Open Access

Overexpression of Gremlin 1 by sonic hedgehog signaling promotes pancreatic cancer progression

  • Authors:
    • Yongtian Yu
    • Liang Cheng
    • Bin Yan
    • Cancan Zhou
    • Weikun Qian
    • Ying Xiao
    • Tao Qin
    • Junyu Cao
    • Liang Han
    • Qingyong Ma
    • Jiguang Ma
  • View Affiliations

  • Published online on: September 26, 2018     https://doi.org/10.3892/ijo.2018.4573
  • Pages: 2445-2457
  • Copyright: © Yu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Sonic hedgehog (SHH) signaling is an important promotor of desmoplasia, a critical feature in pancreatic cancer stromal reactions involving the activation of pancreatic stellate cells (PSCs). Gremlin 1 is widely overexpressed in cancer-associated stromal cells, including activated PSCs. In embryonic development, SHH is a potent regulator of Gremlin 1 through an interaction network. This subtle mechanism in the cancer microenvironment remains to be fully elucidated. The present study investigated the association between Gremlin 1 and SHH, and the effect of Gremlin 1 in pancreatic cancer. The expression of Gremlin 1 in different specimens was measured using immunohistochemistry. The correlations among clinicopathological features and levels of Gremlin 1 were evaluated. Primary human PSCs and pancreatic cancer cell lines were exposed to SHH, cyclopamine, GLI family zinc finger-1 (Gli-1) small interfering RNA (siRNA), and Gremlin 1 siRNA to examine their associations and effects using an MTT assay, reverse transcription-quantitative polymerase chain reaction analysis, western blot analysis, and migration or invasion assays. The results revealed the overexpression of Gremlin 1 in pancreatic cancer tissues, mainly in the stroma. The levels of Gremlin 1 were significantly correlated with survival rate and pT status. In addition, following activation of the PSCs, the expression levels of Gremlin 1 increased substantially. SHH acts as a potent promoter of the expression of Gremlin 1, and cyclopamine and Gli-1 siRNA modulated this effect. In a screen of pancreatic cancer cell lines, AsPC-1 and BxPC-3 cells expressed high levels of Gremlin 1, but only AsPC-1 cells exhibited a high expression level of SHH. The results of the indirect co-culture experiment suggested that paracrine SHH from the AsPC-1 cells induced the expression of Gremlin 1 in the PSCs. Furthermore, Gremlin 1 siRNA negatively regulated the proliferation and migration of PSCs, and the proliferation, invasion and epithelial-mesenchymal transition of AsPC-1 and BxPC-3 cells. Based on the data from the present study, it was concluded that an abnormal expression level of Gremlin 1 in pancreatic cancer was induced by SHH signaling, and that the overexpression of Gremlin 1 enabled pancreatic cancer progression.
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December-2018
Volume 53 Issue 6

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

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Copy and paste a formatted citation
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Spandidos Publications style
Yu Y, Cheng L, Yan B, Zhou C, Qian W, Xiao Y, Qin T, Cao J, Han L, Ma Q, Ma Q, et al: Overexpression of Gremlin 1 by sonic hedgehog signaling promotes pancreatic cancer progression. Int J Oncol 53: 2445-2457, 2018
APA
Yu, Y., Cheng, L., Yan, B., Zhou, C., Qian, W., Xiao, Y. ... Ma, J. (2018). Overexpression of Gremlin 1 by sonic hedgehog signaling promotes pancreatic cancer progression. International Journal of Oncology, 53, 2445-2457. https://doi.org/10.3892/ijo.2018.4573
MLA
Yu, Y., Cheng, L., Yan, B., Zhou, C., Qian, W., Xiao, Y., Qin, T., Cao, J., Han, L., Ma, Q., Ma, J."Overexpression of Gremlin 1 by sonic hedgehog signaling promotes pancreatic cancer progression". International Journal of Oncology 53.6 (2018): 2445-2457.
Chicago
Yu, Y., Cheng, L., Yan, B., Zhou, C., Qian, W., Xiao, Y., Qin, T., Cao, J., Han, L., Ma, Q., Ma, J."Overexpression of Gremlin 1 by sonic hedgehog signaling promotes pancreatic cancer progression". International Journal of Oncology 53, no. 6 (2018): 2445-2457. https://doi.org/10.3892/ijo.2018.4573