EMT and Inflammation: Crossroads in HCC

Sengez, Burcu; Carr, Brian I.; Alotaibi, Hani

doi:10.1007/s12029-021-00801-z

Cited by 13 publications

(8 citation statements)

References 133 publications

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“…It is this broad spectrum of actions that positions HBx as a key factor in the malignancy of HCC and a potential prognostic indicator and therapeutic target for HBV-HCC [24]. In agreement with the overarching concept of EMT being a crucial step in tumor invasion and metastasis, our research reiterates that tumor cells achieve enhanced invasion and metastasis capabilities through the EMT process [25], with HBx mediating this process in HCC cells. This was illustrated by the notable elevation in E-cadherin content post-HBx knockdown, with a concurrent reduction in N-cadherin, Vimentin, Slug, and Snail content, indicating the potential of HBx knockout in modulating cellular multiplication by attenuating the EMT process of HCC cells.…”

Section: Discussionsupporting

confidence: 78%

HBx Modulates Drug Resistance of Sorafenib-Resistant Hepatocellular Carcinoma Cells

Liu,

Luo

et al. 2023

Discovery Medicine

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Background: Approximately 50% of hepatocellular carcinoma (HCC) arises due to the infection by hepatitis B virus X protein (HBx). Sorafenib, a unique targeted oral kinase inhibitor, is the therapeutic agent of choice for advanced HCC. The mechanism of HBx in drug resistance of sorafenib-resistant HCC cells was evaluated in this study. Methods: Employing a stepwise increase of the sorafenib content, Hep3B and HepG2 cells were iteratively induced to establish drug-resistant cell lines (Hep3B/R and HepG2/R). The survival rate of Hep3B, Hep3B/R, HepG2, and HepG2/R cells was estimated using the cell counting kit-8 (CCK-8) assay. The IC50 values of sorafenib were calculated, exploring its effects under varying concentrations. The HBx content was quantified via quantitative reverse transcription PCR (RT-qPCR) and Western Blot. HBx overexpression and interfering virus vectors were constructed and transfected into Hep3B/R and HepG2/R cells. Cell viability and metastasis were assessed by colony formation, wound healing, and transwell assays. E-cadherin, N-cadherin, Vimentin, Slug, and Snail content was evaluated via Western Blot. Results: HBx content was significantly elevated in Hep3B/R and HepG2/R subgroups compared to Hep3B and HepG2 subgroups. The proliferation, clonogenicity, invasiveness, and migratory abilities of Hep3B/R and HepG2/R cells in the HBx subgroup were markedly enhanced; E-cadherin content was significantly reduced, whereas the content of N-cadherin, Vimentin, Slug, and Snail was significantly elevated in the HBx subgroup. Conversely, in the sh-HBx subgroup, the proliferation, clonogenicity, invasion, and migration of Hep3B/R and HepG2/R cells were significantly reduced, E-cadherin content was markedly increased, and Ncadherin, Vimentin, Slug, and Snail content was significantly reduced, compared to the sh-negative control (NC) subgroup. Conclusions: HBx knockout may affect the development of HCC by reducing the proliferation, invasion, and migration of Hep3B/R and HepG2/R cells through the inhibition of Epithelial-Mesenchymal Transition (EMT).

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Section: Discussionsupporting

confidence: 78%

HBx Modulates Drug Resistance of Sorafenib-Resistant Hepatocellular Carcinoma Cells

Liu,

Luo

et al. 2023

Discovery Medicine

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“…It has been reported that miR-223 inhibits liver inflammation by attenuating the NLRP3 inflammasome,11 12 the NF-κB pathway,13 CXCL1014 and so on. Given myeloid cells are enriched in human HCC,3–8 we speculate that myeloid-enriched miR-223 may play a critical role in regulating tumour microenvironment and modulating HCC progression, but its exact role remains unknown. MiR-223 levels were reported to be significantly decreased in HCC tissues15 and in the plasma from patients with HCC 16.…”

Section: Introductionmentioning

confidence: 99%

“…To develop such therapies, we need to better understand HCC tumour microenvironment. The majority of HCC develops post chronic liver injury and inflammation from different aetiologies, including viral hepatitis, alcohol-associated liver disease and non-alcoholic fatty liver disease 3 4. Chronic liver inflammation is strongly associated with intrahepatic infiltration of myeloid cells such as macrophages and neutrophils,3–8 however, how myeloid cells regulate tumour microenvironment and HCC progression is still poorly understood.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-223 attenuates hepatocarcinogenesis by blocking hypoxia-driven angiogenesis and immunosuppression

