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Metastasis suppressor NME 1 regulates melanoma cell morphology, self‐adhesion and motility via induction of fibronectin expression
Author(s) -
Novak Marián,
Leonard Mary Kathryn,
Yang Xiuwei H.,
Kowluru Anjan,
Belkin Alexey M.,
Kaetzel David M.
Publication year - 2015
Publication title -
experimental dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.108
H-Index - 96
eISSN - 1600-0625
pISSN - 0906-6705
DOI - 10.1111/exd.12697
Subject(s) - fibronectin , motility , extracellular matrix , biology , cell culture , microbiology and biotechnology , integrin , metastasis suppressor gene , focal adhesion , cell adhesion , gene expression , cell , signal transduction , gene , biochemistry , genetics
Abstract Expression of the metastasis suppressor NME 1 in melanoma is associated with reduced cellular motility and invasion in vitro and metastasis in vivo , but the underlying molecular mechanisms are not completely understood. Herein, we report a novel mechanism through which NME 1 controls melanoma cell morphology via upregulation of the extracellular matrix ( ECM ) protein fibronectin. Expression of NME 1 strongly suppressed cell motility in melanoma cell lines 1205 LU and M14. The resulting sedentary phenotype was associated with a more flattened appearance and marked increases in actin stress fibre and focal adhesion formation. NME 1‐induced focal adhesions were colocalized with dense deposits of fibronectin, which were absent or minimal in the corresponding NME 1‐deficient parental lines. NME 1 was a strong inducer of fibronectin mRNA and protein expression, shown with reciprocal approaches of forced NME 1 expression and sh RNA ‐mediated knock‐down. Increased synthesis and ECM deposition of fibronectin was necessary for NME 1‐induced cell spreading, as knock‐down of fibronectin opposed the effects of NME 1 on cell morphology. Fibronectin knock‐down also reversed the ability of NME 1 to promote aggregation when cells were plated on a non‐adherent substratum. Similarly, inhibiting activation of the fibronectin receptor integrin α 4 β 1 with an anti‐ α 4 antibody reversed the motility‐suppressing effect of NME 1. A positive correlation was observed between NME 1 and fibronectin mRNA in clinical biopsies of normal skin, benign nevi and primary melanomas, but not in metastatic forms, suggesting the NME 1/fibronectin axis represents a barrier to melanoma progression. In summary, these findings indicate fibronectin is an important effector of the motility‐suppressing function of NME 1 in melanoma cells.