Oncotarget

Research Papers:

Gli is activated and promotes epithelial-mesenchymal transition in human esophageal adenocarcinoma

Lei Wang, Joy Q. Jin, Yong Zhou, Ziqiang Tian, David M. Jablons and Biao He _

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Oncotarget. 2018; 9:853-865. https://doi.org/10.18632/oncotarget.22856

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Abstract

Lei Wang1,2,*, Joy Q. Jin2,*, Yong Zhou2,3, Ziqiang Tian1, David M. Jablons2 and Biao He2

1Department of Thoracic Surgery, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, China

2Thoracic Oncology Program, Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94115, USA

3Department of Respiratory Diseases, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang 310016, China

*These authors have contributed equally to this work

Correspondence to:

Biao He, email: [email protected]

David M. Jablons, email: [email protected]

Keywords: sonic hedgehog; Gli; epithelial-mesenchymal transition; esophageal adenocarcinoma

Received: September 19, 2017    Accepted: November 09, 2017    Published: December 01, 2017

ABSTRACT

Esophageal adenocarcinoma (EAC) accounts for the most esophageal cancer cases in the US, and is notoriously aggressive. This study examines the role of Sonic Hedgehog (SHh)/Gli signaling in the regulation of epithelial-mesenchymal transition (EMT), a process tied to invasion and metastasis, in EAC.

Gli/EMT protein expression levels were examined by western blot in paired EAC patient tissues (n = 24) and cell lines (OE19, OE33). Functional analyses were performed (siRNA, treatment with Gli-inhibitor, AKT-inhibitor, and N-Shh recombinant proteins) to investigate SHh/Gli signaling and EMT, cell cycle, and prognostic markers in EAC cell lines. MTS, luciferase reporter, qRT-PCR, western blot, wound healing, and transwell assays were executed to analyze pathway activity, cell migration, and invasion.

Aberrant Gli1/2 expression was found in EAC patient tissues, and was significantly associated with increased EMT and AKT pathway activity. Stimulation of SHh/Gli resulted in EMT signaling, including expression of E-cadherin, N-cadherin, Vimentin, β-catenin, Snail, and Slug, as well as cell cycle progression at mRNA and protein levels in EAC cell lines. Gli inhibition via small molecule administration and siRNA significantly reduced EMT, decreasing cell mobility and invasion. Both Gli and AKT inhibition rescued E-cadherin expression and suppressed AKT phosphorylation.

This study provides evidence for a strong association between aberrant Gli1/2 expression and AKT/EMT markers in EAC; activated SHh/Gli signaling may be a critical component in promoting cell survival, metastases, and resistance to chemotherapy, and represents a promising avenue to target tumor proliferation and mobility.


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