Metformin inhibits the radiation-induced invasive phenotype of esophageal squamous cell carcinoma

  • Authors:
    • Akira Nakayama
    • Itasu Ninomiya
    • Shinichi Harada
    • Tomoya Tsukada
    • Koichi Okamoto
    • Shinichi Nakanuma
    • Seisho Sakai
    • Isamu Makino
    • Jun Kinoshita
    • Hironori Hayashi
    • Katsunobu Oyama
    • Tomoharu Miyashita
    • Hidehiro Tajima
    • Hiroyuki Takamura
    • Sachio Fushida
    • Tetsuo Ohta
  • View Affiliations

  • Published online on: August 31, 2016     https://doi.org/10.3892/ijo.2016.3676
  • Pages: 1890-1898
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Esophageal cancer is one of the most aggressive tumor types because of its invasiveness and metastatic potential. Several reports have described an association between increased invasiveness after ionizing radiation (IR) treatment and epithelial-to-mesenchymal transition (EMT). The biguanide metformin is reported to prevent transforming growth factor-β (TGF-β)-induced EMT and proliferation of cancer. This study examined whether IR induces EMT and promotes the invasive potential of TE-9 esophageal squamous cell carcinoma cells and the effect of metformin on IR-induced EMT. After IR exposure, TE-9 cells showed a spindle-shaped morphology and lost cell-cell adhesion. Immunoblotting showed that IR induced expression of mesenchymal markers (vimentin and N-cadherin), transcription factors (Slug, Snail, and Twist), and matrix metalloproteinases. A scratch wound assay and Matrigel invasion assay showed that IR enhanced the invasive potential and migratory capacity of TE-9 cells. Expression of hypoxia-related factor-1α and TGF-β was increased after IR. IR also induced phosphorylation of Smad2 and Smad3. Metformin inhibited radiation-induced EMT-like morphological changes, and enhanced invasion and migration of TE-9 cells. Metformin inhibited IR-induced phosphorylation of Smad2 and Smad3. Although phosphorylation of AMP-activated protein kinase was enhanced by IR and metformin, phosphorylation of mammalian target of rapamycin was enhanced by IR and suppressed by metformin. These results indicated that metformin suppressed IR-induced EMT via suppression of the TGF-β-Smad phosphorylation pathway, and a part of the non-Smad pathway. Metformin might be useful to prevent IR-induced invasion and metastasis of esophageal squamous cell carcinoma.
View Figures
View References

Related Articles

Journal Cover

November-2016
Volume 49 Issue 5

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

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
x
Spandidos Publications style
Nakayama A, Ninomiya I, Harada S, Tsukada T, Okamoto K, Nakanuma S, Sakai S, Makino I, Kinoshita J, Hayashi H, Hayashi H, et al: Metformin inhibits the radiation-induced invasive phenotype of esophageal squamous cell carcinoma. Int J Oncol 49: 1890-1898, 2016
APA
Nakayama, A., Ninomiya, I., Harada, S., Tsukada, T., Okamoto, K., Nakanuma, S. ... Ohta, T. (2016). Metformin inhibits the radiation-induced invasive phenotype of esophageal squamous cell carcinoma. International Journal of Oncology, 49, 1890-1898. https://doi.org/10.3892/ijo.2016.3676
MLA
Nakayama, A., Ninomiya, I., Harada, S., Tsukada, T., Okamoto, K., Nakanuma, S., Sakai, S., Makino, I., Kinoshita, J., Hayashi, H., Oyama, K., Miyashita, T., Tajima, H., Takamura, H., Fushida, S., Ohta, T."Metformin inhibits the radiation-induced invasive phenotype of esophageal squamous cell carcinoma". International Journal of Oncology 49.5 (2016): 1890-1898.
Chicago
Nakayama, A., Ninomiya, I., Harada, S., Tsukada, T., Okamoto, K., Nakanuma, S., Sakai, S., Makino, I., Kinoshita, J., Hayashi, H., Oyama, K., Miyashita, T., Tajima, H., Takamura, H., Fushida, S., Ohta, T."Metformin inhibits the radiation-induced invasive phenotype of esophageal squamous cell carcinoma". International Journal of Oncology 49, no. 5 (2016): 1890-1898. https://doi.org/10.3892/ijo.2016.3676