Afaloniati Hara, Angelopoulou Katerina, Giakoustidis Alexander, Hardas Alexandros, Pseftogas Athanasios, Makedou Kali, Gargavanis Athanasios, Goulopoulos Thomas, Iliadis Stavros, Papadopoulos Vasileios, Papalois Apostolos, Mosialos George, Poutahidis Theofilos, Giakoustidis Dimitrios
Laboratory of Biochemistry and Toxicology, School of Veterinary Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece.
First Department of Surgery, Medical School, Aristotle University of Thessaloniki, General Hospital Papageorgiou, Thessaloniki, Greece.
Onco Targets Ther. 2020 Jun 15;13:5575-5588. doi: 10.2147/OTT.S250233. eCollection 2020.
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.
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.
Romidepsin suppressed cancer progression. This effect was associated with decreased proliferation and increased apoptosis of cancer cells. The cell cycle regulator , 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.
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.
肝细胞癌（HCC）是一种常见的诊断癌症，也是全球癌症相关死亡的主要原因。其快速进展，加上晚期治疗选择有限，使得早期检测和积极干预成为必要。基于肝癌发生受组蛋白乙酰化显著影响的认识，我们在组蛋白去乙酰化抑制剂（HDACi）中寻找新型HCC治疗药物。本研究的目的是在二乙基亚硝胺（DEN）诱导的HCC成熟小鼠模型中研究HDAC1/2抑制剂罗米地辛的作用。
C56BL/6小鼠在DEN攻击后10个月的关键时间点用罗米地辛治疗，2个月后使用组织病理学和形态计量学检查其肝脏。使用ELISA评估血清中的蛋白质水平，使用蛋白质免疫印迹和免疫组织化学（原位检测）评估肝组织中的蛋白质水平。使用实时PCR定量基因表达。
罗米地辛抑制癌症进展。这种作用与癌细胞增殖减少和凋亡增加有关。在治疗的HCC中，细胞周期调节因子、抗炎分子PPAR-γ以及肿瘤抑制因子PTEN和CYLD上调。相比之下，PI3K、NF-κB p65和c-Jun的表达降低。与该结果一致，与未治疗的HCC小鼠相比，治疗小鼠血清中两种主要凋亡调节因子BAD和多功能蛋白c-Met的水平较低。
这些发现表明，罗米地辛这种目前用于治疗淋巴瘤的药物，也可考虑用于早期HCC的治疗。
