Cargando…

Genomic Loss of Tumor Suppressor miRNA-204 Promotes Cancer Cell Migration and Invasion by Activating AKT/mTOR/Rac1 Signaling and Actin Reorganization

Increasing evidence suggests that chromosomal regions containing microRNAs are functionally important in cancers. Here, we show that genomic loci encoding miR-204 are frequently lost in multiple cancers, including ovarian cancers, pediatric renal tumors, and breast cancers. MiR-204 shows drastically...

Descripción completa

Detalles Bibliográficos
Autores principales: Imam, J. Saadi, Plyler, Jason R., Bansal, Hima, Prajapati, Suresh, Bansal, Sanjay, Rebeles, Jennifer, Chen, Hung-I Harry, Chang, Yao-Fu, Panneerdoss, Subbarayalu, Zoghi, Behyar, Buddavarapu, Kalyan C., Broaddus, Russell, Hornsby, Peter, Tomlinson, Gail, Dome, Jeffrey, Vadlamudi, Ratna K., Pertsemlidis, Alexander, Chen, Yidong, Rao, Manjeet K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3528651/
https://www.ncbi.nlm.nih.gov/pubmed/23285024
http://dx.doi.org/10.1371/journal.pone.0052397
_version_ 1782253845250834432
author Imam, J. Saadi
Plyler, Jason R.
Bansal, Hima
Prajapati, Suresh
Bansal, Sanjay
Rebeles, Jennifer
Chen, Hung-I Harry
Chang, Yao-Fu
Panneerdoss, Subbarayalu
Zoghi, Behyar
Buddavarapu, Kalyan C.
Broaddus, Russell
Hornsby, Peter
Tomlinson, Gail
Dome, Jeffrey
Vadlamudi, Ratna K.
Pertsemlidis, Alexander
Chen, Yidong
Rao, Manjeet K.
author_facet Imam, J. Saadi
Plyler, Jason R.
Bansal, Hima
Prajapati, Suresh
Bansal, Sanjay
Rebeles, Jennifer
Chen, Hung-I Harry
Chang, Yao-Fu
Panneerdoss, Subbarayalu
Zoghi, Behyar
Buddavarapu, Kalyan C.
Broaddus, Russell
Hornsby, Peter
Tomlinson, Gail
Dome, Jeffrey
Vadlamudi, Ratna K.
Pertsemlidis, Alexander
Chen, Yidong
Rao, Manjeet K.
author_sort Imam, J. Saadi
collection PubMed
description Increasing evidence suggests that chromosomal regions containing microRNAs are functionally important in cancers. Here, we show that genomic loci encoding miR-204 are frequently lost in multiple cancers, including ovarian cancers, pediatric renal tumors, and breast cancers. MiR-204 shows drastically reduced expression in several cancers and acts as a potent tumor suppressor, inhibiting tumor metastasis in vivo when systemically delivered. We demonstrated that miR-204 exerts its function by targeting genes involved in tumorigenesis including brain-derived neurotrophic factor (BDNF), a neurotrophin family member which is known to promote tumor angiogenesis and invasiveness. Analysis of primary tumors shows that increased expression of BDNF or its receptor tropomyosin-related kinase B (TrkB) parallel a markedly reduced expression of miR-204. Our results reveal that loss of miR-204 results in BDNF overexpression and subsequent activation of the small GTPase Rac1 and actin reorganization through the AKT/mTOR signaling pathway leading to cancer cell migration and invasion. These results suggest that microdeletion of genomic loci containing miR-204 is directly linked with the deregulation of key oncogenic pathways that provide crucial stimulus for tumor growth and metastasis. Our findings provide a strong rationale for manipulating miR-204 levels therapeutically to suppress tumor metastasis.
format Online
Article
Text
id pubmed-3528651
institution National Center for Biotechnology Information
language English
publishDate 2012
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-35286512013-01-02 Genomic Loss of Tumor Suppressor miRNA-204 Promotes Cancer Cell Migration and Invasion by Activating AKT/mTOR/Rac1 Signaling and Actin Reorganization Imam, J. Saadi Plyler, Jason R. Bansal, Hima Prajapati, Suresh Bansal, Sanjay Rebeles, Jennifer Chen, Hung-I Harry Chang, Yao-Fu Panneerdoss, Subbarayalu Zoghi, Behyar Buddavarapu, Kalyan C. Broaddus, Russell Hornsby, Peter Tomlinson, Gail Dome, Jeffrey Vadlamudi, Ratna K. Pertsemlidis, Alexander Chen, Yidong Rao, Manjeet K. PLoS One Research Article Increasing evidence suggests that chromosomal regions containing microRNAs are functionally important in cancers. Here, we show that genomic loci encoding miR-204 are frequently lost in multiple cancers, including ovarian cancers, pediatric renal tumors, and breast cancers. MiR-204 shows drastically reduced expression in several cancers and acts as a potent tumor suppressor, inhibiting tumor metastasis in vivo when systemically delivered. We demonstrated that miR-204 exerts its function by targeting genes involved in tumorigenesis including brain-derived neurotrophic factor (BDNF), a neurotrophin family member which is known to promote tumor angiogenesis and invasiveness. Analysis of primary tumors shows that increased expression of BDNF or its receptor tropomyosin-related kinase B (TrkB) parallel a markedly reduced expression of miR-204. Our results reveal that loss of miR-204 results in BDNF overexpression and subsequent activation of the small GTPase Rac1 and actin reorganization through the AKT/mTOR signaling pathway leading to cancer cell migration and invasion. These results suggest that microdeletion of genomic loci containing miR-204 is directly linked with the deregulation of key oncogenic pathways that provide crucial stimulus for tumor growth and metastasis. Our findings provide a strong rationale for manipulating miR-204 levels therapeutically to suppress tumor metastasis. Public Library of Science 2012-12-21 /pmc/articles/PMC3528651/ /pubmed/23285024 http://dx.doi.org/10.1371/journal.pone.0052397 Text en © 2012 Imam et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Imam, J. Saadi
