Study On The Involvement Of Wif-1 In Oral Carcinogenesis Via Egfr And Wnt Signaling Pathways
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Date
2015-08
Authors
TAN WEI, CHOW
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Abstract
WNT inhibitory factor 1 (WIF-1) is a physiological inhibitor in WNT signaling pathway via its WIF domain. The function of EGF-like domain in WIF-1 remains unclear. Recent studies had indicated an increase in WIF-1 expression in progressive cancer cells, a phenomenon contradicting to the known cell signaling mechanisms in cancer cell progression. The present study aimed at elucidating the potential binding of WIF-1 to EGFR, leading to initiation of EGFR downstream signaling cascades and/or via the crosstalk between EGFR and downstream of WNT signaling pathways, which ultimately resulting in cancer formation. Initial protein-protein docking between WIF-1 and EGFR molecules was performed using CAPRI-listed online servers, namely ZDOCK, GRAMM-X, HEX and PatchDock. Co-immunoprecipitation and Western blot were designed to study the binding of EGFR/WIF-1 and the potential activation of EGFR and WNT downstream signaling pathways resulting upon the binding. Stable mutant cell lines were established to study the crosstalk between WNT and EGFR signaling pathways. Downstream gene expression initiated by the crosstalk was investigated using quantitative real-time PCR. The experimental results suggested that WIF-1 could play additional role in EGFR signaling pathway via its EGF-like domain. In silico binding of WIF-1 to EGFR was energetically favorable (-616.40 kcal/mol), as compared to EGF/EGFR binding (-627.18 kcal/mol). In co-immunoprecipitation, WIF-1 was bound to, and hence was co-immunoprecipitated with, EGFR. Downstream key factors in EGFR
signaling pathway were found to be activated following the binding of WIF-1 to
EGFR. Moreover, the results obtained showed a prominent activation of downstream,
but not of upstream, cascades of WNT signaling pathway via crosstalk from WIF-1
activated EGFR signaling pathway. In short, the data obtained have clearly shown
that WIF-1 might play a different role in cancer formation by interacting with EGFR,
rather than acting as an antagonist of WNT members. It is therefore crucial to review
the appropriateness of WIF-1 to be used as an anti-cancer agent in the field.
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Study On The Involvement Of Wif-1 In Oral Carcinogenesis , Via Egfr And Wnt Signaling Pathways