Autor(es):
Romualdo, Guilherme Ribeiro [UNESP] ; Prata, Gabriel Bacil [UNESP] ; da Silva, Tereza Cristina ; Evangelista, Adriane Feijó ; Reis, Rui Manuel ; Vinken, Mathieu ; Moreno, Fernando Salvador ; Cogliati, Bruno ; Barbisan, Luís Fernando [UNESP]
Data: 2020
Identificador Persistente: http://hdl.handle.net/11449/201020
Origem: Oasisbr
Assunto(s): Caffeine; Chlorogenic acid; Hepatocarcinogenesis; Liver fibrosis; miRNA; Trigonelline; Caffeine; Caffeine; Chlorogenic acid; Chlorogenic acid; Hepatocarcinogenesis; Hepatocarcinogenesis; Liver fibrosis; Liver fibrosis; miRNA; miRNA; Trigonelline; Trigonelline
Descrição
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Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Aberrant microRNA expression implicates on hepatocellular carcinoma (HCC) development. Conversely, coffee consumption reduces by ~40% the risk for fibrosis/cirrhosis and HCC, while decaffeinated coffee does not. It is currently unknown whether these protective effects are related to caffeine (CAF), or to its combination with other common and/or highly bioavailable coffee compounds, such as trigonelline (TRI) and chlorogenic acid (CGA). We evaluated whether CAF individually or combined with TRI and/or CGA alleviates fibrosis-associated hepatocarcinogenesis, examining the involvement of miRNA profile modulation. Then, male C3H/HeJ mice were submitted to a diethylnitrosamine/carbon tetrachloride-induced model. Animals received CAF (50 mg/kg), CAF+TRI (50 and 25 mg/kg), CAF+CGA (50 and 25 mg/kg) or CAF+TRI+CGA (50, 25 and 25 mg/kg), intragastrically, 5×/week, for 10 weeks. Only CAF+TRI+CGA combination reduced the incidence, number and proliferation (Ki-67) of hepatocellular preneoplastic foci while enhanced apoptosis (cleaved caspase-3) in adjacent parenchyma. CAF+TRI+CGA treatment also decreased hepatic oxidative stress and enhanced the antioxidant Nrf2 axis. CAF+TRI+CGA had the most pronounced effects on decreasing hepatic pro-inflammatory IL-17 and NFκB, contributing to reduce CD68-positive macrophage number, stellate cell activation, and collagen deposition. In agreement, CAF+TRI+CGA upregulated tumor suppressors miR-144-3p, miR-376a-3p and antifibrotic miR-15b-5p, frequently deregulated in human HCC. CAF+TRI+CGA reduced the hepatic protein levels of pro-proliferative EGFR (miR-144-3p target), antiapoptotic Bcl-2 family members (miR-15b-5p targets), and the number of PCNA (miR-376a-3p target) positive hepatocytes in preneoplastic foci. Our results suggest that the combination of most common and highly bioavailable coffee compounds, rather than CAF individually, attenuates fibrosis-associated hepatocarcinogenesis by modulating miRNA expression profile.
Department of Pathology Botucatu Medical School São Paulo State University (UNESP)
Department of Structural and Functional Biology Biosciences Institute São Paulo State University (UNESP)
Department of Pathology School of Veterinary Medicine and Animal Science University of São Paulo (USP)
Molecular Oncology Research Center Barretos Cancer Hospital
Department of In Vitro Toxicology and Dermato-Cosmetology Faculty of Medicine and Pharmacy Vrije Universiteit Brussel
Department of Food and Experimental Nutrition Faculty of Pharmaceutical Sciences University of São Paulo (USP)
Life and Health Sciences Research Institute (ICVS) School of Medicine University of Minho
3B's - PT Government Associate Laboratory
Department of Pathology Botucatu Medical School São Paulo State University (UNESP)
Department of Structural and Functional Biology Biosciences Institute São Paulo State University (UNESP)
FAPESP: #2016/12015–0
FAPESP: #2016/14420–0
FAPESP: #2017/16596–0
