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Statins may have double-edged effects in patients with lung adenocarcinoma after lung resection

Authors Nishikawa S, Menju T, Takahashi K, Miyata R, Chen-Yoshikawa TF, Sonobe M, Yoshizawa A, Sabe H, Sato T, Date H

Received 8 January 2019

Accepted for publication 21 March 2019

Published 18 April 2019 Volume 2019:11 Pages 3419—3432


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr Chien-Feng Li

Shigeto Nishikawa,1 Toshi Menju,1 Koji Takahashi,1 Ryo Miyata,1 Toyofumi Fengshi Chen-Yoshikawa,1 Makoto Sonobe,1 Akihiko Yoshizawa,2 Hisataka Sabe,3 Tosiya Sato,4 Hiroshi Date1

1Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan; 2Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan; 3Department of Molecular Biology, Faculty of Medicine, Hokkaido University, Sapporo, Japan; 4Department of Biostatistics, Kyoto University School of Public Health, Kyoto, Japan

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.

Keywords: p53, epithelial to mesenchymal transition, statin, survival analysis, non-small cell lung cancer

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