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.
Highlights
Esophageal carcinoma is one of the leading causes of cancer-related deaths worldwide, with low 5-year survival rates at approximately 12-20% [1, 2]
Sonic Hedgehog (SHh)/Gli signaling plays an important role in solid malignancies; downstream pathway effectors are tied to epithelial-mesenchymal transition (EMT), and many serve as potential therapeutic targets in the prevention of tumor aggression and metastasis
Esophageal adenocarcinoma (EAC) tissue specimens from patients demonstrated inverse correlations between Gli1/2 and key EMT markers, including cell adhesion protein E-cadherin, in addition to a positive correlation with N-cadherin, Vimentin, and β-catenin, all three of which are linked to increased EMT [42,43,44, 54]
Summary
Esophageal carcinoma is one of the leading causes of cancer-related deaths worldwide, with low 5-year survival rates at approximately 12-20% [1, 2]. More meaningful treatment strategies are desperately needed to target the mechanisms leading to tumor invasion and metastasis in EAC. EMT involves multiple complex changes in the distribution and function of proteins, including E-cadherin, an adhesive protein inactivated in numerous cancers [8]. This process is regulated by a number of converging signaling cascades, including the Sonic Hedgehog (SHh) pathway, and confers critical traits required for seeding metastasis and developing stem cell properties that allow new cancer cell colonies to be launched [9]. Acquisition of EMT features has been associated with poor prognosis and chemotherapeutic resistance—further knowledge can improve our understanding of tumor recurrence and metastasis to identify potential therapeutic targets in EAC [10,11,12,13]
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