HK1 from hepatic stellate cell–derived extracellular vesicles promotes progression of hepatocellular carcinoma

Chen, Qi-Tao; Zhang, Zhiyuan; Huang, Qiaoling; Chen, Hang-zi; Hong, Wen-bin; Lin, Tianwei; Zhao, Wenxiu; Wang, Xiaomin; Ju, Cui-yu; Wu, Liu-zheng; Huang, Ya-ying; Hou, Peipei; Wang, Weijia; Zhou, Dawang; Deng, Xianming; Wu, Qiao

doi:10.1038/s42255-022-00642-5

Cited by 59 publications

(35 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Notably, FFC-EtOH increased transforming growth factor beta ( Tgfb ) expression compared to EtOH, suggesting that FFC-EtOH promotes more pro-fibrotic signaling compared to EtOH, as TGFβ induces hepatic stellate cells to produce extracellular matrix proteins such as collagens [ 30 ]. Although TGFβ is associated with AKT activation in stellate cell models [ 31 ], TGFβ is also known to induce SMAD3-mediated gluconeogenic gene expression with associated decreased AKT activation in mice [ 32 ].…”

Section: Resultsmentioning

confidence: 99%

Concomitant western diet and chronic-binge alcohol dysregulate hepatic metabolism

et al. 2023

View full text Add to dashboard Cite

Background and aims There is significant overlap between non-alcoholic fatty liver disease (NAFLD) and alcohol-associated liver disease (ALD) with regards to risk factors and disease progression. However, the mechanism by which fatty liver disease arises from concomitant obesity and overconsumption of alcohol (syndrome of metabolic and alcohol-associated fatty liver disease; SMAFLD), is not fully understood. Methods Male C57BL6/J mice were fed chow diet (Chow) or high-fructose, high-fat, high-cholesterol diet (FFC) for 4 weeks, then administered either saline or ethanol (EtOH, 5% in drinking water) for another 12 weeks. The EtOH treatment also consisted of a weekly 2.5 g EtOH/kg body weight gavage. Markers for lipid regulation, oxidative stress, inflammation, and fibrosis were measured by RT-qPCR, RNA-seq, Western blot, and metabolomics. Results Combined FFC-EtOH induced more body weight gain, glucose intolerance, steatosis, and hepatomegaly compared to Chow, EtOH, or FFC. Glucose intolerance by FFC-EtOH was associated with decreased hepatic protein kinase B (AKT) protein expression and increased gluconeogenic gene expression. FFC-EtOH increased hepatic triglyceride and ceramide levels, plasma leptin levels, hepatic Perilipin 2 protein expression, and decreased lipolytic gene expression. FFC and FFC-EtOH also increased AMP-activated protein kinase (AMPK) activation. Finally, FFC-EtOH enriched the hepatic transcriptome for genes involved in immune response and lipid metabolism. Conclusions In our model of early SMAFLD, we observed that the combination of an obesogenic diet and alcohol caused more weight gain, promoted glucose intolerance, and contributed to steatosis by dysregulating leptin/AMPK signaling. Our model demonstrates that the combination of an obesogenic diet with a chronic-binge pattern alcohol intake is worse than either insult alone.

show abstract

Section: Resultsmentioning

confidence: 99%

Concomitant western diet and chronic-binge alcohol dysregulate hepatic metabolism

et al. 2023

View full text Add to dashboard Cite

show abstract

“…Similarly, exosomal miR-1247-3p derived from high-metastatic HCC cells (HMHs) in the lung metastatic niche reportedly triggered and stimulated β1-integrin/NF-κB signaling pathway in fibroblasts by directly targeting beta 1,4-galactosyltransferase, polypeptide 3 (B4GALT3) and activated CAFs in turn accelerated the development of HCC via producing IL-6 and IL-8 ( 77 ). A recent study reported that the palmitoylation of hexokinase 1 (HK1) is induced in HSCs after stimulated by TGF-β, thus more HK1 is secreted by forming large extracellular vesicles, which can be absorbed by HCC cells, causing enhanced glycolysis and HCC development ( 78 ).…”

