Fibrosis-associated hepatocarcinogenesis revisited: Establishing standard medium-term chemically-induced male and female models

Romualdo, Guilherme Ribeiro; Prata, Gabriel Bacil; Silva, Tereza Cristina da; Fernandes, Ana Angélica Henrique; Moreno, Fernando Salvador; Cogliati, Bruno; Barbisan, Luı́s Fernando

doi:10.1371/journal.pone.0203879

Cited by 20 publications

(18 citation statements)

References 53 publications

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“…Chemical carcinogens commonly used to mimic HCC in rodent models induce HCC either selectively or much more aggressively in males. As a result, studies of HCC in females have been fewer, although progress is being made to model the disease in both sexes (61). Our data provide mechanistic insight into the association of lipid metabolism dysregulation and HCC risk for both sexes, an association that will likely be important in the decades to come, considering the prevalence of NAFLD and its association with HCC development.…”

Section: Discussionmentioning

confidence: 91%

HNF4α-Deficient Fatty Liver Provides a Permissive Environment for Sex-Independent Hepatocellular Carcinoma

et al. 2019

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The incidence of hepatocellular carcinoma (HCC) is on the rise worldwide. Although the incidence of HCC in males is considerably higher than in females, the projected rates of HCC incidence are increasing for both sexes. A recently appreciated risk factor for HCC is the growing problem of non-alcoholic fatty liver disease (NAFLD), which is usually associated with obesity and the metabolic syndrome. In this study, we showed that under conditions of fatty liver, female mice were more likely to develop HCC than expected from previous models. Using an inducible knockout model of the tumor-suppressive isoform of hepatocyte nuclear factor 4 alpha ("P1-HNF4α") in the liver in combination with prolonged high fat (HF) diet, we found that HCC developed equally in male and female mice as early as 38 weeks of age. Similar sex-independent HCC occurred in the "STAM" model of mice, in which severe hyperglycemia and HF feeding results in rapid hepatic lipid deposition, fibrosis, and ultimately HCC. In both sexes, reduced P1-HNF4α activity, which also occurs under chronic high-fat diet feeding, increased hepatic lipid deposition and produced a greatly augmented circadian rhythm in interleukin 6 (Il6), a factor previously linked with higher HCC incidence in males. Loss of HNF4α combined with HF feeding induced epithelial-mesenchymal transition in an IL-6-dependent manner. Collectively, these data provide a mechanism-based working hypothesis that could explain the rising incidence of aggressive HCC.

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Section: Discussionmentioning

confidence: 91%

HNF4α-Deficient Fatty Liver Provides a Permissive Environment for Sex-Independent Hepatocellular Carcinoma

et al. 2019

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“…In addition, DEN-induced C57BL/6J mice liver cancer model was used to simulate the development of human HCC in vivo. 27 We found that the expression of GRK2 gradually decreased when the degree of malignancy increased, while there was no significant change in GRK3 expression. In vitro, GRK2 expression was obviously decreased in HCCLM3 and MHCC97H cell lines with high metastatic potential than in SMC7721 and HepG2 cell lines with low metastatic potential.…”

Section: Discussionmentioning

confidence: 65%

<p>GRK2 Suppresses Hepatocellular Carcinoma Metastasis and Invasion Through Down-Regulation of Prostaglandin E Receptor 2</p>

Chen

et al. 2020

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Background: Hepatocellular carcinoma (HCC) is an aggressive form of human liver cancer and the fifth most common malignancy worldwide. Novel effective treatment strategies for HCC are urgently in clinical because of its poor response to conventional therapies. G protein-coupled receptor kinases (GRKs), including GRK2 and GRK3, are known that involves in various essential cellular processes and regulates numerous signaling pathways. However, the role of GRK2/3 in invasion and metastasis of HCC still remains unclear. Materials and Methods: Immunohistochemistry, Western blot, laser confocal microscopy and qRT-PCR were used to detect the expression of GRK2/3 and EP2 in liver tissues of HCC patients and DEN-induced HCC mice. Wound healing and transwell assay were applied to measure the migration and invasion of HCC cells after transfected with GRK2 siRNA. The downstream pathway of Akt and ERK was verified by Western blot. Results: The expression of GRK2 was significantly decreased, while GRK3 was not significantly changed in HCC tissues compared with noncancerous tissues of HCC patients. Moreover, GRK2 expression was reduced during liver tumorigenesis in diethylnitrosamineinduced liver tumor model. In addition, our in vitro study showed that GRK2 expression was gradually decreased with increasing HCC cell line metastatic potential, and GRK2 knockdown significantly promoted the migration and invasion of HCC cells. Furthermore, low GRK2 expression was associated with increased expression of EP2 receptor translocation to HCC cell membrane, and the activation of Akt pathway. Conclusion: These data suggest that GRK2 inhibits HCC metastasis and invasion may be through regulating EP2 receptor translocation, and this effect appears to be mediated by Akt pathway.

