Protein Tyrosine Phosphatase 4A3 (PTP4A3) Promotes Human Uveal Melanoma Aggressiveness Through Membrane Accumulation of Matrix Metalloproteinase 14 (MMP14).
OBJECTIVE
To study PTP4A3 phosphatase and MMP14 metalloprotease synergy in uveal melanoma aggressiveness.


METHODS
Cell membrane localization of matrix metalloprotease 14 (MMP14) in uveal melanoma cells expressing protein tyrosine phosphatase A3 (PTP4A3) was assessed by flow cytometry or immunohistochemistry. The vesicular trafficking of MMP14 in the presence of PTP4A3 was evaluated in OCM-1 cells expressing either the wild-type or mutated phosphatase. Finally, MMP14 localization at the cell membrane of OCM-1 cells was impaired using RNA interference, and the PTP4A3-related migration in vitro and invasiveness in vivo of the treated cells were evaluated.


RESULTS
We found that the membrane-anchored MMP14 is enriched at the cell surface of OCM-1 cells, patient-derived xenograft cells, and human primary uveal melanoma tumors expressing PTP4A3. Moreover, we show that PTP4A3 and MMP14 colocalize and that the vesicular trafficking of MMP14 is faster in the presence of active PTP4A3. Finally, we demonstrate that inhibition of MMP14 expression in uveal melanoma cells expressing PTP4A3 impairs their migration in vitro and invasiveness in vivo.


CONCLUSIONS
Our observations indicate that PTP4A3 increases cell membrane accumulation of MMP14 as a result of increased cellular trafficking of the metalloprotease. We also show that downregulation of MMP14 expression reduced PTP4A3-induced cell migration and invasiveness. Taken together, our findings suggest that PTP4A3-related subcellular localization of MMP14 is an important event in metastasis induction.
Institut Curie, PSL Research University, Centre National de La Recherche Scientifique (CNRS), Institut National de la Santé Et de la Recherche Médicale (INSERM), Unité Mixte de Recherche 3347 (UMR), Unité 1021 Orsay, France 2Université Paris Sud, Universi.
Selma
S
Maacha
Institut Curie, PSL Research University, Centre National de La Recherche Scientifique (CNRS), Institut National de la Santé Et de la Recherche Médicale (INSERM), Unité Mixte de Recherche 3347 (UMR), Unité 1021 Orsay, France 2Université Paris Sud, Universi.
Océane
O
Anezo
Institut Curie, PSL Research University, Centre National de La Recherche Scientifique (CNRS), Institut National de la Santé Et de la Recherche Médicale (INSERM), Unité Mixte de Recherche 3347 (UMR), Unité 1021 Orsay, France 2Université Paris Sud, Universi.
Malika
M
Foy
Institut Curie, PSL Research University, Centre National de La Recherche Scientifique (CNRS), Institut National de la Santé Et de la Recherche Médicale (INSERM), Unité Mixte de Recherche 3347 (UMR), Unité 1021 Orsay, France 2Université Paris Sud, Universi.
Géraldine
G
Liot
Institut Curie, PSL Research University, Centre National de La Recherche Scientifique (CNRS), Institut National de la Santé Et de la Recherche Médicale (INSERM), Unité Mixte de Recherche 3347 (UMR), Unité 1021 Orsay, France 2Université Paris Sud, Universi.
Laurence
L
Mery
Residual Tumor & Response to Treatment Lab, Institut Curie - Translational Research Department, Paris, France.
Cécile
C
Laurent
Tumor Biology Department, Institut Curie, Paris, France.
Xavier
X
Sastre-Garau
Department of Medical Oncology, Institut Curie, Paris, France.
Sophie
S
Piperno-Neumann
Department of Surgical Oncology, Institut Curie, Paris, France.
Nathalie
N
Cassoux
Institut Curie, PSL Research University, Centre National de La Recherche Scientifique (CNRS), Institut National de la Santé Et de la Recherche Médicale (INSERM), Unité Mixte de Recherche 3347 (UMR), Unité 1021 Orsay, France 7Université Paris Diderot, Sorb.
Nathalie
N
Planque
Institut Curie, PSL Research University, Centre National de La Recherche Scientifique (CNRS), Institut National de la Santé Et de la Recherche Médicale (INSERM), Unité Mixte de Recherche 3347 (UMR), Unité 1021 Orsay, France 2Université Paris Sud, Universi.
Simon
S
Saule
D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D002465:Cell Movement / Q000502:physiology; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000502:physiology*; D008545:Melanoma / Q000378:metabolism / Q000503:physiopathology*; D009361:Neoplasm Invasiveness / Q000503:physiopathology; D009362:Neoplasm Metastasis / Q000503:physiopathology; D009363:Neoplasm Proteins / Q000502:physiology*; D017027:Protein Tyrosine Phosphatases / Q000502:physiology*; D034622:RNA Interference; D014602:Uvea / Q000378:metabolism / Q000503:physiopathology; D014604:Uveal Neoplasms / Q000378:metabolism / Q000503:physiopathology*
D009363:Neoplasm Proteins; C484730:PTP4A3 protein, human; D017027:Protein Tyrosine Phosphatases; D053511:Matrix Metalloproteinase 14