Xiao Junjie, Sun Qi, Bei Yihua, Zhang Ling, Dimitrova-Shumkovska Jasmina, Lv Dongchao, Yang Yuefeng, Cao Yan, Zhao Yingying, Song Meiyi, Song Yang, Wang Fei, Yang Changqing
Regeneration and Ageing Lab, Experimental Centre of Life Sciences, School of Life Science, Shanghai University, Shanghai 200444, China
Regeneration and Ageing Lab, Experimental Centre of Life Sciences, School of Life Science, Shanghai University, Shanghai 200444, China.
Clin Sci (Lond). 2016 Jul 1;130(13):1125-36. doi: 10.1042/CS20160087. Epub 2016 Apr 13.
Hepatocellular carcinoma (HCC) represents a leading cause of deaths worldwide. Novel therapeutic targets for HCC are needed. Phospholipase D (PD) is involved in cell proliferation and migration, but its role in HCC remains unclear. In the present study, we show that PLD1, but not PLD2, was overexpressed in HCC cell lines (HepG2, Bel-7402 and Bel-7404) compared with the normal human L-02 hepatocytes. PLD1 was required for the proliferation, migration and invasion of HCC cells without affecting apoptosis and necrosis, and PLD1 overexpression was sufficient to promote those effects. By using HCC xenograft models, we demonstrated that therapeutic inhibition of PLD1 attenuated tumour growth and epithelial-mesenchymal transition (EMT) in HCC mice. Moreover, PLD1 was found to be highly expressed in tumour tissues of HCC patients. Finally, mTOR (mechanistic target of rapamycin) and Akt (protein kinase B) were identified as critical pathways responsible for the role of PLD1 in HCC cells. Taken together, the present study indicates that PLD1 activation contributes to HCC development via regulation of the proliferation, migration and invasion of HCC cells, as well as promoting the EMT process. These observations suggest that inhibition of PLD1 represents an attractive and novel therapeutic modality for HCC.
肝细胞癌（HCC）是全球主要的死亡原因之一。需要针对HCC的新型治疗靶点。磷脂酶D（PD）参与细胞增殖和迁移，但其在HCC中的作用仍不清楚。在本研究中，我们发现与正常人L-02肝细胞相比，PLD1而非PLD2在HCC细胞系（HepG2、Bel-7402和Bel-7404）中过表达。PLD1是HCC细胞增殖、迁移和侵袭所必需的，且不影响细胞凋亡和坏死，PLD1过表达足以促进这些效应。通过使用HCC异种移植模型，我们证明对PLD1的治疗性抑制可减弱HCC小鼠的肿瘤生长和上皮-间质转化（EMT）。此外，发现PLD1在HCC患者的肿瘤组织中高表达。最后，mTOR（雷帕霉素作用靶点）和Akt（蛋白激酶B）被确定为PLD1在HCC细胞中发挥作用的关键信号通路。综上所述，本研究表明PLD1激活通过调节HCC细胞的增殖、迁移和侵袭以及促进EMT过程，从而促进HCC的发展。这些观察结果表明，抑制PLD1是一种有吸引力的新型HCC治疗方式。
