Mu Haixi, Wang Na, Zhao Lijuan, Li Shuman, Li Qianqian, Chen Ling, Luo Xinrong, Qiu Zhu, Li Lili, Ren Guosheng, Xu Yongzhu, Zhou Xiangyang, Xiang Tingxiu
Molecular Oncology and Epigenetics Laboratory, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China; Department of Endocrine and breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
Molecular Oncology and Epigenetics Laboratory, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Exp Cell Res. 2015 Mar 15;332(2):179-89. doi: 10.1016/j.yexcr.2015.01.017. Epub 2015 Feb 2.
Our previous study showed that PLCD1 significantly decreases cell proliferation and affects cell cycle progression in breast cancer cells. In the present study, we aimed to investigate its functional and molecular mechanisms, and whether or not can become a new target for gene therapies. We found reduced PLCD1 protein expression in breast tumor tissues compared with paired surgical margin tissues. PLCD1 promoter CpG methylation was detected in 55 of 96 (57%) primary breast tumors, but not in surgical-margin tissues and normal breast tissues. Ectopic expression of PLCD1 inhibited breast tumor cell proliferation in vivo by inducing apoptosis and suppressed tumor cell migration by regulating cytoskeletal reorganization proteins including RhoA and phospho-cofilin. Furthermore, we found that PLCD1 induced p53 accumulation, increased p27 and p21 protein levels, and cleaved PARP. Finally, we constructed an adenoviral vector expressing PLCD1 (AdH5-PLCD1), which exhibited strong cytotoxicity in breast cancer cells. Our findings provide insights into the development of PLCD1 gene therapies for breast cancer and perhaps, other human cancers.
我们之前的研究表明，PLCD1可显著降低乳腺癌细胞的增殖并影响细胞周期进程。在本研究中，我们旨在探究其功能及分子机制，以及它是否能成为基因治疗的新靶点。我们发现，与配对的手术切缘组织相比，乳腺肿瘤组织中PLCD1蛋白表达降低。在96例原发性乳腺肿瘤中有55例（57%）检测到PLCD1启动子CpG甲基化，而手术切缘组织和正常乳腺组织中未检测到。PLCD1的异位表达通过诱导凋亡在体内抑制乳腺肿瘤细胞增殖，并通过调节包括RhoA和磷酸化丝切蛋白在内的细胞骨架重组蛋白来抑制肿瘤细胞迁移。此外，我们发现PLCD1可诱导p53积累，增加p27和p21蛋白水平，并切割PARP。最后，我们构建了一种表达PLCD1的腺病毒载体（AdH5-PLCD1），其在乳腺癌细胞中表现出强大的细胞毒性。我们的研究结果为开发针对乳腺癌以及可能其他人类癌症的PLCD1基因治疗提供了见解。
