miRNA expression in Fibrosis-associated Hepatocarcinogenesis: Modulation by Caffeine, Trigonelline and Chlorogenic Acid.

• Grant number: 16/14420-0
• Support Opportunities: Regular Research Grants
• Start date: December 01, 2016
• End date: November 30, 2018
• Field of knowledge: Health Sciences - Nutrition
• Principal Investigator: Luís Fernando Barbisan
• Grantee: Luís Fernando Barbisan
• Host Institution: Instituto de Biociências (IBB). Universidade Estadual Paulista (UNESP). Campus de Botucatu. Botucatu , SP, Brazil
• Associated researchers: Bruno Cogliati ; Fernando Salvador Moreno

Abstract

Recently, hepatic fibrosis and carcinogenesis have been linked to altered expression of several miRNAs. In contrast, studies indicate that coffee drinking is associated with a 40% lower risk of developing fibrosis or liver cancer, while decaf drinking is not. Thus, the present project will evaluate whether caffeine alone or associated with trigoneline and/or chlorogenic acid (CGA), abundant compounds in coffee: (A) attenuates fibrosis-associated hepatocarcinogenesis (FAH) in vivo; (B) attenuates the fibrosis in vitro; (C) alters the miRNAs global expression profile and the expression of target genes of differentially expressed miRNAs in the liver. Thus, C3H/He male mice will be submitted to FAH model induced by diethylnitrosamine (DEN) and carbon tetrachloride (CCl4). Moreover, C3A (malignant hepatocytes) and LPS-treated LX-2 (HSC) will be used to perform 3D co-culture. Both mice and 3D co-culture will be exposed to caffeine alone or associated to trigonelline and/or CGA. Co-culture samples will be collected for collagen I determination, hepatocyte and HSCs counting, quantification of pro-inflammatory cytokines (IL-6, TNF-±, TGFb-1, I-17A and IL-23) and gene expression (collagen ±1(I), ±-SMA, TGF²-1, MMP-2, MMP-9, MMP-13 and TIMP-1). Liver samples will be collected for histopathological evaluation (HE), analysis of collagen content (Picro sirius Red) and immunohistochemistry (Ki-67, cleaved caspase-3, CK 8/18, F4/80, desmin and ±-SMA). Other liver samples will be used for global miRNA expression. After identification of differentially expressed miRNAs, bioinformatics prediction of target genes will be performed. The list of predicted genes will be used to evaluate the expression of target mRNAs. Additive or synergistic effects of the coffee compounds are expected and could represent novel therapeutic tools to chronic liver disease-associated Hepatocarcinogenesis. (AU)

Scientific publications

(7)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

ROMUALDO, GUILHERME RIBEIRO; LEROY, KAAT; COSTA, CICERO JULIO SILVA; PRATA, GABRIEL BACIL; VANDERBORGHT, BART; DA SILVA, TEREZA CRISTINA; BARBISAN, LUIS FERNANDO; ANDRAUS, WELLINGTON; DEVISSCHER, LINDSEY; CAMARA, NIELS OLSEN SARAIVA; et al. In Vivo and In Vitro Models of Hepatocellular Carcinoma: Current Strategies for Translational Modeling. CANCERS, v. 13, n. 21, NOV 2021. (16/14420-0, 16/12015-0, 18/10953-9)

ROMUALDO, GUILHERME RIBEIRO; PRATA, GABRIEL BACIL; DA SILVA, TEREZA CRISTINA; HENRIQUE FERNANDES, ANA ANGELICA; MORENO, FERNANDO SALVADOR; COGLIATI, BRUNO; BARBISAN, LUIS FERNANDO. Fibrosis-associated hepatocarcinogenesis revisited: Establishing standard medium-term chemically-induced male and female models. PLoS One, v. 13, n. 9, SEP 13 2018. (16/14420-0)

ROMUALDO, GUILHERME RIBEIRO; ROCHA, ARIANE BARTOLOMEU; VINKEN, MATHIEU; COGLIATI, BRUNO; MORENO, FERNANDO SALVADOR; GARCIA CHAVES, MARIA ANGEL; BARBISAN, LUIS FERNANDO. Drinking for protection? Epidemiological and experimental evidence on the beneficial effects of coffee or major coffee compounds against gastrointestinal and liver carcinogenesis. Food Research International, v. 123, p. 567-589, SEP 2019. (16/12015-0, 16/14420-0, 17/26217-7)

ROMUALDO, GUILHERME RIBEIRO; PRATA, GABRIEL BACIL; DA SILVA, TEREZA CRISTINA; EVANGELISTA, ADRIANE FEIJO; REIS, RUI MANUEL; VINKEN, MATHIEU; MORENO, FERNANDO SALVADOR; COGLIATI, BRUNO; BARBISAN, LUIS FERNANDO. The combination of coffee compounds attenuates early fibrosis-associated hepatocarcinogenesis in mice: involvement of miRNA profile modulation. JOURNAL OF NUTRITIONAL BIOCHEMISTRY, v. 85, NOV 2020. (16/14420-0, 16/12015-0, 17/16596-0)

ROMUALDO, GUILHERME RIBEIRO; DE SOUZA, ISADORA PENEDO; DE SOUZA, LUCAS VILHEGAS; PRATA, GABRIEL BACIL; DE CAMPOS FRAGA-SILVA, THAIS FERNANDA; SARTORI, ALEXANDRINA; BORGUINI, RENATA GALHARDO; DE ARAUJO SANTIAGO, MANUELA CRISTINA PESSANHA; HENRIQUE FERNANDES, ANA ANGELICA; COGLIATI, BRUNO; et al. Beneficial effects of anthocyanin-rich peels of Myrtaceae fruits on chemically-induced liver fibrosis and carcinogenesis in mice. Food Research International, v. 139, JAN 2021. (16/14420-0, 17/17516-0)

ROMUALDO, GUILHERME RIBEIRO; DA SILVA, TEREZA CRISTINA; COGLIATI, BRUNO; BARBISAN, LUIS FERNANDO. The association of caffeine, trigonelline, and chlorogenic acid, active components from coffee, enhances caffeine-induced cytotoxicity in hepatocellular carcinoma cells.. Clinical Cancer Research, v. 24, n. 1, p. 2-pg., 2018-01-01. (16/14420-0)

BARTOLOMEU, ARIANE ROCHA; ROMUALDO, GUILHERME RIBEIRO; LISON, CARMEN GRINAN; BESHARAT, ZEIN MERSINI; MARCHAL CORRALES, JUAN ANTONIO; GARCIA CHAVES, MARIA ANGEL; BARBISAN, LUIS FERNANDO. Caffeine and Chlorogenic Acid Combination Attenuate Early-Stage Chemically Induced Colon Carcinogenesis in Mice: Involvement of oncomiR miR-21a-5p. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 23, n. 11, p. 16-pg., 2022-06-01. (17/26217-7, 16/12015-0, 16/14420-0)