Dataset Information

Nrf2 in Neoplastic and Non-Neoplastic Liver Diseases.

ABSTRACT: Activation of the Keap1/Nrf2 pathway, the most important cell defense signal, triggered to neutralize the harmful effects of electrophilic and oxidative stress, plays a crucial role in cell survival. Therefore, its ability to attenuate acute and chronic liver damage, where oxidative stress represents the key player, is not surprising. On the other hand, while Nrf2 promotes proliferation in cancer cells, its role in non-neoplastic hepatocytes is a matter of debate. Another topic of uncertainty concerns the nature of the mechanisms of Nrf2 activation in hepatocarcinogenesis. Indeed, it remains unclear what is the main mechanism behind the sustained activation of the Keap1/Nrf2 pathway in hepatocarcinogenesis. This raises doubts about the best strategies to therapeutically target this pathway. In this review, we will analyze and discuss our present knowledge concerning the role of Nrf2 in hepatic physiology and pathology, including hepatocellular carcinoma. In particular, we will critically examine and discuss some findings originating from animal models that raise questions that still need to be adequately answered.

SUBMITTER: Orru C

PROVIDER: S-EPMC7599585 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Nrf2 in Neoplastic and Non-Neoplastic Liver Diseases.

Orrù Claudia C Giordano Silvia S Columbano Amedeo A

Cancers 20201012 10

Activation of the Keap1/Nrf2 pathway, the most important cell defense signal, triggered to neutralize the harmful effects of electrophilic and oxidative stress, plays a crucial role in cell survival. Therefore, its ability to attenuate acute and chronic liver damage, where oxidative stress represents the key player, is not surprising. On the other hand, while Nrf2 promotes proliferation in cancer cells, its role in non-neoplastic hepatocytes is a matter of debate. Another topic of uncertainty co ...[more]

PMID: 33053665

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Project description:BackgroundAlcohol consumption is an important risk factor for hepatic neoplastic and non-neoplastic diseases. Questions remain, however, about the relevance to disease risk of drinking patterns and alcohol tolerability, which differ appreciably between Chinese and Western populations.MethodsThe prospective China Kadoorie Biobank included 512,715 adults (41% men) aged 30-79 years recruited from ten areas during 2004-2008, recording alcohol intake, drinking patterns, and other characteristics. After median 10 years' follow-up, 2531 incident liver cancer, 2040 liver cirrhosis, 260 alcoholic liver disease (ALD), and 1262 non-alcoholic fatty liver disease (NAFLD) cases were recorded among 492,643 participants without prior cancer or chronic liver disease at baseline. Cox regression was used to estimate adjusted hazard ratios (HR) relating alcohol intake and drinking patterns to each disease.ResultsOverall, 33% of men and 2% of women drank alcohol regularly (i.e. at least weekly) at baseline. Among male current regular drinkers, alcohol consumption showed positive dose-response associations with risks of several major chronic liver diseases, with HRs per 280 g/week (i.e. around four drinks/day) higher usual alcohol intake of 1.44 (95% CI 1.23-1.69) for liver cancer (n = 547), 1.83 (1.60-2.09) for liver cirrhosis (n = 388), 2.01 (1.77-2.28) for ALD (n = 200), 1.71 (1.35-2.16) for NAFLD (n = 198), and 1.52 (1.40-1.64) for total liver disease (n = 1775). The association with ALD appeared stronger among men reporting flushing (i.e., with low alcohol tolerance). After adjustment for the total amount of weekly alcohol consumption, daily drinkers had significantly increased risk of ALD (2.15, 1.40-3.31) compared with non-daily drinkers, and drinking without meals was associated with significantly greater risks of liver cancer (1.32, 1.01-1.72), liver cirrhosis (1.37, 1.02-1.85), and ALD (1.60, 1.09-2.33) compared with drinking with meals. Female current regular drinkers had significantly higher risk of ALD, but not other liver diseases, than female abstainers.ConclusionsIn Chinese men, alcohol intake was associated with significantly increased risks of several major chronic liver diseases, and certain drinking patterns (e.g. drinking daily, drinking without meals) may further exacerbate the disease risks.

