Epithelial-mesenchymal transition via transforming growth factor beta in pancreatic cancer is potentiated by the inflammatory glycoprotein leucine-rich alpha-2 glycoprotein

Toru Otsuru; Shogo Kobayashi; Hiroshi Wada; Tsuyoshi Takahashi; Kunihito Gotoh; Yoshifumi Iwagami; Daisaku Yamada; Takehiro Noda; Tadafumi Asaoka; Satoshi Serada; Minoru Fujimoto; Hidetoshi Eguchi; Masaki Mori; Yuichiro Doki; Testuji Naka

doi:10.1111/cas.13918

Epithelial-mesenchymal transition via transforming growth factor beta in pancreatic cancer is potentiated by the inflammatory glycoprotein leucine-rich alpha-2 glycoprotein

Toru Otsuru, Shogo Kobayashi, Hiroshi Wada, Tsuyoshi Takahashi, Kunihito Gotoh, Yoshifumi Iwagami, Daisaku Yamada, Takehiro Noda, Tadafumi Asaoka, Satoshi Serada, Minoru Fujimoto, Hidetoshi Eguchi, Masaki Mori, Yuichiro Doki, Testuji Naka

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Abstract

We previously showed that an inflammation-related, molecule leucine-rich alpha-2 glycoprotein (LRG) enhances the transforming growth factor (TGF)-β1-induced phosphorylation of Smad proteins and is elevated in patients with pancreatic ductal adenocarcinoma (PDAC). As TGF-β/Smad signaling is considered to play a key role in epithelial-mesenchymal transition (EMT), we attempted to clarify the mechanism underlying LRG-related EMT in relation to metastasis in PDAC. We cultured LRG-overexpressing PDAC cells (Panc1/LRG) and evaluated the morphology, EMT-related molecules and TGF-β/Smad signaling pathway in these cells. We also assessed the LRG levels in plasma and resected specimens from patients with PDAC. Inflammatory cytokines induced LRG production in PDAC cells. A spindle-like shape was visualized more frequently than other shapes in Panc1/LRG with TGF-β1 exposure. The expression of E-cadherin in Panc1/LRG was decreased with TGF-β1 exposure. Invasion increased with TGF-β1 stimulation of Panc1/LRG. The phosphorylation of smad2 in Panc1/LRG was increased in comparison with parental Panc1 under TGF-β1 stimulation. In the plasma LRG-high group, the recurrence rate tended to be higher and the recurrence-free survival (RFS) tended to be worse in comparison with the plasma LRG-low group. LRG enhanced EMT induced by TGF-β signaling, thus indicating that LRG has a significant effect on the metastasis of PDAC.

Original language	English
Pages (from-to)	985-996
Number of pages	12
Journal	Cancer Science
Volume	110
Issue number	3
DOIs	https://doi.org/10.1111/cas.13918
Publication status	Published - Mar 2019

All Science Journal Classification (ASJC) codes

Oncology
Cancer Research

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Otsuru, T., Kobayashi, S., Wada, H., Takahashi, T., Gotoh, K., Iwagami, Y., Yamada, D., Noda, T., Asaoka, T., Serada, S., Fujimoto, M., Eguchi, H., Mori, M., Doki, Y., & Naka, T. (2019). Epithelial-mesenchymal transition via transforming growth factor beta in pancreatic cancer is potentiated by the inflammatory glycoprotein leucine-rich alpha-2 glycoprotein. Cancer Science, 110(3), 985-996. https://doi.org/10.1111/cas.13918

Epithelial-mesenchymal transition via transforming growth factor beta in pancreatic cancer is potentiated by the inflammatory glycoprotein leucine-rich alpha-2 glycoprotein. / Otsuru, Toru; Kobayashi, Shogo; Wada, Hiroshi; Takahashi, Tsuyoshi; Gotoh, Kunihito; Iwagami, Yoshifumi; Yamada, Daisaku; Noda, Takehiro; Asaoka, Tadafumi; Serada, Satoshi; Fujimoto, Minoru; Eguchi, Hidetoshi; Mori, Masaki; Doki, Yuichiro; Naka, Testuji.

In: Cancer Science, Vol. 110, No. 3, 03.2019, p. 985-996.

