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Metastasis formation requires active energy production and is regulated at multiple levels by mitochondrial metabolism. The hyperactive metabolism of cancer cells supports their extreme adaptability and plasticity and facilitates resistance to common anticancer therapies. In spite the potential relevance of a metastasis metabolic control therapy, so far, limited experience is available in this direction. Here, we evaluated the effect of the recently described α-ketoglutarate dehydrogenase (KGDH) inhibitor, (S)-2-[(2,6-dichlorobenzoyl) amino] succinic acid (AA6), in an orthotopic mouse model of breast cancer 4T1 and in other human breast cancer cell lines. In all conditions, AA6 altered Krebs cycle causing intracellular α-ketoglutarate (α-KG) accumulation. Consequently, the activity of the α-KG-dependent epigenetic enzymes, including the DNA demethylation ten-eleven translocation translocation hydroxylases (TETs), was increased. In mice, AA6 injection reduced metastasis formation and increased 5hmC levels in primary tumours. Moreover, in vitro and in vivo treatment with AA6 determined an α-KG accumulation paralleled by an enhanced production of nitric oxide (NO). This epigenetically remodelled metabolic environment efficiently counteracted the initiating steps of tumour invasion inhibiting the epithelial-to-mesenchymal transition (EMT). Mechanistically, AA6 treatment could be linked to upregulation of the NO-sensitive anti-metastatic miRNA 200 family and down-modulation of EMT-associated transcription factor Zeb1 and its CtBP1 cofactor. This scenario led to a decrease of the matrix metalloproteinase 3 (MMP3) and to an impairment of 4T1 aggressiveness. Overall, our data suggest that AA6 determines an α-KG-dependent epigenetic regulation of the TET–miR200–Zeb1/CtBP1–MMP3 axis providing an anti-metastatic effect in a mouse model of breast cancer-associated metastasis.

The clinical outcome of hepatocellular carcinoma (HCC) treatment remains unsatisfactory, contributing to the high mortality of HCC worldwide. Circulating miRNAs have the potential to be a predictor of therapy response. Microarray profiling was performed in serum samples of 20 HCC patients before treatment. Circulating miRNAs associated with treatment response were validated in 86 serum HCC samples using the qRT-PCR system. Patients were treated either with curative treatments (resection or radiofrequency) or trans-arterial chemoembolization (TACE), and grouped according to therapy response in complete responders (CR) and partial responders or progressive disease (PRPD), following mRECIST criteria. Four miRNA candidates from the discovery phase (miR-4443, miR-4454, miR-4492, and miR-4530) were validated. Before therapy, miR-4454 and miR-4530 were up-regulated in CR to curative treatments (2.83 fold, p = 0.02 and 2.33 fold, p = 0.008, respectively) and were able to differentiate CR from PRPD (area under the curve (AUC) = 0.74, sens/spec 79/63% and AUC = 0.77, sens/spec 72/73%). On the contrary, miR-4443 was 1.95 times down-regulated in CR (p = 0.05) with an AUC of 0.72 (sens = 70%, spec = 60%) in distinguishing CR vs. PRPD). The combination of the three miRNAs was able to predict the response to curative treatment with an AUC of 0.84 (sens = 72%, spec = 75%). The higher levels of miR-4454 and miR-4530 in were associated to longer overall survival (HR = 2.79, p = 0.029 and HR = 2.97, p = 0.011, respectively). Before TACE, miR-4492 was significantly up-regulated in CR patients (FC = 2.67, p = 0.01) and able to differentiate CR from PRPD (AUC = 0.84, sens/spec 84.6/71%). We demonstrated that different miRNAs predictors can be used as potential prognostic circulating biomarkers according to the selected treatment for HCC.

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Background Spleen stiffness (SS) has gained a lot of interest in the context of liver cirrhosis and portal hypertension stratification. However, there is a paucity of data on confounding factors that may alter SS values. Methods Between January 2018 and October 2019, we enrolled 120 healthy subjects and 117 patients with hepatitis C virus (HCV) infection who did not have significant liver fibrosis (i.e., F0-1). Abdominal ultrasound evaluation was performed on each individual to measure portal vein diameter, portal flow velocity, spleen bipolar diameter, and splenic area. We also performed liver and spleen elastography. Results HCV patients had higher SS (p < 0.001), portal vein diameter (p = 0.031), portal flow velocity (p = 0.035), spleen bipolar diameter (p = 0.042) and area (p = 0.025), and ALT levels (p < 0.001). Linear regression models showed that SS increased by 3.220 kPa for each mm of portal vein diameter, by 0.7 kPa for each cm/s of portal flow velocity, by 2.239 kPa for each cm of spleen bipolar diameter, and by 0.233 kPa for each cm 2 of spleen area. Patients with HCV infection were stratified according to median ALT levels (i.e. 32 IU/L). SS and spleno-portal axis parameters were significantly higher in patients with an ALT level > 32 IU/L. Besides, the relationship between SS and ALT was described by cubic polynomial regression according to the following equation: 11.735 + 0.404 (ALT) 1 − 0.002 (ALT) 2 + 4.26 × 10 -6 (ALT) 3 . Conclusions Our results bring new light to the role of inflammation as a confounding factor for SS measurement. Therefore, particular attention should be paid to serum transaminase for a correct evaluation of spleen elastography.

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