Effects of Wnt‑1 blockade in DEN‑induced hepatocellular adenomas of mice

Sklavos, A.; Poutahidis, Theofilos; Giakoustidis, Alexandros; Makedou, Kali; Angelopoulou, Katerina; Hardas, Alexandros; Andreani, P.; Zacharioudaki, Argyro; Saridis, George; Goulopoulos, Thomas; Tsarea, Kalliopi; Karamperi, Maria; Papadopoulos, V. N.; Papanikolaou, Vasilis K.; Papalois, Αpostolos; Iliadis, Stavros; Mudan, Satvinder; Azoulay, Daniel; Giakoustidis, Dimitrios

doi:10.3892/ol.2017.7427

Cited by 7 publications

(9 citation statements)

References 49 publications

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“…HDACi were shown to play a crucial role in cancer progression through regulation of cell proliferation and apoptosis. 33 Although apoptosis has been reported to be a rare event in early HCC lesions in mouse, 29,30 in our study despite the low number of apoptotic cells, morphometric analysis revealed a significant increase of Caspase-3-positive (apoptotic) neoplastic cells in Romidepsin-treated HCC mice, as compared to their non-treated counterparts, which supports a role of Romidepsin in promoting apoptosis. 23 This was further strengthened by the significant elevation of BAD, a major apoptosis regulator, detected in serum of Romidepsin-treated mice, as compared to the HCC untreated controls.…”

Section: Discussionsupporting

confidence: 70%

“…With Caspase-3-specific IHC we first found that apoptotic cells in HCC lesions are particularly scarce, which matches our previous observations in DEN-induced early hepatocellular carcinogenesis. 29,30 Notably, morphometric counts of Caspase-3-positive cancer cells suggested that HDAC1/2 inhibition upregulates apoptosis in HCC at statistically significant levels (Figure 2). Likewise, using the proliferation marker Ki-67, we found that HCC tumors of Romidepsin-treated mice contained significantly less Ki-67-positive cancer cells compared to their untreated counterparts (Figure 2A).…”

Section: Hdac1/2 Inhibition Affects Apoptosis and Proliferation Of Hcc Cellsmentioning

confidence: 99%

“…In our previous research, we used a DEN mouse model of HCC, which at 10 months after carcinogen challenge, consistently presented with multiple hepatocellular adenomas. 29,30 The same mouse model was used here to evaluate the effect of HDAC blockade on HCC evolution and growth. For that, we treated mice with the HDAC1/2 inhibitor Romidepsin at the critical point of 10 months after DEN challenge and examined their livers 2 months later.…”

Section: Inhibition Of Hdac1/2 Reduces Den-induced Hepatocellular Cancermentioning

confidence: 99%

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<p>HDAC1/2 Inhibitor Romidepsin Suppresses DEN-Induced Hepatocellular Carcinogenesis in Mice</p>

Afaloniati

Angelopoulou

Giakoustidis

et al. 2020

OTT

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Background: Hepatocellular carcinoma (HCC) is a frequently diagnosed cancer and a leading cause of cancer-related death worldwide. Its rapid progression, combined with the limited treatment options at late stages, imposes the need for early detection and aggressive intervention. Based on the knowledge that hepatocarcinogenesis is significantly influenced by histone acetylation, we directed our search for novel HCC therapeutics among histone deacetylation inhibitors (HDACi). The aim of the present study was to investigate the effect of HDAC1/2 inhibitor Romidepsin in the well-established mouse model of diethylnitrosamine (DEN)-induced HCC. Materials and Methods: C56BL/6 mice were treated with Romidepsin at the critical point of 10 months after DEN challenge and their livers were examined 2 months later using histopathology and morphometry. Protein levels were assessed in serum using ELISA and in liver tissues using Western blot and immunohistochemistry (in-situ detection). Gene expression was quantified using real-time PCR. Results: Romidepsin suppressed cancer progression. This effect was associated with decreased proliferation and increased apoptosis of cancer cells. The cell cycle regulator CK2a, the anti-inflammatory molecule PPAR-γ, and the tumor suppressors PTEN and CYLD were upregulated in treated HCC. By contrast, the expression of PI3K, NF-κB p65 and c-Jun was reduced. In line with this result, the levels of two major apoptosis regulators, ie, BAD and the multifunctional protein c-Met, were lower in the blood serum of treated mice compared to the untreated mice with HCC. Conclusion: These findings suggest that Romidepsin, a drug currently used in the treatment of lymphoma, could also be considered in the management of early-stage HCC.

