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Hepatocellular carcinoma (HCC) is a hypervascular tumor and derive most of its blood supply from the hepatic artery. The locoregional treatment transarterial chemoembolization (TACE) represents the gold standard for HCC patients at intermediated stage, with survival rates ranging from 20 to 36 months. Despite the proven effectiveness of TACE, the identification of biomarkers predictive of response to the first or subsequent TACE cycle remains an unmet clinical need. MicroRNAs are pivotal players in drug resistance in HCC and show ideal characteristics as circulating biomarkers. MiR-22-3p is a tumor suppressor gene in several cancers, including HCC. Here, we aimed at identifying novel miR-22-3p targets involved in TACE resistance and at exploring circulating miR-22 as a candidate of TACE response. Serum and tissue miR-22-3p and WEE1 levels were quantified by qPCR and digital droplets PCR in HCC patients at early and intermediate stages, as well as in HCC cell lines. Functional analysis and luciferase reporter assay assessed WEE1 targeting by miR-22-3p in HCC cell lines and xenograft mice. Flow cytometric analysis evaluated cell cycle modulation after miR-22 overexpression or silencing in HCC cells. Live imaging and WB analyses evaluated cell growth and apoptotic cell death in miR-22 modulated HCC cells subjected to hypoxia and doxorubicin treatment. Statistical analysis was performed to investigate clinicopathological associations in TACE-treated patients. An inverse correlation between serum and tissue miR-22 levels was detected in surgically resected HCC patients. Functional analysis and luciferase reporter assay demonstrated WEE1 targeting by miR-22-3p in HCC cell lines and xenograft mice. Cell cycle and BrdU analyses showed a downregulation of G2/M in miR-22-overexpressing cells, and an upregulation in miR-22 stably silenced cells. An increase of cell growth and an inhibition of apoptotic markers was shown in miR-22 silenced cells undergoing hypoxia and doxorubicin treatment. Increased miR-22 serum levels were observed after each TACE cycle with respect to pre-treatment levels. Higher miR-22 levels associated with TACE resistance at 3 and 6 months of follow-up when assessed two days after treatment. Post-treatment miR-22 levels associated with alfa-fetoprotein and tumor size in TACE-treated patients. The cell cycle checkpoint inhibitor WEE1 is a novel miR-22-3p target in HCC and contributes to TACE resistance in low miR-22-expressing HCC cells. If validated in larger cohorts, miR-22-3p represents a promising circulating biomarker of TACE response when analyzed few days after treatment. [ABSTRACT FROM AUTHOR]

Neural progenitor cells (NPCs) are often used to study the subcellular mechanisms underlying differentiation into neurons in vitro. Works published to date have focused on the pathways that distinguish undifferentiated NPCs from mature neurons, neglecting the earlier and intermediate stages of this process. Current evidence suggests that mitochondria interaction with the ER is fundamental to a wide range of intracellular processes. However, it is not clear whether and how the mitochondria-ER interactions differ between NPCs and their differentiated counterparts. Here we take advantage of the widely used NPC line LUHMES to provide hints on the mitochondrial dynamic trait changes that occur during the first stage of their maturation into dopaminergic-like neurons. We observed that the morphology of mitochondria, their interaction with the ER, and the expression of several mitochondria-ER contact site resident proteins change, which suggests the potential contribution of mitochondria dynamics to NPC differentiation. Further studies will be needed to explore in depth these changes, and their functional outcomes, which may be relevant to the scientific community focusing on embryonic neurogenesis and developmental neurotoxicity.

Hepatocellular carcinoma (HCC) is a heterogeneous tumor associated with several risk factors, with non-alcoholic fatty liver disease (NAFLD) emerging as an important cause of liver tumorigenesis. Due to the obesity epidemics, the occurrence of NAFLD has significantly increased with nearly 30% prevalence worldwide. HCC often arises in the background of chronic liver disease (CLD), such as nonalcoholic steatohepatitis (NASH) and cirrhosis. Gut microbiome (GM) alterations have been linked to NAFLD progression and HCC development, with several investigations reporting a crucial role for the gut-liver axis and microbial metabolites in promoting CLD. Moreover, the GM affects liver homeostasis, energy status, and the immune microenvironment, influencing the response to immunotherapy with interesting therapeutic implications. In this review, we summarize the main changes in the GM and derived metabolites (e.g., short-chain fatty acids and bile acids) occurring in HCC patients and influencing NAFLD progression, emphasizing their potential as early diagnostic biomarkers and prognostic tools. We discuss the weight loss effects of diet-based interventions and healthy lifestyles for the treatment of NAFLD patients, highlighting their impact on the restoration of the intestinal barrier and GM structure. We also describe encouraging preclinical findings on the modulation of GM to improve liver functions in CLD, boost the antitumor immune response (e.g., probiotic supplementations or anti-hypercholesterolemic drug treatment), and ultimately delay NAFLD progression to HCC. The development of safe and effective strategies that target the gut-liver axis holds promise for liver cancer prevention and treatment, especially if personalized options will be considered.