Autophagy is a conserved catabolic process that eliminates dysfunctional cytosolic biomolecules through vacuole-mediated sequestration and lysosomal degradation. Although the molecular mechanisms that regulate autophagy are not fully understood, recent work indicates that dysfunctional/impaired autophagic functions are associated with the development and progression of nonalcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease (AFLD), and hepatocellular carcinoma (HCC). Autophagy prevents NAFLD and AFLD progression through enhanced lipid catabolism and decreasing hepatic steatosis, which is characterized by the accumulation of triglycerides and increased inflammation. However, as both diseases progress, autophagy can become impaired leading to exacerbation of both pathological conditions and progression into HCC. Due to the significance of impaired autophagy in these diseases, there is increased interest in studying pathways and targets involved in maintaining efficient autophagic functions as potential therapeutic targets. In this review, we summarize how impaired autophagy affects liver function and contributes to NAFLD, AFLD, and HCC progression. We will also explore how recent discoveries could provide novel therapeutic opportunities to effectively treat these diseases.

Exosomes are membrane-bound extracellular vesicles (EVs) that transport bioactive materials between cells and organs. The cargo delivered by exosomes can alter a wide range of cellular responses in recipient cells and play an important pathophysiological role in human cancers. In hepatocellular carcinoma (HCC), for example, adipocyte- and tumor-secreted factors contained in exosomes contribute to the creation of a chronic inflammatory state, which contributes to disease progression. The exosome-mediated crosstalk between adipocytes and liver cancer cells is a key aspect of a dynamic tumor microenvironment. In this review, we summarize the role of increased adiposity and the role of adipocyte-derived exosomes (AdExos) and HCC-derived exosomes (HCCExos) in the modulation of HCC progression. We also discuss recent advances regarding how malignant cells interact with the surrounding adipose tissue and employ exosomes to promote a more aggressive phenotype.

MicroRNAs (miRNAs) are small non-coding RNA molecules that bind with the 3′ untranslated regions (UTRs) of genes to regulate expression. Downregulation of miR-483-5p (miR-483) is associated with the progression of hepatocellular carcinoma (HCC). However, the significant roles of miR-483 in nonalcoholic fatty liver disease (NAFLD), alcoholic fatty liver diseases (AFLD), and HCC remain elusive. In the current study, we investigated the biological significance of miR-483 in NAFLD, AFLD, and HCC in vitro and in vivo. The downregulation of miR-483 expression in HCC patients’ tumor samples was associated with Notch 3 upregulation. Overexpression of miR-483 in a human bipotent progenitor liver cell line HepaRG and HCC cells dysregulated Notch signaling, inhibited cell proliferation/migration, induced apoptosis, and increased sensitivity towards antineoplastic agents sorafenib/regorafenib. Interestingly, the inactivation of miR-483 upregulated cell steatosis and fibrosis signaling by modulation of lipogenic and fibrosis gene expression. Mechanistically, miR-483 targets PPARα and TIMP2 gene expression, which leads to the suppression of cell steatosis and fibrosis. The downregulation of miR-483 was observed in mice liver fed with a high-fat diet (HFD) or a standard Lieber-Decarli liquid diet containing 5% alcohol, leading to increased hepatic steatosis/fibrosis. Our data suggest that miR-483 inhibits cell steatosis and fibrogenic signaling and functions as a tumor suppressor in HCC. Therefore, miR-483 may be a novel therapeutic target for NAFLD/AFLD/HCC management in patients with fatty liver diseases and HCC.

Hypoxia and hypoxia-related biomarkers are the major determinants of prostate cancer (PCa) aggressiveness. Therefore, a better understanding of molecular players involved in PCa cell survival under hypoxia could offer novel therapeutic targets. We previously reported a central role of mitochondrial protein carnitine palmitoyltransferase (CPT1A) in PCa progression, but its role in regulating PCa survival under hypoxia remains unknown. Here, we employed PCa cells (22Rv1 and MDA-PCa-2b) with knockdown or overexpression of CPT1A and assessed their survival under hypoxia, both in cell culture and in vivo models. The results showed that CPT1A knockdown in PCa cells significantly reduced their viability, clonogenicity, and sphere formation under hypoxia, while its overexpression increased their proliferation, clonogenicity, and sphere formation. In nude mice, 22Rv1 xenografts with CPT1A knockdown grew significantly slower compared to vector control cells (~59% reduction in tumor volume at day 29). On the contrary, CPT1A-overexpressing 22Rv1 xenografts showed higher tumor growth compared to vector control cells (~58% higher tumor volume at day 40). Pathological analyses revealed lesser necrotic areas in CPT1A knockdown tumors and higher necrotic areas in CPT1A overexpressing tumors. Immunofluorescence analysis of tumors showed that CPT1A knockdown strongly compromised the hypoxic areas (pimonidazole+), while CPT1A overexpression resulted in more hypoxia areas with strong expression of proliferation biomarkers (Ki67 and cyclin D1). Finally, IHC analysis of tumors revealed a significant decrease in VEGF or VEGF-D expression but without significant changes in biomarkers associated with microvessel density. These results suggest that CPT1A regulates PCa survival in hypoxic conditions and might contribute to their aggressiveness.

Targeting the stress oncoprotein LEDGF/p75 to sensitize chemoresistant prostate cancer cells to taxanes

Freshwater prokaryotic cyanobacteria within harmful algal blooms produce cyanotoxins which are considered major pollutants in the aquatic system. Direct exposure to cyanotoxins through inhalation, skin contact, or ingestion of contaminated drinking water can target the liver and may cause hepatotoxicity. In the current study, we investigated the effect of low concentrations of cyanotoxins on cytotoxicity, inflammation, modulation of unfolded protein response (UPR), steatosis, and fibrosis signaling in human hepatocytes and liver cell models. Exposure to low concentrations of microcystin-LR (MC-LR), microcystin-RR (MC-RR), nodularin (NOD), and cylindrospermopsin (CYN) in human bipotent progenitor cell line HepaRG and hepatocellular carcinoma (HCC) cell lines HepG2 and SK-Hep1 resulted in increased cell toxicity. MC-LR, NOD, and CYN differentially regulated inflammatory signaling, activated UPR signaling and lipogenic gene expression, and induced cellular steatosis and fibrotic signaling in HCC cells. MC-LR, NOD, and CYN also regulated AKT/mTOR signaling and inhibited autophagy. Chronic exposure to MC-LR, NOD, and CYN upregulated the expression of lipogenic and fibrosis biomarkers. Moreover, RNA sequencing (RNA seq) data suggested that exposure of human hepatocytes, HepaRG, and HCC HepG2 cells to MC-LR and CYN modulated expression levels of several genes that regulate non-alcoholic fatty liver disease (NAFLD). Our data suggest that low concentrations of cyanotoxins can cause hepatotoxicity and cell steatosis and promote NAFLD progression.