Research output: Contribution to journal › Article › peer-review

Otsuru, T, Kobayashi, S, Wada, H, Takahashi, T, Gotoh, K, Iwagami, Y, Yamada, D, Noda, T, Asaoka, T, Serada, S, Fujimoto, M, Eguchi, H, Mori, M, Doki, Y & Naka, T 2019, 'Epithelial-mesenchymal transition via transforming growth factor beta in pancreatic cancer is potentiated by the inflammatory glycoprotein leucine-rich alpha-2 glycoprotein', Cancer Science, vol. 110, no. 3, pp. 985-996. https://doi.org/10.1111/cas.13918

Otsuru, Toru ; Kobayashi, Shogo ; Wada, Hiroshi ; Takahashi, Tsuyoshi ; Gotoh, Kunihito ; Iwagami, Yoshifumi ; Yamada, Daisaku ; Noda, Takehiro ; Asaoka, Tadafumi ; Serada, Satoshi ; Fujimoto, Minoru ; Eguchi, Hidetoshi ; Mori, Masaki ; Doki, Yuichiro ; Naka, Testuji. / Epithelial-mesenchymal transition via transforming growth factor beta in pancreatic cancer is potentiated by the inflammatory glycoprotein leucine-rich alpha-2 glycoprotein. In: Cancer Science. 2019 ; Vol. 110, No. 3. pp. 985-996.

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title = "Epithelial-mesenchymal transition via transforming growth factor beta in pancreatic cancer is potentiated by the inflammatory glycoprotein leucine-rich alpha-2 glycoprotein",

abstract = "We previously showed that an inflammation-related, molecule leucine-rich alpha-2 glycoprotein (LRG) enhances the transforming growth factor (TGF)-β1-induced phosphorylation of Smad proteins and is elevated in patients with pancreatic ductal adenocarcinoma (PDAC). As TGF-β/Smad signaling is considered to play a key role in epithelial-mesenchymal transition (EMT), we attempted to clarify the mechanism underlying LRG-related EMT in relation to metastasis in PDAC. We cultured LRG-overexpressing PDAC cells (Panc1/LRG) and evaluated the morphology, EMT-related molecules and TGF-β/Smad signaling pathway in these cells. We also assessed the LRG levels in plasma and resected specimens from patients with PDAC. Inflammatory cytokines induced LRG production in PDAC cells. A spindle-like shape was visualized more frequently than other shapes in Panc1/LRG with TGF-β1 exposure. The expression of E-cadherin in Panc1/LRG was decreased with TGF-β1 exposure. Invasion increased with TGF-β1 stimulation of Panc1/LRG. The phosphorylation of smad2 in Panc1/LRG was increased in comparison with parental Panc1 under TGF-β1 stimulation. In the plasma LRG-high group, the recurrence rate tended to be higher and the recurrence-free survival (RFS) tended to be worse in comparison with the plasma LRG-low group. LRG enhanced EMT induced by TGF-β signaling, thus indicating that LRG has a significant effect on the metastasis of PDAC.",

author = "Toru Otsuru and Shogo Kobayashi and Hiroshi Wada and Tsuyoshi Takahashi and Kunihito Gotoh and Yoshifumi Iwagami and Daisaku Yamada and Takehiro Noda and Tadafumi Asaoka and Satoshi Serada and Minoru Fujimoto and Hidetoshi Eguchi and Masaki Mori and Yuichiro Doki and Testuji Naka",

note = "Funding Information: This work was supported in part by the Practical Project for Rare/ Intractable Diseases from Japan Agency for Medical Research and Development (15ek0109045h0002), the JSPS KAKENHI Grant-in-Aid for Young Scientists (Start-up) (15H06918), a Grant-in-Aid for Scientific Research (17H04215), and Bristol-Myers Squibb Foundation Grants, and the present study was supported by a Grant-in-Aid for Scientific Research (C) 15K10202. Funding Information: Japan Agency for Medical Research and Development, Grant/Award Number: 15ek0109045h0002; JSPS KAKENHI Grant- in-Aid for Young Scientists (Start-up), Grant/ Award Number: 15H06918; Grant-in-Aid for Scientific Research, Grant/Award Number: 17H04215 and 15K10202; Bristol-Myers Squibb Foundation Publisher Copyright: {\textcopyright} 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.",

year = "2019",

month = mar,

doi = "10.1111/cas.13918",

language = "English",

volume = "110",

pages = "985--996",

journal = "Cancer Science",

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T1 - Epithelial-mesenchymal transition via transforming growth factor beta in pancreatic cancer is potentiated by the inflammatory glycoprotein leucine-rich alpha-2 glycoprotein