Section: The Roles Of Cafs or Hscs In Cellular Crosstalkmentioning

confidence: 99%

A key driver to promote HCC: Cellular crosstalk in tumor microenvironment

et al. 2023

View full text Add to dashboard Cite

Liver cancer is the third greatest cause of cancer-related mortality, which of the major pathological type is hepatocellular carcinoma (HCC) accounting for more than 90%. HCC is characterized by high mortality and is predisposed to metastasis and relapse, leading to a low five-year survival rate and poor clinical prognosis. Numerous crosstalk among tumor parenchymal cells, anti-tumor cells, stroma cells, and immunosuppressive cells contributes to the immunosuppressive tumor microenvironment (TME), in which the function and frequency of anti-tumor cells are reduced with that of associated pro-tumor cells increasing, accordingly resulting in tumor malignant progression. Indeed, sorting out and understanding the signaling pathways and molecular mechanisms of cellular crosstalk in TME is crucial to discover more key targets and specific biomarkers, so that develop more efficient methods for early diagnosis and individualized treatment of liver cancer. This piece of writing offers insight into the recent advances in HCC-TME and reviews various mechanisms that promote HCC malignant progression from the perspective of mutual crosstalk among different types of cells in TME, aiming to assist in identifying the possible research directions and methods in the future for discovering new targets that could prevent HCC malignant progression.

show abstract

“…Inhibition of IRF8 impairs HCC cell progression, which is important for increasing the potential of anti-PD-1 therapy [ 23 ]. The extracellular vesicles derived from hepatic stellate cells are able to secrete HK1 to increase the malignancy of HCC by stimulating glycolysis [ 24 ]. Even more interestingly, dysregulation of molecular signaling pathways may lead to drug resistance in HCC [ 25 ].…”

Section: Introductionmentioning

confidence: 99%

Deciphering STAT3 signaling potential in hepatocellular carcinoma: tumorigenesis, treatment resistance, and pharmacological significance

et al. 2023

View full text Add to dashboard Cite

Hepatocellular carcinoma (HCC) is considered one of the greatest challenges to human life and is the most common form of liver cancer. Treatment of HCC depends on chemotherapy, radiotherapy, surgery, and immunotherapy, all of which have their own drawbacks, and patients may develop resistance to these therapies due to the aggressive behavior of HCC cells. New and effective therapies for HCC can be developed by targeting molecular signaling pathways. The expression of signal transducer and activator of transcription 3 (STAT3) in human cancer cells changes, and during cancer progression, the expression tends to increase. After induction of STAT3 signaling by growth factors and cytokines, STAT3 is phosphorylated and translocated to the nucleus to regulate cancer progression. The concept of the current review revolves around the expression and phosphorylation status of STAT3 in HCC, and studies show that the expression of STAT3 is high during the progression of HCC. This review addresses the function of STAT3 as an oncogenic factor in HCC, as STAT3 is able to prevent apoptosis and thus promote the progression of HCC. Moreover, STAT3 regulates both survival- and death-inducing autophagy in HCC and promotes cancer metastasis by inducing the epithelial–mesenchymal transition (EMT). In addition, upregulation of STAT3 is associated with the occurrence of chemoresistance and radioresistance in HCC. Specifically, non-protein-coding transcripts regulate STAT3 signaling in HCC, and their inhibition by antitumor agents may affect tumor progression. In this review, all these topics are discussed in detail to provide further insight into the role of STAT3 in tumorigenesis, treatment resistance, and pharmacological regulation of HCC. Graphical Abstract

show abstract

HK1 from hepatic stellate cell–derived extracellular vesicles promotes progression of hepatocellular carcinoma

Cited by 59 publications

References 62 publications

Concomitant western diet and chronic-binge alcohol dysregulate hepatic metabolism

Concomitant western diet and chronic-binge alcohol dysregulate hepatic metabolism

A key driver to promote HCC: Cellular crosstalk in tumor microenvironment

Deciphering STAT3 signaling potential in hepatocellular carcinoma: tumorigenesis, treatment resistance, and pharmacological significance

Contact Info

Product

Resources

About