Romidepsin hepatocellular carcinoma suppression in mice is associated with deregulated gene expression of bone morphogenetic protein and Notch signaling pathway components.
Recently, our group showed that Romidepsin, a histone deacetylase inhibitor (HDACi), suppressed diethylnitrosamine (DEN)-induced hepatocellular carcinoma (HCC) in mice. In the present study, we investigated the effect of Romidepsin-treatment on gene expression levels of components of Bmp and Notch signaling pathways, which are both known to be aberrantly regulated in hepatocarcinogenesis. Total RNA from liver tissue samples and paraffin-embedded livers were retrieved from a recent experiment where C57BL/6 mice were treated with Romidepsin 10 months after DEN challenge and sacrificed 2 months later. RT qPCR was used for quantification of gene expression and immunohistochemistry for in situ protein detection. Regarding Bmp pathway, Romidepsin HCC-suppression was found to correlate significantly with Bmp2 and Bmp7 ligand up- and down-regulation, respectively. Intracellularly, Romidepsin-treated HCC mice exhibited a significant elevation of Bmp-inhibitor Smurf2 and Bmp-target gene Id3, as compared to the HCC untreated controls. Concerning Notch signaling, higher expression levels of ligands Jag1/Dll4, accompanied by a decreased expression of receptor Notch2, were identified in the Romidepsin-treated group. Τhe anti-oncogenic effect of Romidepsin, also correlated significantly with an increased expression of Hes1 target, as well as an up- and down-regulation of Klf4 and Sox9 transcription factors, respectively. Moreover, the cancer-related genes Snai2 and p21, known to be involved in many signaling pathways, including Bmp and Notch, were also found to be downregulated in Romidepsin-treated mice. Romidepsin HCC suppression is associated with gene expression deregulation of selective components of both Bmp and Notch signaling cascades.
['Afaloniati|Hara|H|', 'Poutahidis|Theofilos|T|', 'Giakoustidis|Alexander|A|', 'Gargavanis|Athanasios|A|', 'Giakoustidis|Dimitrios|D|', 'Angelopoulou|Katerina|K|http://orcid.org/0000-0003-2566-4762']
D000818:Animals D055396:Bone Morphogenetic Protein 2 D055419:Bone Morphogenetic Protein 7 D006528:Carcinoma, Hepatocellular D045744:Cell Line, Tumor D049109:Cell Proliferation D047630:Depsipeptides D004052:Diethylnitrosamine D004195:Disease Models, Animal D015972:Gene Expression Regulation, Neoplastic D056572:Histone Deacetylase Inhibitors D006801:Humans D000090062:Kruppel-Like Factor 4 D008113:Liver Neoplasms D051379:Mice D008810:Mice, Inbred C57BL D051883:Receptor, Notch2 D015398:Signal Transduction
Romidepsin Notch Histone deacetylase inhibitors (HDACi) Hepatocellular carcinoma (HCC) Bone morphogenetic proteins (Bmp) Diethylnitrosamine (DEN)