MicroRNA-Antagonism Regulates Breast Cancer Stemness and Metastasis via TET-Family-Dependent Chromatin Remodeling
Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels, en induisant une transition épithélio-mésenchymateuse, le micro-ARN 22 favorise le processus métastatique d'un cancer du sein
Tumor cells metastasize to distant organs through genetic and epigenetic alterations, including changes in microRNA (miR) expression. Here we find miR-22 triggers epithelial-mesenchymal transition (EMT), enhances invasiveness and promotes metastasis in mouse xenografts. In a conditional mammary gland-specific transgenic (TG) mouse model, we show that miR-22 enhances mammary gland side-branching, expands the stem cell compartment, and promotes tumor development. Critically, miR-22 promotes aggressive metastatic disease in MMTV-miR-22 TG mice, as well as compound MMTV-neu or -PyVT-miR-22 TG mice. We demonstrate that miR-22 exerts its metastatic potential by silencing antimetastatic miR-200 through direct targeting of the TET (Ten eleven translocation) family of methylcytosine dioxygenases, thereby inhibiting demethylation of the mir-200 promoter. Finally, we show that miR-22 overexpression correlates with poor clinical outcomes and silencing of the TET-miR-200 axis in patients. Taken together, our findings implicate miR-22 as a crucial epigenetic modifier and promoter of EMT and breast cancer stemness toward metastasis. "miR-22 triggers epithelial-mesenchymal transition, invasion, and metastasis "miR-22 enhances murine mammary gland side-branching, stemness, and tumor development "miR-22 antagonizes miR-200 by directly targeting TET family members "Elevated miR-22 expression is linked to poor clinical outcomes in patients miR-22 targets TET family chromatin modifiers that promote demethylation of miR-200 promoters, dampening the expression of these miRNAs, which play a role in EMT. This pathway modulates tumorigenesis and metastasis in mammary glands and miR-22 could serve as a biomarker for breast cancer metastasis.