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Section: Discussionsupporting

confidence: 70%

Section: Hdac1/2 Inhibition Affects Apoptosis and Proliferation Of Hcc Cellsmentioning

confidence: 99%

Section: Inhibition Of Hdac1/2 Reduces Den-induced Hepatocellular Cancermentioning

confidence: 99%

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<p>HDAC1/2 Inhibitor Romidepsin Suppresses DEN-Induced Hepatocellular Carcinogenesis in Mice</p>

Afaloniati

Angelopoulou

Giakoustidis

et al. 2020

OTT

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“…An anti-Wnt1-antibody has been found to inhibit Wnt/β-catenin signaling and tumor growth in a xenograft mouse model (Wei et al, 2009). In contrast, anti-Wnt1 suppressed proliferation and apoptosis, but did not affect tumor size and growth in diethylnitrosamine-induced hepatocellular adenomas (Sklavos et al, 2018). Interestingly, garlic-derived compound S-allylmercaptocysteine reduced HCC tumorigenesis by directly targeting Lrp6 at the plasma membrane (Xiao et al, 2018).…”

Section: Liver Cancermentioning

confidence: 99%

Regulation of Wnt Signaling Pathways at the Plasma Membrane and Their Misregulation in Cancer

Azbazdar

Karabicici

Erdal

et al. 2021

Front. Cell Dev. Biol.

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Wnt signaling is one of the key signaling pathways that govern numerous physiological activities such as growth, differentiation and migration during development and homeostasis. As pathway misregulation has been extensively linked to pathological processes including malignant tumors, a thorough understanding of pathway regulation is essential for development of effective therapeutic approaches. A prominent feature of cancer cells is that they significantly differ from healthy cells with respect to their plasma membrane composition and lipid organization. Here, we review the key role of membrane composition and lipid order in activation of Wnt signaling pathway by tightly regulating formation and interactions of the Wnt-receptor complex. We also discuss in detail how plasma membrane components, in particular the ligands, (co)receptors and extracellular or membrane-bound modulators, of Wnt pathways are affected in lung, colorectal, liver and breast cancers that have been associated with abnormal activation of Wnt signaling. Wnt-receptor complex components and their modulators are frequently misexpressed in these cancers and this appears to correlate with metastasis and cancer progression. Thus, composition and organization of the plasma membrane can be exploited to develop new anticancer drugs that are targeted in a highly specific manner to the Wnt-receptor complex, rendering a more effective therapeutic outcome possible.

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“…HCC model was induced by intraperitoneal (i.p.) injection with one dose of DEN (Sigma-Aldrich, St. Louis, MO) at 20 mg·kg -1 body weight, while the normal mice received an equivalent volume of sterilized saline instead 17 . After 40 weeks, all mice were performed euthanasia sacrificed after collecting blood.…”

Section: Methodsmentioning

confidence: 99%

β-arrestin2 regulating β2-adrenergic receptor signaling in hepatic stellate cells contributes to hepatocellular carcinoma progression

Li¹,

Peng²,

Shan³

et al. 2021

J. Cancer

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Background: β-arrestin2 and β2-adrenergic receptor (β2-AR) have important roles in malignant tumors, the present study aims to investigate the role of activated β2-AR in hepatic stellate cells (HSCs) during hepatocellular carcinoma (HCC) progression and the regulatory effect of β-arrestin2. Methods: Immunofluorescence and Western blot were used to detect the expression of β-arrestin2 and β2-AR in HSCs of liver tissues from human HCC samples and diethylnitrosamine (DEN)-induced HCC model mice. We next used β-arrestin2 -/- mice to demonstrate the regulatory role of β-arrestin2 in DEN mice. The subsets of T cells were quantified by flow cytometry. MTT and wound healing assay were applied to detect the proliferation and migration of cells. Co-immunoprecipitation assay was used to detect the link of β-arrestin2 and β2-AR in HSCs. Effect of β-arrestin2 overexpression on β2-AR downstream signaling pathway was verified by Western blot. The secretion of CCL2 was detected by ELISA. Results: The expression of β2-AR was significantly increased, while β-arrestin2 was decreased in HSCs of HCC tissues. And β-arrestin2 deficiency exacerbates DEN-induced HCC accompanied with increased β2-AR expression. The results of flow cytometry showed that the percentage of activated T cells decreased gradually after DEN injection. β-arrestin2 knockout down-regulated the ratio of activated T cells. In vitro , selective activation of β2-AR in HSCs promoted the proliferation and migration of HCC cells. β-arrestin2 overexpression enhanced co-immunoprecipitation of β-arrestin2 and β2-AR in activated HSCs, and decreased its downstream Akt phosphorylation. Akt inhibitor decreased secretion of CCL2 in activated HSCs. Conclusion: Our study demonstrated that β2-AR activation in HSCs induces the proliferation and migration of HCC cells may be through Akt signaling, and this effect appears to be regulated by β-arrestin2.

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Effects of Wnt‑1 blockade in DEN‑induced hepatocellular adenomas of mice

Cited by 7 publications

References 49 publications

<p>HDAC1/2 Inhibitor Romidepsin Suppresses DEN-Induced Hepatocellular Carcinogenesis in Mice</p>

<p>HDAC1/2 Inhibitor Romidepsin Suppresses DEN-Induced Hepatocellular Carcinogenesis in Mice</p>

Regulation of Wnt Signaling Pathways at the Plasma Membrane and Their Misregulation in Cancer

β-arrestin2 regulating β2-adrenergic receptor signaling in hepatic stellate cells contributes to hepatocellular carcinoma progression

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