Mackowiak

Feng

et al. 2023

Gut

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ObjectiveThe current treatment for hepatocellular carcinoma (HCC) to block angiogenesis and immunosuppression provides some benefits only for a subset of patients with HCC, thus optimised therapeutic regimens are unmet needs, which require a thorough understanding of the underlying mechanisms by which tumour cells orchestrate an inflamed tumour microenvironment with significant myeloid cell infiltration. MicroRNA-223 (miR-223) is highly expressed in myeloid cells but its role in regulating tumour microenvironment remains unknown.DesignWild-type and miR-223 knockout mice were subjected to two mouse models of inflammation-associated HCC induced by injection of diethylnitrosamine (DEN) or orthotopic HCC cell implantation in chronic carbon tetrachloride (CCl4)-treated mice.ResultsGenetic deletion of miR-223 markedly exacerbated tumourigenesis in inflammation-associated HCC. Compared with wild-type mice, miR-223 knockout mice had more infiltrated programmed cell death 1 (PD-1+) T cells and programmed cell death ligand 1 (PD-L1+) macrophages after DEN+CCl4administration. Bioinformatic analyses of RNA sequencing data revealed a strong correlation between miR-223 levels and tumour hypoxia, a condition that is well-documented to regulate PD-1/PD-L1. In vivo and in vitro mechanistic studies demonstrated that miR-223 did not directly target PD-1 and PD-L1 in immune cells rather than indirectly downregulated them by modulating tumour microenvironment via the suppression of hypoxia-inducible factor 1α-driven CD39/CD73-adenosine pathway in HCC. Moreover, gene delivery of miR-223 via adenovirus inhibited angiogenesis and hypoxia-mediated PD-1/PD-L1 activation in both HCC models, thereby hindering HCC progression.ConclusionThe miR-223 plays a critical role in modulating hypoxia-induced tumour immunosuppression and angiogenesis, which may serve as a novel therapeutic target for HCC.

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“… 33 , 34 EMT is also widely considered a reversible physiological process for oncogenesis that mediates the aggressive features in the invasion and migration of neoplastic malignancies. 35 This process can be assessed based on the expression levels of several additional EMT-associated molecular markers, which are independent of cancer type and site. 34 , 36 Here, we demonstrated that low levels of ARFIP2 inhibit the invasion and migration of HepG2 cells, which suggests that ARFIP2 may promote EMT ( Figure 2D and E ).…”

Section: Discussionmentioning

confidence: 99%

ARFIP2 Regulates EMT and Autophagy in Hepatocellular Carcinoma in Part Through the PI3K/Akt Signalling Pathway

Huang¹,

Lin²,

Wang³

et al. 2022

JHC

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ARFIP2, a canonical BAR domain-containing protein, is closely associated with regulating cargo exit from the Golgi. However, the potential biological functions of ARFIP2 in hepatocellular carcinoma (HCC) have not been well investigated. This study aimed to explore the critical role of ARFIP2 in HCC cells. Methods: The expression of proteins related to epithelial to mesenchymal transition (EMT) and cell autophagy in HCC cells and tissues was assayed by quantitative real-time PCR, Western blotting, immunohistochemistry and immunofluorescence staining. The ability of cells to proliferate, migrate and invade was detected by Cell Counting Kit-8, Transwell migration and invasion assays. In addition, the function of ARFIP2 in vivo was assessed using a tumour xenograft model. Results: ARFIP2 expression is significantly upregulated in early recurrent and metastatic HCC patients and was positively correlated with a poor prognosis. ARFIP2 overexpression promoted cell proliferation, migration, and invasion by inducing EMT and inhibiting autophagy in vitro. Furthermore, the regulatory effects of ARFIP2 on autophagy and EMT were partially attributed to its regulation of the PI3K/AKT signalling pathway. The in vivo results also showed that ARFIP2 modulates HCC progression. Conclusion:Our results substantiate a novel mechanism by which ARFIP2 can regulate the activity/phosphorylation of Akt to promote EMT and inhibit autophagy in part via the PI3K/Akt signalling pathway. The ARFIP2/PI3K/Akt axis may be a potential diagnostic biomarker and therapeutic target for HCC.

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EMT and Inflammation: Crossroads in HCC

Cited by 13 publications

References 133 publications

HBx Modulates Drug Resistance of Sorafenib-Resistant Hepatocellular Carcinoma Cells

HBx Modulates Drug Resistance of Sorafenib-Resistant Hepatocellular Carcinoma Cells

MicroRNA-223 attenuates hepatocarcinogenesis by blocking hypoxia-driven angiogenesis and immunosuppression

ARFIP2 Regulates EMT and Autophagy in Hepatocellular Carcinoma in Part Through the PI3K/Akt Signalling Pathway

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