Project description:BackgroundEpigenetic changes during ageing and their relationship with cancer are under the focus of intense research. RASSF1A and NORE1A are novel genes acting in concert in the proapoptotic pathway of the RAS signalling. While NORE1A has not been previously investigated in the human liver, recent reports have suggested that RASSF1A is frequently epigenetically methylated not only in HCC but also in the cirrhotic liver.MethodsTo address whether epigenetic changes take place in connection to age and/or to the underlying disease, we investigated RASSF1A and NORE1A gene promoter methylation by conventional methylation specific PCR and Real-Time MSP in a series of hepatitic and non-hepatitic livers harboring regenerative/hyperplastic (cirrhosis/focal nodular hyperplasia), dysplastic (large regenerative, low and high grade dysplastic nodules) and neoplastic (hepatocellular adenoma and carcinoma) growths.ResultsIn the hepatitic liver (chronic hepatitic/cirrhosis, hepatocellular nodules and HCC) we found widespread RASSF1A gene promoter methylation with a methylation index that increased from regenerative conditions (cirrhosis) to hepatocellular nodules (p < 0.01) to HCC (p < 0.001). In the non-hepatitic liver a consistent pattern of gene methylation was also found in both lesional (focal nodular hyperplasia and hepatocellular adenoma) and non-lesional tissue. Specifically, hepatocellular adenomas (HA) showed a methylation index significantly higher than that detected in focal nodular hyperplasia (FNH) (p < 0.01) and in non-lesional tissue (p < 0.001). In non-lesional liver also the methylation index gradually increased by ageing (p = 0.002), suggesting a progressive spreading of methylated cells over time. As opposed to RASSF1A gene promoter methylation, NORE1A gene was never found epigenetically alterated in both hepatitic and non-hepatitic liver.ConclusionWe have shown that in non-lesional, regenerative and neoplastic liver the RASSF1A gene is increasingly methylated, that this condition takes place as an age-related phenomenon and that the early setting and spreading over time of an epigenetically methylated hepatocyte subpopulation, might be related to liver tumorigenesis.

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Project description:Prominin-1 (CD133) is physiologically expressed at the apical membranes of secretory (serous and mucous) and duct cells of major salivary glands. We investigated its expression in various human salivary gland lesions using two distinct anti-prominin-1 monoclonal antibodies (80B258 and AC133) applied on paraffin-embedded sections and characterized its occurrence in saliva. The 80B258 epitope was extensively expressed in adenoid cystic carcinoma, in lesser extent in acinic cell carcinoma and pleomorphic adenoma, and rarely in mucoepidermoid carcinoma. The 80B258 immunoreactivity was predominately detected at the apical membrane of tumor cells showing acinar or intercalated duct cell differentiation, which lined duct- or cyst-like structures, and in luminal secretions. It was observed on the whole cell membrane in non-luminal structures present in the vicinity of thin-walled blood vessels and hemorrhagic areas in adenoid cystic carcinoma. Of note, AC133 labeled only a subset of 80B258-positive structures. In peritumoral salivary gland tissues as well as in obstructive sialadenitis, an up-regulation of prominin-1 (both 80B258 and AC133 immunoreactivities) was observed in intercalated duct cells. In most tissues, prominin-1 was partially co-expressed with two cancer markers: carcinoembryonic antigen (CEA) and mucin-1 (MUC1). Differential centrifugation of saliva followed by immunoblotting indicated that all three markers were released in association with small membrane vesicles. Immuno-isolated prominin-1-positive vesicles contained CEA and MUC1, but also exosome-related proteins CD63, flotillin-1, flotillin-2 and the adaptor protein syntenin-1. The latter protein was shown to interact with prominin-1 as demonstrated by its co-immunoisolation. A fraction of saliva-associated prominin-1 appeared to be ubiquitinated. Collectively, our findings bring new insights into the biochemistry and trafficking of prominin-1 as well as its immunohistochemical profile in certain types of salivary gland tumors and inflammatory diseases.

Dataset Information

Nrf2 in Neoplastic and Non-Neoplastic Liver Diseases.

Publications

Nrf2 in Neoplastic and Non-Neoplastic Liver Diseases.

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