Extracellular signal-regulated kinase and Akt activation play a critical role in the process of hepatocyte growth factor-induced epithelial-mesenchymal transition

  • Authors:
    • Toshiyuki Tanahashi
    • Shinji Osada
    • Atsuko Yamada
    • Junko Kato
    • Kazunori Yawata
    • Ryutaro Mori
    • Hisashi Imai
    • Yoshiyuki Sasaki
    • Shiro Saito
    • Yoshihiro Tanaka
    • Kenichi Nonaka
    • Kazuhiro Yoshida
  • View Affiliations

  • Published online on: December 3, 2012     https://doi.org/10.3892/ijo.2012.1726
  • Pages: 556-564
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Abstract

Epithelial-mesenchymal transition (EMT) has recently been studied to elucidate mechanisms of the liver metastatic process. We investigated EMT in the process of liver metastasis and the effects of chemotherapy on EMT cells as therapeutic strategy for colorectal liver metastasis. We used the CT26 murine colorectal carcinoma cell line to create an in vivo mouse liver metastasis model. Liver tumors were stained immuno­histochemically. Expression of proteins associated with TGF-β/Smad and hepatocyte growth factor (HGF)/c-Met pathways were investigated by western blotting. Cells with c-Met mRNA knockdown by siRNA techniques showed clearly reduced liver metastases compared with regular cells at 21 days. TGF-β and HGF induced EMT expression, but signal transduction was quite different. TGF-β induced ERK, but not Akt phosphory­lation. HGF mediated both ERK and Akt phosphorylation. Akt inhibitor blocked Akt phosphorylation but did not affect TGF-β-induced activation of ERK, Snail and Slug. U-0126 did not reduce Snail activity by TGF-β at a concentration to block ERK phosphorylation. However, Akt inhibitor and U-0126 completely inhibited HGF-induced Slug activation. 5-FU mediated cell death in the EMT process induced by TGF-β more effectively than HGF. ERK/Akt signaling, but not the Smad pathway, may be one of the main processes in HGF-induced EMT, despite the Smad pathway, but not ERK/Akt, being critical for TGF-β-induced EMT. The MAPK/Akt pathway is indispensable in HGF/c-Met signaling. The ERK/Akt pathway particularly may be critical in the HGF-induced EMT process. However, long-term use of chemotherapeutic agents may induce drug resistance and distant metastases through EMT-related signaling pathway activation.
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February 2013
Volume 42 Issue 2

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

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APA
Tanahashi, T., Osada, S., Yamada, A., Kato, J., Yawata, K., Mori, R. ... Yoshida, K. (2013). Extracellular signal-regulated kinase and Akt activation play a critical role in the process of hepatocyte growth factor-induced epithelial-mesenchymal transition. International Journal of Oncology, 42, 556-564. https://doi.org/10.3892/ijo.2012.1726
MLA
Tanahashi, T., Osada, S., Yamada, A., Kato, J., Yawata, K., Mori, R., Imai, H., Sasaki, Y., Saito, S., Tanaka, Y., Nonaka, K., Yoshida, K."Extracellular signal-regulated kinase and Akt activation play a critical role in the process of hepatocyte growth factor-induced epithelial-mesenchymal transition". International Journal of Oncology 42.2 (2013): 556-564.
Chicago
Tanahashi, T., Osada, S., Yamada, A., Kato, J., Yawata, K., Mori, R., Imai, H., Sasaki, Y., Saito, S., Tanaka, Y., Nonaka, K., Yoshida, K."Extracellular signal-regulated kinase and Akt activation play a critical role in the process of hepatocyte growth factor-induced epithelial-mesenchymal transition". International Journal of Oncology 42, no. 2 (2013): 556-564. https://doi.org/10.3892/ijo.2012.1726