Plyler, Jason R.
Bansal, Hima
Prajapati, Suresh
Bansal, Sanjay
Rebeles, Jennifer
Chen, Hung-I Harry
Chang, Yao-Fu
Panneerdoss, Subbarayalu
Zoghi, Behyar
Buddavarapu, Kalyan C.
Broaddus, Russell
Hornsby, Peter
Tomlinson, Gail
Dome, Jeffrey
Vadlamudi, Ratna K.
Pertsemlidis, Alexander
Chen, Yidong
Rao, Manjeet K.
Genomic Loss of Tumor Suppressor miRNA-204 Promotes Cancer Cell Migration and Invasion by Activating AKT/mTOR/Rac1 Signaling and Actin Reorganization
title Genomic Loss of Tumor Suppressor miRNA-204 Promotes Cancer Cell Migration and Invasion by Activating AKT/mTOR/Rac1 Signaling and Actin Reorganization
title_full Genomic Loss of Tumor Suppressor miRNA-204 Promotes Cancer Cell Migration and Invasion by Activating AKT/mTOR/Rac1 Signaling and Actin Reorganization
title_fullStr Genomic Loss of Tumor Suppressor miRNA-204 Promotes Cancer Cell Migration and Invasion by Activating AKT/mTOR/Rac1 Signaling and Actin Reorganization
title_full_unstemmed Genomic Loss of Tumor Suppressor miRNA-204 Promotes Cancer Cell Migration and Invasion by Activating AKT/mTOR/Rac1 Signaling and Actin Reorganization
title_short Genomic Loss of Tumor Suppressor miRNA-204 Promotes Cancer Cell Migration and Invasion by Activating AKT/mTOR/Rac1 Signaling and Actin Reorganization
title_sort genomic loss of tumor suppressor mirna-204 promotes cancer cell migration and invasion by activating akt/mtor/rac1 signaling and actin reorganization
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3528651/
https://www.ncbi.nlm.nih.gov/pubmed/23285024
http://dx.doi.org/10.1371/journal.pone.0052397
work_keys_str_mv AT imamjsaadi genomiclossoftumorsuppressormirna204promotescancercellmigrationandinvasionbyactivatingaktmtorrac1signalingandactinreorganization
AT plylerjasonr genomiclossoftumorsuppressormirna204promotescancercellmigrationandinvasionbyactivatingaktmtorrac1signalingandactinreorganization
AT bansalhima genomiclossoftumorsuppressormirna204promotescancercellmigrationandinvasionbyactivatingaktmtorrac1signalingandactinreorganization
AT prajapatisuresh genomiclossoftumorsuppressormirna204promotescancercellmigrationandinvasionbyactivatingaktmtorrac1signalingandactinreorganization
AT bansalsanjay genomiclossoftumorsuppressormirna204promotescancercellmigrationandinvasionbyactivatingaktmtorrac1signalingandactinreorganization
AT rebelesjennifer genomiclossoftumorsuppressormirna204promotescancercellmigrationandinvasionbyactivatingaktmtorrac1signalingandactinreorganization
AT chenhungiharry genomiclossoftumorsuppressormirna204promotescancercellmigrationandinvasionbyactivatingaktmtorrac1signalingandactinreorganization
AT changyaofu genomiclossoftumorsuppressormirna204promotescancercellmigrationandinvasionbyactivatingaktmtorrac1signalingandactinreorganization
AT panneerdosssubbarayalu genomiclossoftumorsuppressormirna204promotescancercellmigrationandinvasionbyactivatingaktmtorrac1signalingandactinreorganization
AT zoghibehyar genomiclossoftumorsuppressormirna204promotescancercellmigrationandinvasionbyactivatingaktmtorrac1signalingandactinreorganization
AT buddavarapukalyanc genomiclossoftumorsuppressormirna204promotescancercellmigrationandinvasionbyactivatingaktmtorrac1signalingandactinreorganization
AT broaddusrussell genomiclossoftumorsuppressormirna204promotescancercellmigrationandinvasionbyactivatingaktmtorrac1signalingandactinreorganization
AT hornsbypeter genomiclossoftumorsuppressormirna204promotescancercellmigrationandinvasionbyactivatingaktmtorrac1signalingandactinreorganization
AT tomlinsongail genomiclossoftumorsuppressormirna204promotescancercellmigrationandinvasionbyactivatingaktmtorrac1signalingandactinreorganization
AT domejeffrey genomiclossoftumorsuppressormirna204promotescancercellmigrationandinvasionbyactivatingaktmtorrac1signalingandactinreorganization
AT vadlamudiratnak genomiclossoftumorsuppressormirna204promotescancercellmigrationandinvasionbyactivatingaktmtorrac1signalingandactinreorganization
AT pertsemlidisalexander genomiclossoftumorsuppressormirna204promotescancercellmigrationandinvasionbyactivatingaktmtorrac1signalingandactinreorganization
AT chenyidong genomiclossoftumorsuppressormirna204promotescancercellmigrationandinvasionbyactivatingaktmtorrac1signalingandactinreorganization
AT raomanjeetk genomiclossoftumorsuppressormirna204promotescancercellmigrationandinvasionbyactivatingaktmtorrac1signalingandactinreorganization