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“…The liver-cancer susceptible C3H/HeJ mice strain was submitted to a previously established fibrosis-associated hepatocarcinogenesis model [11]. Briefly, male mice (n = 5 to 10 animals/group) were initiated for liver carcinogenesis by receiving a single intraperitoneal (i.p.)…”

Section: Experimental Designmentioning

confidence: 99%

“…(corresponding to 0.025 µL/g or 0.040 µg/g of pure CCl4) and there were 0.25 µL weekly increments to the utmost dose of 1.50 µL/g b.wt. (corresponding to 0.15 µL/g or 0.24 µg/g of pure CCl4) [11]. In addition, from week 7 to 17, mice received CAF alone (50 mg/kg b.wt.…”

Section: Experimental Designmentioning

confidence: 99%

“…A wealth of evidence points out to the pivotal involvement of miRNAs during hepatocarcinogenesis, as either potential tumor suppressors or onco-miRNAs [8]. In order to unveil the molecular aspects involved in liver fibrosis and carcinogenesis, chemically-induced murine models have been established as suitable tools for pre-clinical research [9][10][11]. These bioassays display striking morphological and molecular similarities to the corresponding human diseases, including aberrant miRNA expression profile [12], enabling the translational screening of preventive and therapeutic strategies for this liver malignancy [9][10][11].…”

Section: Introductionmentioning

confidence: 99%

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The combination of coffee compounds attenuates early fibrosis-associated hepatocarcinogenesis in mice: involvement of miRNA profile modulation

Romualdo

Prata

Silva

et al. 2020

The Journal of Nutritional Biochemistry

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Aberrant microRNA expression implicates on Hepatocellular carcinoma (HCC) development/progression. Conversely, daily coffee consumption reduces by ~40% the risk for fibrosis/cirrhosis and HCC, while decaffeinated coffee does not. Are these beneficial effects related to caffeine (CAF), or to its combination with other common/highly bioavailable coffee compounds, 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 body weight, 5x/week, intragastrically), CAF+TRI (50 and 25 mg/kg), CAF+CGA (50 and 25 mg/kg) or CAF+TRI+CGA (50, 25 and 25 mg/kg) for 10 weeks. Only CAF+TRI+CGA treatment reduced hepatocellular preneoplastic foci development. Moreover, only the combination of all compounds reduced proliferation (Ki-67) in preneoplastic lesions and enhanced apoptosis (cleaved caspase-3) in adjacent tissue. CAF+TRI+CGA also decreased hepatic oxidative stress by enhancing 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 HCC. CAF+TRI+CGA reduced protein levels of proproliferative EGFR (miR-144-3p target) and antiapoptotic Bcl-2 family members (Bcl-2, Mcl-1 and Bcl2l2, miR-15b-5p targets). The results suggest that the combination of coffee compounds, rather than CAF individually, attenuates fibrosisassociated hepatocarcinogenesis by modulating miRNA expression profile. Findings provide translational insights on therapeutic approaches based on miRNA profile modulation by coffee compounds.

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Fibrosis-associated hepatocarcinogenesis revisited: Establishing standard medium-term chemically-induced male and female models

Cited by 20 publications

References 53 publications

HNF4α-Deficient Fatty Liver Provides a Permissive Environment for Sex-Independent Hepatocellular Carcinoma

HNF4α-Deficient Fatty Liver Provides a Permissive Environment for Sex-Independent Hepatocellular Carcinoma

<p>GRK2 Suppresses Hepatocellular Carcinoma Metastasis and Invasion Through Down-Regulation of Prostaglandin E Receptor 2</p>

The combination of coffee compounds attenuates early fibrosis-associated hepatocarcinogenesis in mice: involvement of miRNA profile modulation

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