Department of Respiratory Medicine, Jinling Hospital, Southern Medical University, Nanjing, China.
Intensive Care Unit, Inner Mongolia People's Hospital, Hohhot, China.
J Cell Mol Med. 2018 Apr;22(4):2177-2189. doi: 10.1111/jcmm.13493. Epub 2018 Jan 29.
This study aimed to evaluate the biological role of geranylgeranyl diphosphate synthase (GGPPS) in the progression of lung adenocarcinoma. GGPPS expression was detected in lung adenocarcinoma tissues by qRT-PCR, tissue microarray (TMA) and western blotting. The relationships between GGPPS expression and the clinicopathological characteristics and prognosis of lung adenocarcinoma patients were assessed. GGPPS was down-regulated in SPCA-1, PC9 and A549 cells using siRNA and up-regulated in A549 cells using an adenoviral vector. The biological roles of GGPPS in cell proliferation, apoptosis, migration and invasion were determined by MTT and colony formation assays, flow cytometry, and transwell and wound-healing assays, respectively. In addition, the regulatory roles of GGPPS on the expression of several epithelial-mesenchymal transition (EMT) markers were determined. Furthermore, the Rac1/Cdc42 prenylation was detected after knockdown of GGPPS in SPCA-1 and PC9 cells. GGPPS expression was significantly increased in lung adenocarcinoma tissues compared to that in adjacent normal tissues. Overexpression of GGPPS was correlated with large tumours, high TNM stage, lymph node metastasis and poor prognosis in patients. Knockdown of GGPPS inhibited the migration and invasion of lung adenocarcinoma cells, but did not affect cell proliferation and apoptosis. Meanwhile, GGPPS inhibition significantly increased the expression of E-cadherin and reduced the expression of N-cadherin and vimentin in lung adenocarcinoma cells. In addition, the Rac1/Cdc42 geranylgeranylation was reduced by GGPPS knockdown. Overexpression of GGPPS correlates with poor prognosis of lung adenocarcinoma and contributes to metastasis through regulating EMT.
本研究旨在评估香叶基香叶基二磷酸合酶（GGPPS）在肺腺癌进展中的生物学作用。通过 qRT-PCR、组织微阵列（TMA）和 Western blot 检测肺腺癌组织中的 GGPPS 表达。评估 GGPPS 表达与肺腺癌患者临床病理特征和预后的关系。使用 siRNA 在 SPCA-1、PC9 和 A549 细胞中下调 GGPPS，并用腺病毒载体在 A549 细胞中上调 GGPPS。通过 MTT 和集落形成实验、流式细胞术和 Transwell 和划痕愈合实验分别确定 GGPPS 在细胞增殖、凋亡、迁移和侵袭中的生物学作用。此外，还确定了 GGPPS 对几种上皮间质转化（EMT）标志物表达的调节作用。进一步检测了敲低 GGPPS 后 SPCA-1 和 PC9 细胞中 Rac1/Cdc42 的异戊二烯化。与相邻正常组织相比，肺腺癌组织中 GGPPS 的表达明显增加。GGPPS 的过表达与肿瘤较大、TNM 分期较高、淋巴结转移和患者预后不良有关。敲低 GGPPS 抑制肺腺癌细胞的迁移和侵袭，但不影响细胞增殖和凋亡。同时，GGPPS 抑制显著增加了肺腺癌细胞中 E-钙黏蛋白的表达，降低了 N-钙黏蛋白和波形蛋白的表达。此外，GGPPS 敲低降低了 Rac1/Cdc42 的香叶基香叶基化。GGPPS 的过表达与肺腺癌的不良预后相关，并通过调节 EMT 促进转移。
