Abstract
Purpose
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.
Methods
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.
Results
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.
Conclusion
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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Abbreviations
- FLNa:
-
Filamin A
- EGFR:
-
Epidermal growth factor receptor
- ERK:
-
Ras-extracellular signal-regulated kinase
- JNK:
-
c-Jun NH2-terminal kinase
- MEM:
-
Minimal essential medium
- FBS:
-
Fetal bovine serum
- SFM:
-
Serum-free medium
- EGF:
-
Epidermal growth factor
- ECL:
-
Enhanced chemiluminescence
- pY-EGFR:
-
Phosphorylated form of EGFR
- pERK1/2:
-
Phosphorylated ERK1/2
- IHC:
-
Immunohistochemical
- MMPs:
-
Matrix metalloproteinases
- ECM:
-
Extracellular matrix
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Acknowledgments
This work was supported by the National Natural Science Foundation of China (No. 81071846, to T.N.Z); Natural Science Foundation of Hebei Province of China (No. H2013505059, to T.N.Z); Department of Science and Technology of Hebei Province of China (No. 12396107D, to R.J.Z); Wu Jieping Foundation (No. 320.6750.12604, to T.N.Z) and, in part, by the Intramural Research Program of National Institutes of Health, National Institute on Aging.
Conflict of interest
We, all authors declare that there is no any financial arrangements that could be related to the manuscript and confirm that we do not have any disclosure to make at submission. None of the authors has any potential financial conflict of interest related to this manuscript.
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Zhang, K., Zhu, T., Gao, D. et al. Filamin A expression correlates with proliferation and invasive properties of human metastatic melanoma tumors: implications for survival in patients. J Cancer Res Clin Oncol 140, 1913–1926 (2014). https://doi.org/10.1007/s00432-014-1722-3
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DOI: https://doi.org/10.1007/s00432-014-1722-3