6 (IL-6), IL-10, tumor necrosis factor-a, Src, nuclear factor kappa B (p65/RelA), and c-Jun were quantified. The responses to toll-like receptor ligands and nicotinamide adenine dinucleotide phosphate oxidase activity in Kupffer cells were compared in Hint1(-/-) mice and C57BL/6 mice. After I/R, the levels of serum aminotransferases, parenchymal necrosis, and hepatocellular apoptosis were significantly lower in Hint1(-/-) mice versus control mice. Furthermore, Bax expression decreased more than 2-fold in Hint1(-/-) mice, and the increases in reactive oxygen species and HO-1 expression that were evident in wild-type mice after I/R were absent in Hint1(-/-) mice. The phosphorylation of Src and the nuclear translocation of p65 were increased in Hint1(-/-) mice, whereas the nuclear expression of phosphorylated c-Jun was decreased. The levels of the protective cytokines IL-6 and IL-10 were increased in Hint1(-/-) mice. These effects increased survival after I/R in mice lacking Hint1. Hint1(-/-) Kupffer cells were less activated than control cells after stimulation with lipopolysaccharides. Conclusion: The Hint1 protein influences the course of I/R injury, and its ablation in Kupffer cells may limit the extent of the injury. (HEPATOLOGY 2011;53:243-252)

2011

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Deciphering the Role of LRH-1 in Liver Intermediary Metabolism and Cancer

Pan Xu

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death worldwide. Gaining insight into the molecular pathways involved in the development of HCC is hence a prerequisite to design and develop novel and effective therapeutic strategies. Metabolic reprogramming is a universal feature of tumor cells and is characterized by increased glycolysis and diminished oxidative phosphorylation, a phenomenon known as the Warburg effect. More recently, it has become evident that tumor cells heavily rely on gluta-mine metabolism to compensate for the Warburg effect and to replenish the tricarboxylic acid (TCA) cycle. However, the molecular mechanisms by which glutamine supports tumor cell metabolism remain largely unexplored. In this thesis, I have established the role of the nuclear receptor LRH-1 as a key regulator in the process of hepatic tumorigenesis. I observed that LRH-1 promotes DEN-induced hepatocellular carcinogenesis (HCC). I demonstrated that LRH-1 facilitates the production of NADPH from glutamine by favoring a non-canonical glutamine pathway that optimizes reductive biosynthesis. Importantly, chronic and acute disrup-tion of LRH-1 also impaired glutamine-induced anaplerosis and Î±-KG availability, ultimately leading to im-paired mTORC1 signaling to block cell proliferation. Moreover, LRH-1 also coordinates glutamine-dependent asparagine synthesis to protect tumor cell from apoptosis induced by glutamine depletion itself. As a result, gain-of-function of LRH-1 sustained aspar-agine homeostasis upon glutamine-deprivation to promote cell survival. Collectively, these studies unveiled an unexpected role of LRH-1 in cancer intermediary metabolism, and warranted further studies on pharma-cological inhibition of LRH-1 to interfere with hepatocellular carcinogenesis.

EPFL2016

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