Transforming growth factor β and Ras/MEK/ERK signaling regulate the expression level of a novel tumor suppressor lefty

Naoteru Miyata, Toshifumi Azuma, Shigenari Hozawa, Hajime Higuchi, Akiko Yokoyama, Ayano Kabashima, Toru Igarashi, Keita Saeki, Toshifumi Hibi

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Objectives: The objectives of the present study were (i) to identify a novel tumor suppressor gene whose expression level was regulated by transforming growth factor (TGF-β) and (ii) to evaluate the effect of Ras/MEK/ERK signaling on TGF-β-dependent Lefty up-regulation. Methods: Human pancreatic cancer cell lines were used. The effect of Ras/MEK/ERK pathway on TGF-β-mediated Lefty up-regulation was tested by adding K-ras small interfering RNA, MEK inhibitor U0126, or extracellular signal-regulated kinase (ERK) inhibitor LY294002. Results: Transforming growth factor β upregulated Lefty messenger RNA levels within 6 of the 7 cell lines. Lefty exerts an antagonistic effect against the tumor-promoting molecule, Nodal, as recombinant Lefty suppressed Nodal-mediated proliferation. Interestingly, inhibition of the Ras/MEK/ERK pathway dramatically enhanced TGF-mediated Lefty upregulation, suggesting that Ras/MEK/ERK signaling suppresses TGF-β-Lefty pathway. Conclusions: Our data suggest that Lefty is a novel TGF-β target molecule that mediates growth inhibition of pancreatic cancer cells. In addition, activation of the Ras/MEK/ERK pathway serves as a mechanism by which pancreatic cancer escapes from growth inhibition by the TGF-β-Lefty axis. The results imply a novel therapeutic strategy for pancreatic cancer, that is, combination treatment with Ras/MEK/ERK inhibitors and TGF-β.

Original languageEnglish
Pages (from-to)745-752
Number of pages8
JournalPancreas
Volume41
Issue number5
DOIs
Publication statusPublished - 2012 Jul

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Mitogen-Activated Protein Kinase Kinases
Extracellular Signal-Regulated MAP Kinases
Transforming Growth Factors
Pancreatic Neoplasms
Neoplasms
Up-Regulation
Cell Line
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Growth
Tumor Suppressor Genes
Small Interfering RNA
Gene Expression
Messenger RNA

Keywords

  • C-Jun N-terminal kinase
  • Extracellular signal-regulated kinase
  • P38 map kinase
  • Phosphoinositide 3-kinase
  • Smad-dependent pathway
  • Small interfering RNA

ASJC Scopus subject areas

  • Hepatology
  • Internal Medicine
  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

Cite this

Transforming growth factor β and Ras/MEK/ERK signaling regulate the expression level of a novel tumor suppressor lefty. / Miyata, Naoteru; Azuma, Toshifumi; Hozawa, Shigenari; Higuchi, Hajime; Yokoyama, Akiko; Kabashima, Ayano; Igarashi, Toru; Saeki, Keita; Hibi, Toshifumi.

In: Pancreas, Vol. 41, No. 5, 07.2012, p. 745-752.

Research output: Contribution to journalArticle

Miyata, N, Azuma, T, Hozawa, S, Higuchi, H, Yokoyama, A, Kabashima, A, Igarashi, T, Saeki, K & Hibi, T 2012, 'Transforming growth factor β and Ras/MEK/ERK signaling regulate the expression level of a novel tumor suppressor lefty', Pancreas, vol. 41, no. 5, pp. 745-752. https://doi.org/10.1097/MPA.0b013e31823b66d3
Miyata, Naoteru ; Azuma, Toshifumi ; Hozawa, Shigenari ; Higuchi, Hajime ; Yokoyama, Akiko ; Kabashima, Ayano ; Igarashi, Toru ; Saeki, Keita ; Hibi, Toshifumi. / Transforming growth factor β and Ras/MEK/ERK signaling regulate the expression level of a novel tumor suppressor lefty. In: Pancreas. 2012 ; Vol. 41, No. 5. pp. 745-752.
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AU - Yokoyama, Akiko

AU - Kabashima, Ayano

AU - Igarashi, Toru

AU - Saeki, Keita

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AB - Objectives: The objectives of the present study were (i) to identify a novel tumor suppressor gene whose expression level was regulated by transforming growth factor (TGF-β) and (ii) to evaluate the effect of Ras/MEK/ERK signaling on TGF-β-dependent Lefty up-regulation. Methods: Human pancreatic cancer cell lines were used. The effect of Ras/MEK/ERK pathway on TGF-β-mediated Lefty up-regulation was tested by adding K-ras small interfering RNA, MEK inhibitor U0126, or extracellular signal-regulated kinase (ERK) inhibitor LY294002. Results: Transforming growth factor β upregulated Lefty messenger RNA levels within 6 of the 7 cell lines. Lefty exerts an antagonistic effect against the tumor-promoting molecule, Nodal, as recombinant Lefty suppressed Nodal-mediated proliferation. Interestingly, inhibition of the Ras/MEK/ERK pathway dramatically enhanced TGF-mediated Lefty upregulation, suggesting that Ras/MEK/ERK signaling suppresses TGF-β-Lefty pathway. Conclusions: Our data suggest that Lefty is a novel TGF-β target molecule that mediates growth inhibition of pancreatic cancer cells. In addition, activation of the Ras/MEK/ERK pathway serves as a mechanism by which pancreatic cancer escapes from growth inhibition by the TGF-β-Lefty axis. The results imply a novel therapeutic strategy for pancreatic cancer, that is, combination treatment with Ras/MEK/ERK inhibitors and TGF-β.

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