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Ezrin mediates both HGF/Met autocrine and non‐autocrine signaling‐induced metastasis in melanoma
Author(s) -
Huang Liping,
Qin Yifei,
Zuo Qiang,
Bhatnagar Kavita,
Xiong Jingbo,
Merlino Glenn,
Yu Yanlin
Publication year - 2017
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.31196
Subject(s) - ezrin , autocrine signalling , cancer research , mapk/erk pathway , signal transduction , metastasis , gene knockdown , melanoma , biology , microbiology and biotechnology , medicine , cancer , cell , cell culture , genetics , cytoskeleton
Aberrant HGF/Met signaling promotes tumor migration, invasion, and metastasis through both autocrine and non‐autocrine mechanisms; however, the molecular downstream signaling mechanisms by which HGF/Met induces metastasis are incompletely understood. We here report that Ezrin expression is stimulated by HGF and correlates with activated HGF/Met, indicating that HGF/Met signaling regulates the expression of Ezrin. We show that HGF/Met signaling activates the transcription factor Sp1 through the MAPK pathway, and activated Sp1 can in turn directly bind to the promoter of Ezrin gene and regulate its transcription. Notably, knockdown of Ezrin expression by shRNAs inhibits the metastasis induced by either HGF/Met autocrine or non‐autocrine signaling in syngeneic wildtype and HGF transgenic mouse hosts. We also used small molecule drugs in preclinical mouse models to confirm that Ezrin is one of the downstream molecules mediating HGF/Met signaling‐induced metastasis in melanoma. We conclude that Ezrin is a key downstream factor involved in the regulation of HGF/Met signaling‐induced metastasis and demonstrate a link between Ezrin and HGF/Met/MAPK/Sp1 activation in the metastatic process. Our data indicate that Ezrin represents a promising therapeutic target for patients bearing tumors with activated HGF/Met signaling.