EWI-2 regulates melanoma growth and lung metastasis in a TGF-?1-dependent manner
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Knoblich Konstantin
PROVIDER: S-ECPF-GEOD-47978 | biostudies-other |
REPOSITORIES: biostudies-other
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Project description:EWI-2 (IgSF8) plays a novel, bifunctional role in melanoma cells. EWI-2 inhibits migration, metastasis, EMT-like changes, and CD271-dependent invasion in multiple melanoma cell lines. On the other hand, EWI-2 supports melanoma cell proliferation, survival, and xenograft growth. Consistent with these results, EWI-2 levels were elevated in human malignant melanoma, but not in metastatic melanoma samples. Altered melanoma cell functions, caused by EWI-2 ablation, are almost entirely dependent on enhanced TRF-M-NM-21 signaling, and also require contributions from tetraspanin proteins CD9 and CD81. In melanoma cells lacking EWI-2, tetraspanins CD9 and CD81 enhance TRF-M-NM-21 signaling by facilitating TM-NM-2R-2M-bM-^HM-^RTM-NM-2R-1 receptor complex formation. When EWI-2 is present, CD9 and CD81 are diverted into EWI-2 complexes, and thus TRF-M-NM-21 signaling is inhibited. 4 samples = 2 Control + 2 EWI-2 KD.
2013-06-15 | E-GEOD-47978 | biostudies-arrayexpress
Project description:EWI-2 (IgSF8) plays a novel, bifunctional role in melanoma cells. EWI-2 inhibits migration, metastasis, EMT-like changes, and CD271-dependent invasion in multiple melanoma cell lines. On the other hand, EWI-2 supports melanoma cell proliferation, survival, and xenograft growth. Consistent with these results, EWI-2 levels were elevated in human malignant melanoma, but not in metastatic melanoma samples. Altered melanoma cell functions, caused by EWI-2 ablation, are almost entirely dependent on enhanced TRF-β1 signaling, and also require contributions from tetraspanin proteins CD9 and CD81. In melanoma cells lacking EWI-2, tetraspanins CD9 and CD81 enhance TRF-β1 signaling by facilitating TβR-2−TβR-1 receptor complex formation. When EWI-2 is present, CD9 and CD81 are diverted into EWI-2 complexes, and thus TRF-β1 signaling is inhibited.
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Project description:In normal melanocytes, TGF-β signaling has a cytostatic effect. However, in primary melanoma cells, TGF-β-induced cytostasis is diminished, thus allowing melanoma growth. Later, a second phase of TGF-β signaling supports melanoma EMT-like changes, invasion and metastasis. In parallel with these "present-absent-present" TGF-β signaling phases, cell surface protein EWI motif-containing protein 2 (EWI-2 or IgSF8) is "absent-present-absent" in melanocytes, primary melanoma, and metastatic melanoma, respectively, suggesting that EWI-2 may serve as a negative regulator of TGF-β signaling. Using melanoma cell lines and melanoma short-term cultures, we performed RNAi and overexpression experiments and found that EWI-2 negatively regulates TGF-β signaling and its downstream events including cytostasis (in vitro and in vivo), EMT-like changes, cell migration, CD271-dependent invasion, and lung metastasis (in vivo). When EWI-2 is present, it associates with cell surface tetraspanin proteins CD9 and CD81 - molecules not previously linked to TGF-β signaling. Indeed, when associated with EWI-2, CD9 and CD81 are sequestered and have no impact on TβR2-TβR1 association or TGF-β signaling. However, when EWI-2 is knocked down, CD9 and CD81 become available to provide critical support for TβR2-TβR1 association, thus markedly elevating TGF-β signaling. Consequently, all of those TGF-β-dependent functions specifically arising due to EWI-2 depletion are reversed by blocking or depleting cell surface tetraspanin proteins CD9 or CD81. These results provide new insights into regulation of TGF-β signaling in melanoma, uncover new roles for tetraspanins CD9 and CD81, and strongly suggest that EWI-2 could serve as a favorable prognosis indicator for melanoma patients.
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