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| Author(s): |
Guilherme Ribeiro Romualdo
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | Botucatu. 2020-03-03. |
| Institution: | Universidade Estadual Paulista (Unesp). Faculdade de Medicina. Botucatu |
| Defense date: | 2020-02-20 |
| Advisor: | Luís Fernando Barbisan |
| Abstract | |
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. (AU) | |
| FAPESP's process: | 16/12015-0 - Caffeine, Trigonelline and Chlorogenic Acid: Modulation of miRNA expression in Fibrosis-associated Hepatocarcinogenesis. |
| Grantee: | Guilherme Ribeiro Romualdo |
| Support Opportunities: | Scholarships in Brazil - Doctorate |