Emerging roles of tyrosine kinases in hepatic inflammatory diseases and therapeutic opportunities

Shaker, Mohamed E.; Gomaa, Hesham A.M.; Abdelgawad, Mohamed A.; El-Mesery, Mohamed; Shaaban, Ahmed A.; Hazem, Sara H.

doi:10.1016/j.intimp.2023.110373

Cited by 2 publications

(1 citation statement)

References 181 publications

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“…Based on all this, further research is required to define the resistance mechanisms to EGFR inhibition that operates in HCC. In this sense, EGFR signaling as a driver or modulator of liver inflammation in CLD and cancer [193,194] should be taken into consideration when thinking about EGFR inhibition to combat HCC. A better comprehension of this specific aspect of the EGFR signaling role in liver disease deserves further research.…”

Section: Tyrosine Kinase Receptors: Met and Egfrmentioning

confidence: 99%

New and Old Key Players in Liver Cancer

Cuesta,

Palao,

Bragado

et al. 2023

IJMS

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Liver cancer represents a major health problem worldwide with growing incidence and high mortality, hepatocellular carcinoma (HCC) being the most frequent. Hepatocytes are likely the cellular origin of most HCCs through the accumulation of genetic alterations, although hepatic progenitor cells (HPCs) might also be candidates in specific cases, as discussed here. HCC usually develops in a context of chronic inflammation, fibrosis, and cirrhosis, although the role of fibrosis is controversial. The interplay between hepatocytes, immune cells and hepatic stellate cells is a key issue. This review summarizes critical aspects of the liver tumor microenvironment paying special attention to platelets as new key players, which exert both pro- and anti-tumor effects, determined by specific contexts and a tight regulation of platelet signaling. Additionally, the relevance of specific signaling pathways, mainly HGF/MET, EGFR and TGF-β is discussed. HGF and TGF-β are produced by different liver cells and platelets and regulate not only tumor cell fate but also HPCs, inflammation and fibrosis, these being key players in these processes. The role of C3G/RAPGEF1, required for the proper function of HGF/MET signaling in HCC and HPCs, is highlighted, due to its ability to promote HCC growth and, regulate HPC fate and platelet-mediated actions on liver cancer.

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Section: Tyrosine Kinase Receptors: Met and Egfrmentioning

confidence: 99%

New and Old Key Players in Liver Cancer

Cuesta,

Palao,

Bragado

et al. 2023

IJMS

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Atg5-deficient mesenchymal stem cells protect against non-alcoholic fatty liver by accelerating hepatocyte growth factor secretion

Zhang,

Ji,

et al. 2024

Cell Commun Signal

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Background/aims Mesenchymal stem cells (MSCs) have shown promising therapeutic potential in treating liver diseases, such as non-alcoholic fatty liver disease (NAFLD). Genetic modification has been employed to enhance the characteristics of MSCs for more effective disease treatment. Here, we present findings on human adipose-derived MSCs with Atg5 deficiency, investigating their therapeutic impact and the associated mechanisms in NAFLD. Methods In vitro, lentiviral transduction was employed to downregulate Atg5 or HGF in human adipose-derived MSCs using short hairpin RNA (shRNA). Subsequently, experiments were conducted to evaluate cell senescence, proliferation, cell cycle, apoptosis, and other pertinent aspects. In vivo, a non-alcoholic fatty liver mouse model was established by feeding them a high-fat diet (HFD), and the effects of MSCs transplantation were assessed through serological, biochemical, and pathological analyses. Results Our research findings indicate that Atg5-deficient MSCs display heightened proliferative activity. Subsequent co-culturing of MSCs with hepatocytes and the transplantation of Atg5-deficient MSCs into NAFLD mouse models demonstrated their ability to effectively reduce lipid accumulation in the NAFLD disease model by modulating the AMPKα/mTOR/S6K/Srebp1 pathway. Furthermore, we observed that Atg5 deficiency enhances the secretion of hepatocyte growth factor (HGF) by promoting recycling endosome (RE) production. Lastly, our study revealed that 3-MA-primed MSCs can improve the characteristics of NAFLD by boosting the secretion of HGF. Conclusions Our research findings suggest that Atg5-deficient MSCs protect against NAFLD by accelerating HGF secretion. This indicates that Atg5 gene-modified MSCs may represent a promising strategy for treating NAFLD. Supplementary Information The online version contains supplementary material available at 10.1186/s12964-024-01950-x.

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Emerging roles of tyrosine kinases in hepatic inflammatory diseases and therapeutic opportunities

Cited by 2 publications

References 181 publications

New and Old Key Players in Liver Cancer

New and Old Key Players in Liver Cancer

Atg5-deficient mesenchymal stem cells protect against non-alcoholic fatty liver by accelerating hepatocyte growth factor secretion

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