Su Ting, Qin Xian-Yang, Dohmae Naoshi, Wei Feifei, Furutani Yutaka, Kojima Soichi, Yu Wenkui
Department of Intensive Care Unit, The Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing 210008, China.
Liver Cancer Prevention Research Unit, RIKEN Cluster for Pioneering Research, Wako, Saitama 351-0198, Japan.
Metabolites. 2021 Mar 15;11(3):167. doi: 10.3390/metabo11030167.
The incidence and mortality of liver cancer, mostly hepatocellular carcinoma (HCC), have increased during the last two decades, partly due to persistent inflammation in the lipid-rich microenvironment associated with lifestyle diseases, such as obesity. Gangliosides are sialic acid-containing glycosphingolipids known to be important in the organization of the membrane and membrane protein-mediated signal transduction. Ganglioside synthesis is increased in several types of cancers and has been proposed as a promising target for cancer therapy. Here, we provide evidence that ganglioside synthesis was increased in the livers of an animal model recapitulating the features of activation and expansion of liver progenitor-like cells and liver cancer (stem) cells. Chemical inhibition of ganglioside synthesis functionally suppressed proliferation and sphere growth of liver cancer cells, but had no impact on apoptotic and necrotic cell death. Proteome-based mechanistic analysis revealed that inhibition of ganglioside synthesis downregulated the expression of AURKA, AURKB, TTK, and NDC80 involved in the regulation of kinetochore metaphase signaling, which is essential for chromosome segregation and mitotic progression and probably under the control of activation of TP53-dependent cell cycle arrest. These data suggest that targeting ganglioside synthesis holds promise for the development of novel preventive/therapeutic strategies for HCC treatment.
在过去二十年中，肝癌（主要是肝细胞癌，HCC）的发病率和死亡率有所上升，部分原因是与肥胖等生活方式疾病相关的富含脂质的微环境中存在持续性炎症。神经节苷脂是含唾液酸的糖鞘脂，已知在细胞膜组织和膜蛋白介导的信号转导中起重要作用。神经节苷脂合成在几种类型的癌症中增加，并已被提议作为癌症治疗的一个有前景的靶点。在这里，我们提供证据表明，在一个再现肝祖细胞样细胞和肝癌（干）细胞激活和扩增特征的动物模型的肝脏中，神经节苷脂合成增加。化学抑制神经节苷脂合成在功能上抑制了肝癌细胞的增殖和球体生长，但对凋亡和坏死性细胞死亡没有影响。基于蛋白质组的机制分析表明，抑制神经节苷脂合成会下调参与动粒中期信号调节的AURKA、AURKB、TTK和NDC80的表达，而动粒中期信号对于染色体分离和有丝分裂进程至关重要，并且可能受TP53依赖性细胞周期停滞激活的控制。这些数据表明，靶向神经节苷脂合成有望为肝癌治疗开发新的预防/治疗策略。
