Liver diseases are a tremendous health burden worldwide. Obesity, in addition to alcohol and viral hepatitis, are major risks for liver disease, the pathological endpoint of which is the devastating hepatocellular carcinoma (HCC), which is currently refractory to chemotherapy. Chemotherapeutic drugs induce cellular senescence, but the epigenetic basis underlying these therapeutic effects remains unclear. The histone macroH2A1.1, a variant of histone H2A, is a marker of senescence and it is also implicated in DNA damage repair. Recently, we found an epigenetic link between macroH2A1.1 and liver carcinogenesis, whereby overexpression of this protein, which occurs in liver cancer, triggers an escape from the effect of the DNA demethylating anti-cancer agent decitabine. However, guadecitabine, a novel generation hypomethylating agent, demonstrated a superior activity against liver cancer. We propose to study here how this new hypomethylating agent can overcome the pro-tumorigenic, anti-senescence and chemoresistant effect of macroH2A1.1, preventing the progression of liver diseases.

Onemocnění jater je obrovskou zdravotní zátěží po celém světě. Mezi hlavní rizikové faktory patří obezita, alkohol a virová hepatitida. Jejich patologickým vyústěním potom může být i ničivý hepatocelulární karcinom (HCC), v současné době rezistentní vůči chemoterapii. Chemoterapeutické léky indukují buněčnou senescenci, zatímco samotný epigenetický mechanismus zůstává nejasný. Histon makroH2A1.1, varianta histonu H2A, je marker senescence, ale účastní se také opravných procesů souvisejících s poškozením DNA. Podle našich nedávných zjištění existuje epigenetická vazba mezi makroH2A1.1 a karcinogenezí jater. Důvodem je skutečnost, že nadměrná exprese tohoto proteinu, typická pro rakovinu jater, způsobuje tzv. únik HCC buněk z DNA de-methylačního účinku léčiva decitabinu. Nové hypo-methylačního léčivo, guadecitabin, však vykazuje mimořádnou aktivitu při léčbě rakoviny jater. Proto je naším záměrem porozumět, jak toto léčivo překonává pro-tumorigenní, anti-senescentní a chemorezistentní účinky proteinu makroH2A1.1 a zabraňuje tak progresi onemocnění jater.

• Klíčová slova
• biomarkery, epigenetika, biomarkers, liver cancer, epigenetics, diet, rakovina jater, strava,

• NLK Publikační typ
• závěrečné zprávy o řešení grantu AZV MZ ČR

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent and represents a growing challenge in terms of prevention and treatment. A minority of affected patients develops inflammation, subsequently fibrosis, cirrhosis and hepatocellular carcinoma (HCC). HCC is a leading cause of cancer-related death. An increased number of senescent cells correlate with age-related tissue degeneration during NAFLD-induced HCC. Senolytics are promising agents that target selectively senescent cells. Previous studies showed that whereas a combination of the senolytic drugs dasatinib and quercetin (D + Q) reduced NAFLD in mice, D + Q lacked efficacy in removing doxorubicin-induced β-gal-positive senescent cells in human HCC xenografted mice. Whether D + Q has an effect on the age-associated spectrum of NAFLD-inflammation-HCC remains unknown. METHODS: Here, we utilized an established model of age- and obesity-associated HCC, the low dose diethylnitrosamine (DEN)/high fat diet (HFD), a regimen promoting liver inflammation and tumorigenesis over a long period of 9 months. Four groups of mice each were created: group 1 included control untreated mice; group 2 included mice treated with D + Q; group 3 included mice undergoing the DEN/HFD protocol; group 4 included mice undergoing the DEN/HFD protocol with the administration of D + Q. At the end of the chemical/dietary regimen, we analyzed liver damage and cell senescence by histopathology, qPCR and immunoblotting approaches. RESULTS: Unexpectedly, D + Q worsened liver disease progression in the DEN/HFD mouse model, slightly increasing histological damage and tumorigenesis, while having no effect on senescent cells removal. CONCLUSIONS: In summary, using an animal model that fully recapitulates NAFLD, we demonstrate that these compounds are ineffective against age-associated NAFLD-induced HCC. Video Abstract.

