Cafeína, trigonelina e ácido clorogênico: modulação da expressão de miRNAs na hepatocarcinogênese associada à fibrose
Carregando...
Data
2020-02-20
Autores
Romualdo, Guilherme Ribeiro [UNESP]
Título da Revista
ISSN da Revista
Título de Volume
Editor
Universidade Estadual Paulista (Unesp)
Resumo
A expressão alterada de microRNAs contribui para o desenvolvimento do carcinoma hepatocelular (CHC). Em contraste, o consumo de café reduz em ~40% o risco de desenvolvimento de fibrose/cirrose hepática e CHC, enquanto o café descafeinado não. Esses efeitos são atribuídos à cafeína (CAF) ou à sua combinação com outros compostos comuns e altamente biodisponíveis no café, como a trigonelina (TRI) e o ácido clorogênico (ACG)? Assim, avaliou-se se a CAF individualmente ou combinada à TRI e/ou ao ACG atenuam a hepatocarcinogênese associada à fibrose, investigando a potencial modulação da expressão global de microRNAs. Camundongos C3H/HeJ foram submetidos a um modelo de hepatocarcinogênese associada à fibrose induzido por dietilnitrosamina/tetracloreto de carbono e tratados com CAF (50 mg/kg peso corpóreo (p.c.) 5x/semana, gavagem), CAF+TRI (50 e 25 mg/kg p.c.), CAF+ACG (50 e 25 mg/kg p.c.) ou CAF+TRI+ACG (50, 25 e 25 mg/kg p.c.) por 10 semanas. Somente o tratamento com CAF+TRI+CGA atenuou o desenvolvimento de focos pré-neoplásicos hepáticos. Somente a combinação de todos os compostos reduziu a proliferação celular (Ki-67) em focos pré-neoplásicos e aumentou a apoptose (caspase-3 clivada) em tecido adjacente. CAF+TRI+CGA reduziu o estresse oxidativo hepático, aumentando a atividade ou os níveis proteicos de membros do eixo antioxidante Nrf2/GSH-Px/SOD. O tratamento com CAF+TRI+CGA também atenuou o eixo pró-inflamatório IL-17/ NFκB, reduzindo a quantidade de macrófagos CD68+, a ativação de células estreladas (α-SMA) e a deposição de colágeno. Por fim, o tratamento com CAF+TRI+ACG aumentou a expressão hepática de miR-144-3p e miR-15b-5p, considerados supressores de tumor ou antifibróticos, reduzindo os níveis proteicos de EGFR (alvo de miR-144-3p) e de membros da família antiapoptótica Bcl-2 (Bcl-2, Mcl-1 e Bcl2l2, alvos de miR-15b-5p). Portanto, a combinação de compostos de café, ao invés de CAF isoladamente, atenuou a hepatocarcinogênese associada à fibrose, em parte, pela modulação da expressão de miRNAs.
Aberrant microRNA expression implicates on hepatocellular carcinoma (HCC) development. Conversely, daily 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 solely 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. 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, 5x/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 tissue. CAF+TRI+CGA treatment also decreased hepatic oxidative stress by enhancing the antioxidant Nrf2 axis. CAF+TRI+CGA had the most pronounced effects on decreasing hepatic pro-inflammatory IL-17/NFκB signaling, contributing to reduce CD68-positive macrophage number, stellate cell activation, and collagen deposition. The miRNAomic profile revealed that CAF+TRI+CGA upregulated tumor suppressors miR-144-3p and antifibrotic miR-15b-5p, frequently altered in human HCC. CAF+TRI+CGA reduced protein levels of pro-proliferative EGFR (miR-144-3p target) and antiapoptotic Bcl-2 family members (miR-15b-5p targets). Our results suggest that the combination of most common and highly bioavailable coffee compounds, rather than CAF individually, attenuates early fibrosis-associated hepatocarcinogenesis by modulating miRNA expression profile.
Aberrant microRNA expression implicates on hepatocellular carcinoma (HCC) development. Conversely, daily 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 solely 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. 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, 5x/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 tissue. CAF+TRI+CGA treatment also decreased hepatic oxidative stress by enhancing the antioxidant Nrf2 axis. CAF+TRI+CGA had the most pronounced effects on decreasing hepatic pro-inflammatory IL-17/NFκB signaling, contributing to reduce CD68-positive macrophage number, stellate cell activation, and collagen deposition. The miRNAomic profile revealed that CAF+TRI+CGA upregulated tumor suppressors miR-144-3p and antifibrotic miR-15b-5p, frequently altered in human HCC. CAF+TRI+CGA reduced protein levels of pro-proliferative EGFR (miR-144-3p target) and antiapoptotic Bcl-2 family members (miR-15b-5p targets). Our results suggest that the combination of most common and highly bioavailable coffee compounds, rather than CAF individually, attenuates early fibrosis-associated hepatocarcinogenesis by modulating miRNA expression profile.
Descrição
Palavras-chave
Cafeína, Trigonelina, Ácido clorogênico, Fibrose hepática, Hepatocarcinogênese, Camundongos C3H/HeJ, Café