haCER2高表达下调神经酰胺在肝癌中的作用、机制及干预

Most of the patients with liver cancer have poor prognosis, enhancing mechanism study and looking for new thereupeutic methods are imminent. It is reported that interfering ceramide signaling pathway is one of the mechanisms by which cells escape from apoptosis leading tumorigenesis, the metabolism of ceramide that is a lipid acting as inhibiting tumor is closely related to hepatocarcinogenesis. We cloned human alkaline ceramidase 2 (haCER2) that hydrolyzes ceramide leading ceramide level decrease. Literature and our previous work confirmed that haCER2 is upregulated in liver cancer, we also found that the level of ceramide is reduced in liver cancer and liver cancer cells’ growth is inhibited by the inhibition of haCER2. Therefore, we hypothesized that upregulation of haCER2 leading the reduction of ceramide, then inhibiting cell apoptosis leading tumor cell growth, results in hepatocarcinogenesis; conversely, inhibition of haCER2 leading the increase of ceramide is benificial to liver caner treatment. In this project, we will study the role and mechanism of “haCER2-ceramide” in liver cancer at molecular level, cellular level, animal model and human tissue, and observe the therapeutic effect of haCER2 inhibitor D-e-MAPP in cell and animal model of liver cancer.

肝癌预后很差，加强机制研究、探索新的治疗方法迫在眉睫。据报道，通过影响神经酰胺(ceramide, Cer)信号通路是细胞逃逸凋亡、导致肿瘤发生的重要机制之一；Cer是一种肿瘤抑制脂质，其代谢与肝癌的发生密切相关。我们克隆了人类碱性神经酰胺酶2（human alkaline ceramidase 2, haCER2），发现haCER2能水解Cer导致其水平下降。文献报道和我们前期工作证明haCER2在肝癌中高表达，我们还发现肝癌中Cer水平下降，抑制haCER2能抑制肝癌细胞生长。因此我们假设：haCER2高表达引起Cer下降抑制凋亡、促进癌细胞生长，导致肝癌形成；反之，抑制haCER2表达、增加Cer水平有助于肝癌治疗。我们将在细胞和分子水平、动物实验以及人组织标本上研究“haCER2-Cer”与肝癌的关系及机制，在细胞和动物模型上观察haCER2抑制剂D-e-MAPP治疗肝癌的效果。

肝癌预后很差，加强机制研究、探索新的治疗方法迫在眉睫。据报道，通过影响神经酰胺（ceramide, Cer）信号通路是细胞逃逸凋亡、导致肿瘤发生的重要机制之一；Cer是一种肿瘤抑制脂质，其代谢与肝癌的发生密切相关。我们克隆了人类碱性神经酰胺酶2（human alkaline ceramidase 2, haCER2，又称ACER2），发现haCER2（ACER2）能水解Cer导致其水平下降。文献报道和我们前期工作证明haCER2在肝癌中高表达，我们还发现肝癌中Cer水平下降，抑制haCER2能抑制肝癌细胞生长。因此我们假设：haCER2高表达引起Cer下降抑制凋亡、促进癌细胞生长，导致肝癌形成；反之，抑制haCER2表达、增加Cer水平有助于肝癌治疗。本研究拟在细胞和分子水平、动物实验以及人组织标本上研究“haCER2-Cer”与肝癌的关系及机制，在细胞和动物模型上观察haCER2抑制剂D-e-MAPP治疗肝癌的效果。我们的研究结果发现ACER2在肝癌中上调，ACER2通过SMPDL3B（酸性神经鞘磷脂酶样磷酸二酯酶3B）促进肝癌细胞的增殖、侵袭和迁移，ACER2/SMPDL3B轴影响肝癌细胞的存活；细胞和动物模型证明haCER2抑制剂D-e-MAPP具有治疗肝癌的效果，ACER2/SMPDL3B轴可能是肝癌的新型治疗靶标。