• MeSH
• dasatinib škodlivé účinky   MeSH
• dieta s vysokým obsahem tuků MeSH
• diethylnitrosamin MeSH
• léky proti stárnutí škodlivé účinky   MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední C57BL MeSH
• nealkoholová steatóza jater krev   genetika   patologie   MeSH
• nemoci jater krev   genetika   patologie   MeSH
• obezita krev   genetika   patologie   MeSH
• progrese nemoci * MeSH
• quercetin škodlivé účinky   MeSH
• regulace genové exprese MeSH
• stárnutí genetika   patologie   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Lipid catabolism and anabolism changes play a role in stemness acquisition by cancer cells, and cancer stem cells (CSCs) are particularly dependent on the activity of the enzymes involved in these processes. Lipidomic changes could play a role in CSCs' ability to cause disease relapse and chemoresistance. The exploration of lipid composition and metabolism changes in CSCs in the context of hepatocellular cancer (HCC) is still incomplete and their lipidomic scenario continues to be elusive. We aimed to evaluate through high-throughput mass spectrometry (MS)-based lipidomics the levels of the members of the six major classes of sphingolipids and phospholipids in two HCC cell lines (HepG2 and Huh-7) silenced for the expression of histone variant macroH2A1 (favoring stemness acquisition), or silenced for the expression of focal adhesion tyrosine kinase (FAK) (hindering aggressiveness and stemness). Transcriptomic changes were evaluated by RNA sequencing as well. We found definite lipidomic and transcriptomic changes in the HCC lines upon knockdown (KD) of macroH2A1 or FAK, in line with the acquisition or loss of stemness features. In particular, macroH2A1 KD increased total sphingomyelin (SM) levels and decreased total lysophosphatidylcholine (LPC) levels, while FAK KD decreased total phosphatidylcholine (PC) levels. In conclusion, in HCC cell lines knocked down for specific signaling/epigenetic processes driving opposite stemness potential, we defined a lipidomic signature that hallmarks hepatic CSCs to be exploited for therapeutic strategies.

• MeSH
• buňky Hep G2 MeSH
• fokální adhezní kinasa 1 antagonisté a inhibitory   nedostatek   genetika   MeSH
• fosfatidylcholiny metabolismus   MeSH
• genový knockdown MeSH
• hepatocelulární karcinom genetika   metabolismus   patologie   MeSH
• histony antagonisté a inhibitory   nedostatek   genetika   MeSH
• lidé MeSH
• lipidomika MeSH
• lysofosfatidylcholiny metabolismus   MeSH
• metabolismus lipidů * genetika   MeSH
• nádorové biomarkery genetika   metabolismus   MeSH
• nádorové buněčné linie MeSH
• nádorové kmenové buňky metabolismus   patologie   MeSH
• nádory jater genetika   metabolismus   patologie   MeSH
• regulace genové exprese u nádorů MeSH
• sekvenování transkriptomu MeSH
• sfingomyeliny metabolismus   MeSH
• stanovení celkové genové exprese MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Living beings spend their lives and carry out their daily activities interacting with environmental situations that present space-time variations and that involve contact with other life forms, which may behave as commensals or as invaders and/or parasites. The characteristics of the environment, as well as the processes that support the maintenance of life and that characterize the execution of activities of daily life generally present periodic variations, which are mostly synchronized with the light-dark cycle determined by Earth's rotation on its axis. These rhythms with 24-h periodicity, defined as circadian, influence events linked to the interaction between hosts and hosted microorganisms and can dramatically determine the outcome of this interplay. As for the various pathological conditions resulting from host-microorganism interactions, a particularly interesting scenario concerns infections by viruses. When a viral agent enters the body, it alters the biological processes of the infected cells in order to favour its replication and to spread to various tissues. Though our knowledge concerning the mutual influence between the biological clock and viruses is still limited, recent studies start to unravel interesting aspects of the clock-virus molecular interplay. Three different aspects of this interplay are addressed in this mini-review and include the circadian regulation of both innate and adaptive immune systems, the impact of the biological clock on viral infection itself, and finally the putative perturbations that the virus may confer to the clock leading to its deregulation.

• Publikační typ
• časopisecké články MeSH
• přehledy MeSH