Open Access

Survivin knockdown induces senescence in TTF‑1-expressing, KRAS-mutant lung adenocarcinomas

  • Authors:
    • Toshiyuki Sumi
    • Sachie Hirai
    • Miki Yamaguchi
    • Yusuke Tanaka
    • Makoto Tada
    • Gen Yamada
    • Tadashi Hasegawa
    • Yohei Miyagi
    • Toshiro Niki
    • Atsushi Watanabe
    • Hiroki Takahashi
    • Yuji Sakuma
  • View Affiliations

  • Published online on: April 11, 2018     https://doi.org/10.3892/ijo.2018.4365
  • Pages: 33-46
  • Copyright: © Sumi et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Survivin plays a key role in regulating the cell cycle and apoptosis, and is highly expressed in the majority of malignant tumors. However, little is known about the roles of survivin in KRAS-mutant lung adenocarcinomas. In the present study, we examined 28 KRAS-mutant lung adenocarcinoma tissues and two KRAS-mutant lung adenocarcinoma cell lines, H358 and H441, in order to elucidate the potential of survivin as a therapeutic target. We found that 19 (68%) of the 28 KRAS-mutant lung adenocarcinomas were differentiated tumors expressing thyroid transcription factor‑1 (TTF‑1) and E-cadherin. Patients with tumors immunohistochemically positive for survivin (n=18) had poorer outcomes than those with survivin-negative tumors (n=10). In the H358 and H441 cells, which expressed TTF‑1 and E-cadherin, survivin knockdown alone induced senescence, not apoptosis. However, in monolayer culture, the H358 cells and H441 cells in which survivin was silenced, underwent significant apoptosis following combined treatment with ABT-263, a Bcl‑2 inhibitor, and trametinib, a MEK inhibitor. Importantly, the triple combination of survivin knockdown with ABT-263 and trametinib treatment, clearly induced cell death in a three-dimensional cell culture model and in an in vivo tumor xenograft model. We also observed that the growth of the H358 and H441 cells was slightly, yet significantly suppressed in vitro when TTF‑1 was silenced. These findings collectively suggest that the triple combination of survivin knockdown with ABT-263 and trametinib treatment, may be a potential strategy for the treatment of KRAS-mutant lung adenocarcinoma. Furthermore, our findings indicate that the well‑differentiated type of KRAS-mutant lung tumors depends, at least in part, on TTF‑1 for growth.
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July 2018
Volume 53 Issue 1

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Copy and paste a formatted citation
APA
Sumi, T., Hirai, S., Yamaguchi, M., Tanaka, Y., Tada, M., Yamada, G. ... Sakuma, Y. (2018). Survivin knockdown induces senescence in TTF‑1-expressing, KRAS-mutant lung adenocarcinomas. International Journal of Oncology, 53, 33-46. https://doi.org/10.3892/ijo.2018.4365
MLA
Sumi, T., Hirai, S., Yamaguchi, M., Tanaka, Y., Tada, M., Yamada, G., Hasegawa, T., Miyagi, Y., Niki, T., Watanabe, A., Takahashi, H., Sakuma, Y."Survivin knockdown induces senescence in TTF‑1-expressing, KRAS-mutant lung adenocarcinomas". International Journal of Oncology 53.1 (2018): 33-46.
Chicago
Sumi, T., Hirai, S., Yamaguchi, M., Tanaka, Y., Tada, M., Yamada, G., Hasegawa, T., Miyagi, Y., Niki, T., Watanabe, A., Takahashi, H., Sakuma, Y."Survivin knockdown induces senescence in TTF‑1-expressing, KRAS-mutant lung adenocarcinomas". International Journal of Oncology 53, no. 1 (2018): 33-46. https://doi.org/10.3892/ijo.2018.4365