TY - JOUR
T1 - Dual targeting of ANGPT1 and TGFBR2 genes by miR-204 controls angiogenesis in breast cancer
AU - Flores-Pérez, Ali
AU - Marchat, Laurence A.
AU - Rodríguez-Cuevas, Sergio
AU - Bautista-Piña, Verónica
AU - Hidalgo-Miranda, Alfredo
AU - Ocampo, Elena Aréchaga
AU - Martínez, Mónica Sierra
AU - Palma-Flores, Carlos
AU - Fonseca-Sánchez, Miguel A.
AU - Astudillo-De La Vega, Horacio
AU - Ruíz-García, Erika
AU - González-Barrios, Juan Antonio
AU - Pérez-Plasencia, Carlos
AU - Streber, María L.
AU - López-Camarillo, César
N1 - Publisher Copyright:
© The Author(s) 2016.
PY - 2016/10/5
Y1 - 2016/10/5
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84990200334&partnerID=8YFLogxK
U2 - 10.1038/srep34504
DO - 10.1038/srep34504
M3 - Artículo
C2 - 27703260
SN - 2045-2322
VL - 6
JO - Scientific Reports
JF - Scientific Reports
M1 - 34504
ER -