Statins may have double-edged effects in patients with lung adenocarcinoma after lung resection
Statins may have double-edged effects in patients with lung adenocarcinoma after lung resection
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DOI：
10.2147/cmar.s200819
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发表时间：
2019-01-01
影响因子：
3.3
通讯作者：
Date, Hiroshi
中科院分区：
文献类型：
--
作者：
Nishikawa, Shigeto;Menju, Toshi;Date, Hiroshi
目的：上皮向间充质转化(EMT)是推动肺癌转移和复发的关键。一些体外研究表明，他汀类药物通过使突变型p53功能失活来抑制EMT。他汀类药物的常规治疗已经进行了几次临床试验，但这些药物对预后的影响仍不确定。本研究旨在探讨他汀类药物对肺腺癌患者EMT及预后的影响。材料与方法：观察辛伐他汀对高表达P53的H1650肺腺癌细胞和含突变型P53突变H1975的肺腺癌细胞在辛伐他汀治疗前后的细胞形态变化及EMT标志物(E-钙粘蛋白、波形蛋白)的表达。Matrigel化学侵袭实验分析这些细胞的侵袭能力。共收集250例肺腺癌标本，均取自本院手术患者。用免疫组织化学方法检测肿瘤标本中的EMT标志物，直接测序确定p53基因突变状态。评估EMT状态、P53突变状态和他汀类药物使用之间的关系，并使用边际结构模型分析预后。结果：突变型P53诱导了EMT，并增加了H1650细胞的侵袭能力。辛伐他汀可恢复H1650和H1975细胞的上皮表型，降低其侵袭能力。他汀类药物仅在突变型P53患者中与EMT失活有关，这与体外结果一致。此外，在突变型p53患者中，使用他汀类药物的患者的存活率明显好于非他汀类药物的患者。相反，他汀类药物显著恶化野生型p53患者的预后(HR为2.10，95%CI为1.14~3.85)。结论：他汀类药物抑制肺腺癌的EMT，并以p53突变依赖的方式改变患者的预后。
Purpose: The epithelial to mesenchymal transition (EMT) is pivotal for driving metastasis and recurrence in lung cancer. Some in vitro reports have shown that statins suppress EMT by inactivating mutant p53 functions. Several clinical trials of conventional treatments with statins have been performed, but the effect of these drugs on prognosis is still uncertain. The purpose of this study is to examine the impact of statins on EMT and the prognosis of patients with lung adenocarcinoma.Materials and methods: Morphological changes were evaluated and EMT markers (E-cadherin, vimentin) were analyzed by Western blotting in p53-overexpressing H1650 and mutant p53-harboring H1975 lung adenocarcinoma cells, with and without simvastatin administration. The invasive ability of these cells was analyzed in a Matrigel chemoinvasion assay. A total of 250 lung adenocarcinoma specimens were also collected from patients who underwent surgery in our institute. EMT markers in these tumor specimens were evaluated by immunostaining and p53 mutation status was determined by direct sequencing. Associations among EMT status, p53 mutation status, and statin use were evaluated, and prognosis was analyzed using a marginal structural model.Results: Mutant p53 induced EMT and increased the invasive ability of H1650 cells. Simvastatin restored the epithelial phenotype and decreased the invasive ability of both H1650 and H1975 cells. Statin administration was associated with inactivation of EMT only in patients with mutant p53, which was consistent with the in vitro results. Moreover, in patients with mutant p53, statin users had significantly better survival than non-statin users. In contrast, statins significantly worsened the prognosis of patients with wild type p53 (HR 2.10, 95% CI 1.14-3.85).Conclusion: Statins suppress EMT and change the prognosis of patients with lung adenocarcinoma in a p53 mutation-dependent manner.