scholarly journals Prohibitin 1 in liver injury and cancer

2020 ◽  
Vol 245 (5) ◽  
pp. 385-394 ◽  
Author(s):  
Lucía Barbier-Torres ◽  
Shelly C Lu
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Injury ◽  
Subcellular Localization ◽  
Oncogenic Signaling ◽  
Alcoholic Fatty Liver ◽  
Post Translational Modifications ◽  
Cholangiocarcinoma Cell ◽  
Liver Health ◽  
Oncogenic Signaling Pathways ◽  
Prohibitin 1

Prohibitin 1 is an evolutionary conserved and ubiquitously expressed protein that exerts different biological functions depending on its subcellular localization. The role of prohibitin 1 in liver cancer is controversial as it can be pro- or anti-tumorigenic. However, most of the studies to date have described prohibitin 1 primarily as a tumor suppressor in the liver. Its deficiency sensitizes the liver to cholestatic liver injury, non-alcoholic fatty liver disease, inflammatory insults, and cancer. Liver-specific Phb1-knockout mice spontaneously develop hepatocellular carcinoma, Phb1 heterozygotes are more susceptible to develop cholangiocarcinoma, and the majority of human hepatocellular carcinomas and cholangiocarcinomas have reduced prohibitin 1 expression. Consistent with a tumor suppressive role in the liver, prohibitin 1 negatively regulates proliferation in hepatocytes and human hepatocellular carcinoma and cholangiocarcinoma cell lines, and multiple oncogenic signaling pathways are activated when prohibitin 1 is deficient. Although best known as a mitochondrial chaperone, prohibitin 1 can protect the liver by mitochondrial-independent mechanisms. This review summarizes what’s known about prohibitin 1’s role in liver pathology, with the focus on hepatoprotection and carcinogenesis. Impact statement This review summarizes the last decades of research on PHB1 in liver pathobiology. PHB1 is a key player for liver health as it is hepatoprotective and tumor suppressive. We highlight the importance of PHB1’s subcellular localization, post-translational modifications, and interacting proteins as major determinants of PHB1 cytoprotective function and anti-tumor activity in the liver.

scholarly journals Fructose and the Liver

2021 ◽  
Vol 22 (13) ◽  
pp. 6969
Author(s):  
Pablo Muriel ◽  
Pedro López-Sánchez ◽  
Erika Ramos-Tovar
Keyword(s):  
Liver Cancer ◽  
Fatty Infiltration ◽  
Scar Tissue ◽  
The Body ◽  
World Health ◽  
Oncogenic Signaling ◽  
Alcoholic Fatty Liver ◽  
Fat Consumption ◽  
Preclinical And Clinical Studies ◽  
Oncogenic Signaling Pathways

Chronic diseases represent a major challenge in world health. Metabolic syndrome is a constellation of disturbances affecting several organs, and it has been proposed to be a liver-centered condition. Fructose overconsumption may result in insulin resistance, oxidative stress, inflammation, elevated uric acid levels, increased blood pressure, and increased triglyceride concentrations in both the blood and liver. Non-alcoholic fatty liver disease (NAFLD) is a term widely used to describe excessive fatty infiltration in the liver in the absence of alcohol, autoimmune disorders, or viral hepatitis; it is attributed to obesity, high sugar and fat consumption, and sedentarism. If untreated, NAFLD can progress to nonalcoholic steatohepatitis (NASH), characterized by inflammation and mild fibrosis in addition to fat infiltration and, eventually, advanced scar tissue deposition, cirrhosis, and finally liver cancer, which constitutes the culmination of the disease. Notably, fructose is recognized as a major mediator of NAFLD, as a significant correlation between fructose intake and the degree of inflammation and fibrosis has been found in preclinical and clinical studies. Moreover, fructose is a risk factor for liver cancer development. Interestingly, fructose induces a number of proinflammatory, fibrogenic, and oncogenic signaling pathways that explain its deleterious effects in the body, especially in the liver.

scholarly journals HepatocyteGHR/STAT5b Signaling Protects Against Liver Injury in NAFLD/NASH Mice Models Independent of Steatosis

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A48-A49
Author(s):  
Mercedes del Río-Moreno ◽  
Mari C Vazquez-Borrego ◽  
Mariyah Mahmood ◽  
Andre Sarmento-Cabral ◽  
Grace Guzman ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Liver Injury ◽  
De Novo ◽  
Corn Oil ◽  
Direct Action ◽  
Liver Weight ◽  
De Novo Lipogenesis ◽  
Wild Type ◽  
Alcoholic Fatty Liver ◽  
Liver Health

