Abstract 2041: Suppression of mutant p53-induced EMT by statins have double-edged effects on the patients with lung adenocarcinoma according to p53 mutation status
Authors: Nishikawa Shigeto , Menju Toshi , Sowa Terumasa , Takahashi Koji , Miyata Ryo , Ishikawa Hiroyuki , Nakajima Daisuke , Hamaji Masatsugu , Motoyama Hideki , Aoyama Akihiro , Sato Toshihiko , Chen-Yoshikawa Fengshi , Sonobe Makoto , Date Hiroshi 
Published: August 2018

Background: Epithelial-mesenchymal transition (EMT) is known to be pivotal for driving metastasis and recurrence in lung cancer. Some reports have shown statins suppressed EMT by inactivating mutant p53 functions in vitro. Although several clinical trials regarding conventional treatments with statins have been performed, the effect of statins on the prognosis is still controversial. The purpose of the present study is to clarify the impact of statins on EMT and the prognosis of patients with lung adenocarcinoma.

Methods: First, we transfected wild-type p53 or mutant p53 (R175H, R273H) to H1650 lung adenocarcinoma cells and administrated simvastatin. We evaluated morphologic changes by microscopic examination and analyzed EMT markers (E-cadherin, vimentin) through Western blotting of whole cell lysate. We also analyzed their invasive ability by Matrigel invasion assay. Second, a total of 282 lung adenocarcinoma specimens were collected from patients who underwent surgery in our institute from January 2001 to December 2007. We analyzed EMT markers through immunostaining of tumor specimens and we determined p53 mutation by direct sequencing. The association between EMT, p53 mutation status, and statin use as well as the patients' clinical information was statistically analyzed after propensity score matching. Correlations were analyzed using Pearson's chi-square test and overall survival was compared using the log-rank test.

Results: Mutant p53 (R175H, R273H) induction to H1650 cells showed EMT-like morphologic changes. E-cadherin expression was decreased and vimentin expression was increased in H1650 harboring mutant p53 (H1650mut.p53). Additionally, H1650mut.p53 obtained more aggressive invasiveness compared to H1650 expressing wild-type p53 (H1650wt.p53). Simvastatin-treated H1650mut.p53 lost EMT character and aggressive invasiveness; on the other hand, simvastatin exacerbated invasive abilities of H1650wt.p53. Approximately 20% of the patients were prescribed statins as a treatment of hyperlipidemia or coronary artery disease. Statin administration was correlated to less EMT only in the patients with mutant p53, which was consistent with the results of our in vitro experiments. Moreover, the statin-administrated group showed significantly better survival compared to the non-statin group, which was observed only in the patients with mutant p53. On the other hand, statins significantly impaired the prognosis of patients with wild-type p53, especially in EGFR mutants.

Conclusion: Statins suppressed EMT and improved the prognosis of patients with lung adenocarcinoma in a p53 mutation-dependent manner, whereas they impaired the prognosis of patients with wild-type p53 harboring EGFR mutations.

Citation Format: Shigeto Nishikawa, Toshi Menju, Terumasa Sowa, Koji Takahashi, Ryo Miyata, Hiroyuki Ishikawa, Daisuke Nakajima, Masatsugu Hamaji, Hideki Motoyama, Akihiro Aoyama, Toshihiko Sato, Fengshi Chen-Yoshikawa, Makoto Sonobe, Hiroshi Date. Suppression of mutant p53-induced EMT by statins have double-edged effects on the patients with lung adenocarcinoma according to p53 mutation status [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2041.