AU - Otsuru, Toru

AU - Kobayashi, Shogo

AU - Wada, Hiroshi

AU - Takahashi, Tsuyoshi

AU - Gotoh, Kunihito

AU - Iwagami, Yoshifumi

AU - Yamada, Daisaku

AU - Noda, Takehiro

AU - Asaoka, Tadafumi

AU - Serada, Satoshi

AU - Fujimoto, Minoru

AU - Eguchi, Hidetoshi

AU - Mori, Masaki

AU - Doki, Yuichiro

AU - Naka, Testuji

N1 - Funding Information: This work was supported in part by the Practical Project for Rare/ Intractable Diseases from Japan Agency for Medical Research and Development (15ek0109045h0002), the JSPS KAKENHI Grant-in-Aid for Young Scientists (Start-up) (15H06918), a Grant-in-Aid for Scientific Research (17H04215), and Bristol-Myers Squibb Foundation Grants, and the present study was supported by a Grant-in-Aid for Scientific Research (C) 15K10202. Funding Information: Japan Agency for Medical Research and Development, Grant/Award Number: 15ek0109045h0002; JSPS KAKENHI Grant- in-Aid for Young Scientists (Start-up), Grant/ Award Number: 15H06918; Grant-in-Aid for Scientific Research, Grant/Award Number: 17H04215 and 15K10202; Bristol-Myers Squibb Foundation Publisher Copyright: © 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

PY - 2019/3

Y1 - 2019/3

N2 - We previously showed that an inflammation-related, molecule leucine-rich alpha-2 glycoprotein (LRG) enhances the transforming growth factor (TGF)-β1-induced phosphorylation of Smad proteins and is elevated in patients with pancreatic ductal adenocarcinoma (PDAC). As TGF-β/Smad signaling is considered to play a key role in epithelial-mesenchymal transition (EMT), we attempted to clarify the mechanism underlying LRG-related EMT in relation to metastasis in PDAC. We cultured LRG-overexpressing PDAC cells (Panc1/LRG) and evaluated the morphology, EMT-related molecules and TGF-β/Smad signaling pathway in these cells. We also assessed the LRG levels in plasma and resected specimens from patients with PDAC. Inflammatory cytokines induced LRG production in PDAC cells. A spindle-like shape was visualized more frequently than other shapes in Panc1/LRG with TGF-β1 exposure. The expression of E-cadherin in Panc1/LRG was decreased with TGF-β1 exposure. Invasion increased with TGF-β1 stimulation of Panc1/LRG. The phosphorylation of smad2 in Panc1/LRG was increased in comparison with parental Panc1 under TGF-β1 stimulation. In the plasma LRG-high group, the recurrence rate tended to be higher and the recurrence-free survival (RFS) tended to be worse in comparison with the plasma LRG-low group. LRG enhanced EMT induced by TGF-β signaling, thus indicating that LRG has a significant effect on the metastasis of PDAC.

AB - We previously showed that an inflammation-related, molecule leucine-rich alpha-2 glycoprotein (LRG) enhances the transforming growth factor (TGF)-β1-induced phosphorylation of Smad proteins and is elevated in patients with pancreatic ductal adenocarcinoma (PDAC). As TGF-β/Smad signaling is considered to play a key role in epithelial-mesenchymal transition (EMT), we attempted to clarify the mechanism underlying LRG-related EMT in relation to metastasis in PDAC. We cultured LRG-overexpressing PDAC cells (Panc1/LRG) and evaluated the morphology, EMT-related molecules and TGF-β/Smad signaling pathway in these cells. We also assessed the LRG levels in plasma and resected specimens from patients with PDAC. Inflammatory cytokines induced LRG production in PDAC cells. A spindle-like shape was visualized more frequently than other shapes in Panc1/LRG with TGF-β1 exposure. The expression of E-cadherin in Panc1/LRG was decreased with TGF-β1 exposure. Invasion increased with TGF-β1 stimulation of Panc1/LRG. The phosphorylation of smad2 in Panc1/LRG was increased in comparison with parental Panc1 under TGF-β1 stimulation. In the plasma LRG-high group, the recurrence rate tended to be higher and the recurrence-free survival (RFS) tended to be worse in comparison with the plasma LRG-low group. LRG enhanced EMT induced by TGF-β signaling, thus indicating that LRG has a significant effect on the metastasis of PDAC.

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Epithelial-mesenchymal transition via transforming growth factor beta in pancreatic cancer is potentiated by the inflammatory glycoprotein leucine-rich alpha-2 glycoprotein

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