Abstract Non-alcoholic fatty liver disease (NAFLD) represents a spectrum of pathologies ranging from simple steatosis to non-alcoholic steatohepatitis (NASH) that can lead to cirrhosis and hepatocellular carcinoma. Clinical and mouse studies indicate GH-signaling is reduced in NAFLD. We reported that chow-fed mice, with adult-onset, hepatocyte-specific GH receptor knockdown (aHepGHRkd) develop steatosis, and with age, a mild NASH-like phenotype. In the present study, we sought to determine if aHepGHRkd accelerates the development of steatosis and fibrosis in the context of diets shown in wild-type male mice, after 6 months of feeding, to produce mild NASH (60% fat [lard] + sucrose in the drinking water [HFS] or a severe NASH-like phenotype (40% fat, with partially hydrogenated corn-oil; 2% cholesterol; 20% fructose [HFCF]). Since aHepGHRkd is associated with a reduction in active STAT5b, aHepGHRkd mice were treated with either a hepatocyte-specific adenoviral-associated vector that expresses constitutively active STAT5b (AAV-TBGp-STAT5bCA = STAT5bCA) or a AAV-Null vector. After only 3 months of feeding either the HFS or HFCF diet, aHepGHRkd, but not GHR-intact controls, mice exhibited clear fibrosis, associated with higher levels of plasma alanine aminotransferase (ALT). STAT5bCA treatment of aHepGHRkd mice reduced fibrosis, as well as plasma ALT. Of note, hepatic TG content did not differ between the treatment groups, within diet. Preliminary studies used GC-MS to reveal aHepGHRkd, in the context of HFS diet, increased hepatic fatty acid ratios indicative of enhanced de novo lipogenesis, while STAT5bCA reversed this effect. These results suggest GHR/STAT5b may protect against liver injury not by controlling absolute fat accumulation, but by modifying the fatty acid composition of hepatic lipids. Finally, in order to determine if STAT5bCA could also reverse established diet-induced NASH, wild-type mice were fed the HFCF diet for 6 months and then treated with AAV-STAT5bCA or AAV-Null vectors, and followed for an additional 3 months. Preliminary findings show STAT5bCA modestly reduced liver weight with no changes in TG content. However, STAT5bCA prevented the rise in plasma ALT observed in Null-treated controls. Of note, some mice developed hepatic tumors, where the number and size of visible tumors was reduced by STAT5bCA. Importantly, in all models examined thus far, changes in the liver phenotype could not be clearly attributed to changes in systemic metabolism, supporting a direct action of GHR/STAT5b signaling on liver health. Taken together, these results suggest that enhancing hepatocyte STAT5b activity could prevent/treat diet-induced NASH. How STAT5b mediates these effects, and if there are other players involved, remains to be elucidated.

scholarly journals Role of Oncogenic Pathways on the Cancer Immunosuppressive Microenvironment and Its Clinical Implications in Hepatocellular Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3666
Author(s):  
Naoshi Nishida
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cells ◽  
Cancer Cells ◽  
Signaling Pathways ◽  
Immune Checkpoint ◽  
Immune Microenvironment ◽  
Oncogenic Signaling ◽  
Oncogenic Pathways ◽  
Tumor Immune Microenvironment ◽  
Oncogenic Signaling Pathways

The tumor immune microenvironment, including hepatocellular carcinoma (HCC), is complex, consisting of crosstalk among tumor components such as the cancer cells, stromal cells and immune cells. It is conceivable that phenotypic changes in cancer cells by genetic and epigenetic alterations affect the cancer–stroma interaction and anti-cancer immunity through the expression of immune checkpoint molecules, growth factors, cytokines, chemokines and metabolites that may act on the immune system in tumors. Therefore, predicting the outcome of ICI therapy requires a thorough understanding of the oncogenic signaling pathways in cancer and how they affect tumor immune evasion. In this review, we have detailed how oncogenic signaling pathways can play a role in altering the condition of the cellular components of the tumor immune microenvironment such as tumor-associated macrophages, regulatory T cells and myeloid-derived suppressor cells. The RAS/MAPK, PI3K/Akt, Wnt/β-catenin and JAK/STAT pathways have all been implicated in anti-tumor immunity. We also found that factors that reflect the immune microenvironment of the tumor, including the status of oncogenic pathways such as the volume of tumor-infiltrating T cells, expression of the immune checkpoint protein PD-1 and its ligand PD-L1, and activation of the Wnt/β-catenin signaling pathway, predict a response to ICI therapy in HCC cases.

scholarly journals Liver-specific deletion of prohibitin 1 results in spontaneous liver injury, fibrosis, and hepatocellular carcinoma in mice

