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Sci Rep. 2016 Oct 5;6:34504. doi: 10.1038/srep34504.

Dual targeting of ANGPT1 and TGFBR2 genes by miR-204 controls angiogenesis in breast cancer.

Author information

1
Posgrado en Ciencias Genómicas, Universidad Autónoma de la Ciudad de México, Ciudad de México, México.
2
Programa en Biomedicina Molecular y Red de Biotecnología, Escuela Nacional de Medicina y Homeopatía, Instituto Politécnico Nacional, Ciudad de México, México.
3
Instituto de Enfermedades de la Mama, FUCAM, Ciudad de México, México.
4
Laboratorio de Genómica, Instituto Nacional de Medicina Genómica, Ciudad de México, México.
5
Departamento de Ciencias Naturales, Universidad Autónoma Metropolitana, Ciudad de México, México.
6
Laboratorio de Genética y Diagnóstico Molecular, Hospital Juárez, Ciudad de México, México.
7
Departamento de Genética Humana, Hospital General de Mexico "Dr Eduardo Liceaga", Ciudad de México, México.
8
Laboratorio de Investigación en Cáncer Translacional y Terapia Celular, Centro Médico Siglo XXI, Ciudad de México, México.
9
Laboratorio de Medicina Translacional, Instituto Nacional de Cancerología, Ciudad de México, México.
10
Laboratorio de Medicina Genómica, Hospital Regional 1 de Octubre ISSSTE, Ciudad de México, México.
11
Laboratorio de Genómica, Instituto Nacional de Cancerología, Ciudad de México, México; Universidad Nacional Autónoma de México UNAM, FES-Iztacala, UBIMED, Tlalnepantla, Estado de México, México.
12
Laboratorio de Investigación Experimental y Animal. Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, México.

Abstract

Deregulated expression of microRNAs has been associated with angiogenesis. Studying the miRNome of locally advanced breast tumors we unsuspectedly found a dramatically repression of miR-204, a small non-coding RNA with no previous involvement in tumor angiogenesis. Downregulation of miR-204 was confirmed in an independent cohort of patients and breast cancer cell lines. Gain-of-function analysis indicates that ectopic expression of miR-204 impairs cell proliferation, anchorage-independent growth, migration, invasion, and the formation of 3D capillary networks in vitro. Likewise, in vivo vascularization and angiogenesis were suppressed by miR-204 in a nu/nu mice model. Genome-wide profiling of MDA-MB-231 cells expressing miR-204 revealed changes in the expression of hundred cancer-related genes. Of these, we focused on the study of pro-angiogenic ANGPT1 and TGFβR2. Functional analysis using luciferase reporter and rescue assays confirmed that ANGPT1 and TGFβR2 are novel effectors downstream of miR-204. Accordingly, an inverse correlation between miR-204 and ANGPT1/TGFβR2 expression was found in breast tumors. Knockdown of TGFβR2, but not ANGPT1, impairs cell proliferation and migration whereas inhibition of both genes inhibits angiogenesis. Taken altogether, our findings reveal a novel role for miR-204/ANGPT1/TGFβR2 axis in tumor angiogenesis. We propose that therapeutic manipulation of miR-204 levels may represent a promising approach in breast cancer.

PMID:
27703260
PMCID:
PMC5050489
DOI:
10.1038/srep34504
[Indexed for MEDLINE]
Free PMC Article

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