Abstract
Extracellular matrix components play an active role in cancer progression and prognosis. Versican, a large extracellular matrix proteoglycan, can promote cancer metastasis through facilitating cell proliferation, adhesion, migration and angiogenesis. We had previously demonstrated that amiodarone caused ectopic overexpression of similar to versican b (s-vcanb), inhibited EGFR/GSK3β/Snail signaling, and enhanced Cdh5 at the heart field of zebrafish, indicating interference with epithelial-mesenchymal transition (EMT). Since S-vcanb is homologous to mammalian versican V2 isoform, we examined the effects of amiodarone on mammalian tumor proliferation, migration, invasion and metastasis in vitro and in vivo and on EMT signaling pathways. Monolayer wound assays and extracellular matrix transwell invasion assays showed reduced migration and invasion by 15 μM amiodarone treated B16OVA, JC, 4T-1, MDA-MB-231 and MCF-7 tumor cell lines. All cancer cell lines showed reduced metastatic capabilities in vivo after treatment with amiodarone in experimental animals. Western blots revealed that EMT-related transcription factors Snail and Twist were reduced and E-cadherin was enhanced in amiodarone treated cells through an EGFR/ERK/GSK3β-dependent pathway. Immunohistochemistry showed amiodarone lead to increased expression of versican V2 isoform concomitant with reduced versican V1. Our study illustrated the role of versican v2 in EMT modulation and cancer suppression by amiodarone treatment.
Highlights
Cancer metastasis is the major cause of cancerrelated mortality [1]
We demonstrated that Amiodarone caused the ectopic expression of versican V2, conserved as zebrafish ortholog s-vcanb, and cancer growth/metastasis inhibition through Epithelial-Mesenchymal Transition (EMT) modulation and suppressing EGFR signaling
We demonstrate that the expressions of extracellularrelated kinase (ERK), AKT and GSK3β, and Twist protein level were affected in the cell lines treated with recombinant si-Versican V2 and zS-vcanbmE
Summary
Cancer metastasis is the major cause of cancerrelated mortality [1]. Discovering molecular targets that regulate metastasis or act as predicting/prognostic biomarkers is essential for developing effective therapies. EMT has been well implicated in cancer metastasis, characterized by loss of E-cadherin and increased expression of several transcriptional repressors of E-cadherin, such as Twist and Snail [5,6,7,8]. EMT in cancer stem cells has been related to therapy resistance [9, 10]. Extracellular matrix components (ECM) play an active role in tumor progression and are important determinants for the growth and progression of solid tumors [11]. In vitro and in vivo studies reveal that Versican modulates cell adhesion, proliferation, and migration, and, plays a central role in tissue development, as well as a number of pathologic processes [15,16,17]
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