Hepatology ◽  
2010 ◽  
Vol 52 (6) ◽  
pp. 2096-2108 ◽  
Author(s):  
Kwang Suk Ko ◽  
Maria Lauda Tomasi ◽  
Ainhoa Iglesias-Ara ◽  
Barbara A. French ◽  
Samuel W. French ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Injury ◽  
Prohibitin 1 ◽  
Specific Deletion

Phytosterols and Triterpenoids for Prevention and Treatment of Metabolic-related Liver Diseases and Hepatocellular Carcinoma

2019 ◽  
Vol 20 (3) ◽  
pp. 197-214 ◽  
Author(s):  
Isabel Sánchez-Crisóstomo ◽  
Eduardo Fernández-Martínez ◽  
Raquel Cariño-Cortés ◽  
Gabriel Betanzos-Cabrera ◽  
Rosa A. Bobadilla-Lugo
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Disease ◽  
Anticancer Agents ◽  
Liver Diseases ◽  
Membrane Receptors ◽  
New Drugs ◽  
Sexual Hormones ◽  
Steroid Nucleus ◽  
Alcoholic Fatty Liver ◽  
Prevention And Treatment

Background: Liver ailments are among the leading causes of death; they originate from viral infections, chronic alcoholism, and autoimmune illnesses, which may chronically be precursors of cirrhosis; furthermore, metabolic syndrome may worsen those hepatopathies or cause Non-alcoholic Fatty Liver Disease (NAFLD) that may advance to non-alcoholic steatohepatitis (NASH). Cirrhosis is the late-stage liver disease and can proceed to hepatocellular carcinoma (HCC). Pharmacological treatment options for liver diseases, cirrhosis, and HCC, are limited, expensive, and not wholly effective. The use of medicinal herbs and functional foods is growing around the world as natural resources of bioactive compounds that would set the basis for the development of new drugs. Review and Conclusion: Plant and food-derived sterols and triterpenoids (TTP) possess antioxidant, metabolic-regulating, immunomodulatory, and anti-inflammatory activities, as well as they are recognized as anticancer agents, suggesting their application strongly as an alternative therapy in some chronic diseases. Thus, it is interesting to review current reports about them as hepatoprotective agents, but also because they structurally resemble cholesterol, sexual hormones, corticosteroids and bile acids due to the presence of the steroid nucleus, so they all can share pharmacological properties through activating nuclear and membrane receptors. Therefore, sterols and TTP appear as a feasible option for the prevention and treatment of chronic metabolic-related liver diseases, cirrhosis, and HCC.

MALAT1 as a Versatile Regulator of Cancer: Overview of the updates from Predatory role as Competitive Endogenous RNA to Mechanistic In-sights

2020 ◽  
Vol 20 ◽  
Author(s):  
Ammad Ahmad Farooqi ◽  
Evangelia Legaki ◽  
Maria Gazouli ◽  
Silvia Rinaldi ◽  
Rossana Berardi
Keyword(s):  
Molecular Biology ◽  
Detailed Analysis ◽  
Signaling Pathways ◽  
Individualized Medicine ◽  
Signaling Cascades ◽  
Oncogenic Signaling ◽  
Non Coding Rnas ◽  
Oncogenic Signaling Pathways ◽  
Competitive Endogenous Rna

: Central dogma of molecular biology has remained cornerstone of classical molecular biology but serendipitous discovery of microRNAs (miRNAs) in nematodes paradigmatically shifted our current understanding of the intricate mech-anisms which occur during transitions from transcription to translation. Discovery of miRNA captured tremendous attention and appreciation and we had witnessed an explosion in the field of non-coding RNAs. Ground-breaking discoveries in the field of non-coding RNAs have helped in better characterization of microRNAs and long non-coding RNAs (LncRNAs). There is an ever-increasing list of miRNA targets which are regulated by MALAT1 to stimulate or repress expression of tar-get genes. However, in this review our main focus is to summarize mechanistic insights related to MALAT1-mediated regu-lation of oncogenic signaling pathways. We have discussed how MALAT1 modulated TGF/SMAD and Hippo pathways in various cancers. We have also comprehensively summarized how JAK/STAT and Wnt/β-catenin pathways stimulated MALAT1 expression and consequentially how MALAT1 potentiated these signaling cascades to promote cancer. MALAT1 research has undergone substantial broadening however, there is still a need to identify additional mechanisms. MALAT1 is involved in multi-layered regulation of multiple transduction cascades and detailed analysis of different pathways will be helpful in getting a step closer to individualized medicine.

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