Elsevier

Surgery

Volume 158, Issue 1, July 2015, Pages 211-224
Surgery

Pancreas
Gli1 promotes transforming growth factor-beta1– and epidermal growth factor–induced epithelial to mesenchymal transition in pancreatic cancer cells

https://doi.org/10.1016/j.surg.2015.03.016Get rights and content

Background

The Hedgehog signaling pathway and its key target effector Gli1 are linked closely to the development of the epithelial to mesenchymal transition (EMT) in many cancers. The definite function of Gli1 in regulating the EMT of pancreatic cancer (PC), however, is still unclear.

Methods

At the cell and tissue levels, we investigated the role of Gli1 in the initiation of EMT in PC with and without external stimulus treatments.

Results

The immunohistochemistry results showed that Gli1 was associated positively with MMP9 but not with E-cad or Vimentin. Gli1 expression was associated positively with tumor T (P = .025) and Union for International Cancer Control stage (P = .032), whereas MMP9 expression was associated positively with lymph node metastasis (P = .017) and Union for International Cancer Control stage (P = .006). Furthermore, patients with Gli1 and MMP9 coexpression had poor overall survival (P = .015). Silencing of Gli1 alone without external stimulus had no effect on EMT but inhibited transforming growth factor-beta1 (TGFβ1)- and epidermal growth factor (EGF)-induced EMT in PANC-1, AsPC-1, and BxPC-3 PC cell lines, along with the inhibition of TGFβ1- and EGF-induced EMT-like cell morphology and invasion, down-regulation of E-cad, and up-regulation of MMP9 and Vimentin in those 3 cell lines, respectively.

Conclusion

Gli1 silencing alone has no effect on EMT initiation; however, it exerts a protumor role in the aggressive invasion of PC cells by promoting TGFβ1- and EGF-induced EMT.

Section snippets

Tissue samples

This study was approved by the institutional review board of the First Hospital of China Medical University, and every participant signed a consent form. Sixty-two formalin-fixed and paraffin-embedded pancreatic ductal adenocarcinoma tissues were obtained from patients at the First Hospital of China Medical University between 2006 and 2011. All diagnoses were confirmed pathologically, and all tissue samples were analyzed according to the 7th edition of the Union for International Cancer Control

The clinicopathologic significance of and relationships between Gli1, MMP9, E-cad, and Vimentin in PC tissues

In 62 PC tissue samples, the expressions of Gli1 in the nucleus and cytoplasm, MMP9 and Vimentin in the cytoplasm, and E-cad in the membrane were considered for scoring (E-cad–negative expression and localization in the cytoplasm were considered as abnormal expression) (Fig 1). IHC showed that the positive expression rates of Gli1, MMP9, E-cadherin (membrane location), and Vimentin in the PC tissue samples were 53.2% (33/62), 58.1% (36/62), 38.7% (24/62), and 29.0% (18/62), respectively.

Discussion

EMT has been shown to contribute to PC tumor formation and metastasis, but the mechanisms by which EMT is regulated are not completely clear.2, 16 Aberrant activation of the Hedgehog (Hh)-Gli1 axis has been described as a key mediator of cancer metastasis via EMT.17, 18, 19 Our previous study showed that Gli1 promoted cell invasion and migration of PC.7 Thus, we hypothesize that Hh-Gli1 regulates PC invasion and motility in an EMT-dependent manner.

However, the roles of Gli1 in EMT regulation in

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    Qingfeng Liu and Weiwei Sheng contributed equally to this work.

    The authors declare no conflicts of interest.

    This work was supported by the Social Development Program from Shenyang Science and Technology Bureau, China (no. F15-139-9-19) and by the Chinese National Science Foundation for Youth Scholar (no. 81401941 to Weiwei Sheng).

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