期刊
MOLECULAR CELL
卷 59, 期 4, 页码 664-676出版社
CELL PRESS
DOI: 10.1016/j.molcel.2015.06.028
关键词
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资金
- I-CORE Gene Regulation in Complex Human Disease, Center [41/11]
- Israel Cancer Association (ICA)
- Israel Cancer Research Fund (ICRF)
- Fritz Thyssen Stiftung
- Marie Curie Career Integration Grants (CIG)
- Dalya Gridinger Fund
- Fingerhot Carol and Lionara Fund
- Shtacher Family award
The most critical stage in initiation of melanoma metastasis is the radial to vertical growth transition, yet the triggers of this transition remain elusive. We suggest that the microenvironment drives melanoma metastasis independently of mutation acquisition. Here we examined the changes in microenvironment that occur during melanoma radial growth. We show that direct contact of melanoma cells with the remote epidermal layer triggers vertical invasion via Notch signaling activation, the latter serving to inhibit MITF function. Briefly, within the native Notch ligand-free microenvironment, MITF, the melanocyte lineage master regulator, binds and represses miR222/221 promoter in an RBPJK-dependent manner. However, when radial growth brings melanoma cells into contact with distal differentiated keratinocytes that express Notch ligands, the activated Notch intracellular domain impairs MITF binding to miR222/221 promoter. This de-repression of miR-222/221 expression triggers initiation of invasion. Our findings may direct melanoma prevention opportunities via targeting specific microenvironments.
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