Journal
JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY
Volume 140, Issue 11, Pages 1913-1926Publisher
SPRINGER
DOI: 10.1007/s00432-014-1722-3
Keywords
Malignant melanoma; FLNa; EGFR; Metastasis; Proliferation
Categories
Funding
- National Natural Science Foundation of China [81071846]
- Natural Science Foundation of Hebei Province of China [H2013505059]
- Department of Science and Technology of Hebei Province of China [12396107D]
- Wu Jieping Foundation [320.6750.12604]
- Intramural Research Program of National Institutes of Health, National Institute on Aging
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Filamin A (FLNa) cross-links actin filaments into dynamic orthogonal networks and interacts with binding proteins of diverse cellular functions that are implicated in cell growth and motility regulation. Here, we tested the hypothesis that FLNa plays a role in cancer proliferation and metastasis via the regulation of epidermal growth factor receptor (EGFR) function. Ectopic expression and knockdown of FLNa in human melanoma cell lines was performed to investigate changes in cellular proliferation, migration and invasion in vitro and tumor growth in a xenograft model in the mouse. The role of FLNa in EGFR expression and signaling was evaluated by Western blot. Immunohistochemistry was performed on histological sections of human melanoma tumors to determine whether an association existed between FLNa and overall survival. The depletion of FLNa significantly reduced the proliferation, migration and invasion of two melanoma cell lines in vitro and was associated with smaller tumors in a xenograft model in vivo. EGF-induced phosphorylation of EGFR and activation of the Raf-MEK-ERK cascade was negatively affected by the silencing of FLNa both in vitro and in vivo. Cancer patients with low melanoma tumor FLNa expression have improved survival benefit. These data indicate that enhanced tumorigenesis occurs through increase in EGF-induced EGFR activation in FLNa-expressing melanoma cells and that high FLNa levels are predictors of negative outcome for patients with melanoma tumors.
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