Exosomes play an important role in intercellular communication and metastatic progression of hepatocellular carcinoma (HCC). However, cellular communication between heterogeneous HCC cells with different metastatic potentials and the resultant cancer progression are not fully understood in HCC. Here, HCC cells with high-metastatic capacity (97hm and Huhm) were constructed by continually exerting selective pressure on primary HCC cells (MHCC-97H and Huh7). Through performing exosomal miRNA sequencing in HCC cells with different metastatic potentials (MHCC-97H and 97hm), many significantly different miRNA candidates were found. Among these miRNAs, miR-92a-3p was the most abundant miRNA in the exosomes of highly metastatic HCC cells. Exosomal miR92a-3p was also found enriched in the plasma of HCC patient-derived xenograft mice (PDX) model with high-metastatic potential. Exosomal miR-92a-3p promotes epithelial-mesenchymal transition (EMT) in recipient cancer cells via targeting PTEN and regulating its downstream Akt/Snail signaling. Furthermore, through mRNA sequencing in HCC cells with different metastatic potentials and predicting potential transcription factors of miR92a-3p, upregulated transcript factors E2F1 and c-Myc were found in high-metastatic HCC cells promote the expression of cellular and exosomal miR-92a-3p in HCC by directly binding the promoter of its host gene, miR17HG. Clinical data showed that a high plasma exosomal miR92a-3p level was correlated with shortened overall survival and disease-free survival, indicating poor prognosis in HCC patients. In conclusion, hepatoma-derived exosomal miR92a-3p plays a critical role in the EMT progression and promoting metastasis by inhibiting PTEN and activating Akt/Snail signaling. Exosomal miR92a-3p is a potential predictive biomarker for HCC metastasis, and this may provoke the development of novel therapeutic and preventing strategies against metastasis of HCC.
Lipopolysaccharide (LPS)-induced
liver injury is the main factor
in acute liver failure. The current study aims to investigate the
protection of limonin, an antioxidant compound from citrus fruit,
against LPS-induced liver toxicity and elucidate the potential mechanisms.
We found that limonin elevated cell viability and reduced LDH release
in LPS-treated HepG2 cells. Limonin also inhibited LPS-induced pyroptosis
by inhibiting membrane rupture, reducing ROS generation, and decreasing
gasdermin D activation. Moreover, limonin inhibited the formation
of a NOD-like receptor protein 3 (NLRP3)/Apoptosis-associated speck-like
protein containing a CARD (ASC) complex by reducing the related protein
expression and the colocalization cytosolic of NLRP3 and caspase-1
and then suppressed IL-1β maturation. Ultimately, we established
LPS-induced hepatotoxicity in vivo by using C57BL/6
mice administrated LPS (10 mg/kg) intraperitoneally and limonin (50
and 100 mg/kg) orally. We found that limonin dereased the serum ALT
and AST activity and LDH release and increased the hepatic GSH amount
in LPS-treated mice. Additionally, the liver histological evaluation
revealed that limonin protects against LPS-induced liver damage. We
further demonstrated that limonin ameliorated LPS-induced hepatotoxicity
by inhibiting pyroptosis via the NLRP3/gasdermin
D signaling pathway. In summary, this study uncovered the mechanism
whereby limonin mitigated LPS-induced hepatotoxicity and documented
that limonin might be a promising candidate drug for LPS-induced hepatotoxicity.
Metallacage-based nanoparticles have superior therapeutic performance against liver cancer stem cells in both traditional 2D model and 3D multicellular spheroids, providing a promising strategy for efficient cancer treatment.
Acute myeloid leukaemia (AML) is a highly heterogeneous haematologic malignancy with poor prognosis. We previously showed synergistic antileukaemic interaction between exportin 1 (XPO1) inhibitor KPT‐330 (Selinexor) and Bcl‐2 inhibitor venetoclax (ABT‐199) in preclinical models of AML, which was partially meditated by Mcl‐1, although the full mechanism of action remains unknown. In this study, using real‐time RT‐PCR and Western blot analysis, we show that inhibition of XPO1 via KPT‐330 or KPT‐8602 (Eltanexor) decreases the mRNA and protein levels of c‐Myc, CHK1, WEE1, RAD51 and RRM2. KPT‐330 and KPT‐8602 induce DNA damage, as determined by alkaline comet assay. In addition, we demonstrate that venetoclax enhances KPT‐330‐ and KPT‐8602‐induced DNA damage, likely through inhibition of DNA damage repair. This study provides new insight into the molecular mechanism underlying the synergistic antileukaemic activity between venetoclax and XPO1 inhibitors against AML. Our data support the clinical evaluation of this promising combination therapy for the treatment of AML.
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