TY - JOUR
T1 - DNp73 Exerts Function in Metastasis Initiation by Disconnecting the Inhibitory Role of EPLIN on IGF1R-AKT/STAT3 Signaling
AU - Steder, Marc
AU - Alla, Vijay
AU - Meier, Claudia
AU - Spitschak, Alf
AU - Pahnke, Jens
AU - Fürst, Katharina
AU - Kowtharapu, Bhavani S.
AU - Engelmann, David
AU - Petigk, Janine
AU - Egberts, Friederike
AU - Schäd-Trcka, Susanne G.
AU - Gross, Gerd
AU - Nettelbeck, Dirk M.
AU - Niemetz, Annett
AU - Pützer, Brigitte M.
N1 - Funding Information:
This work was supported by the FORUN program of Rostock University Medical Center (grant to M.S. and B.M.P.) and the German Federal Ministry of Education and Research as part of the project eBio:SysMet (0316171 to B.M.P.). We thank Maria Soengas, Isaiah J. Fidler, Jeffrey Schlom, and Danny Welch for providing melanoma cell lines; Thorsten Stiewe for p63 plasmids; Ilona Klamfuß for assistance with mouse studies; Frank Lüthen for help with laser scanning microscopy; and Ottmar Herchenröder for critical reading of the manuscript. We appreciate the efforts of the International Genomics Consortium and expO.
PY - 2013/10/14
Y1 - 2013/10/14
N2 - Dissemination of cancer cells from primary tumors is the key event in metastasis, but specific determinants are widely unknown. Here, we show that DNp73, an inhibitor of the p53 tumor suppressor family, drives migration and invasion of nonmetastatic melanoma cells. Knockdown of endogenous DNp73 reduces this behavior in highly metastatic cell lines. Tumor xenografts expressing DNp73 show a higher ability to invade and metastasize, while growth remains unaffected. DNp73 facilitates an EMT-like phenotype with loss of E-cadherin and Slug upregulation. We provide mechanistic insight toward regulation of LIMA1/EPLIN by p73/DNp73 and demonstrate a direct link between the DNp73-EPLIN axis and IGF1R-AKT/STAT3 activation. These findings establish initiation of the invasion-metastasis cascade via EPLIN-dependent IGF1R regulation as major activity of DNp73.
AB - Dissemination of cancer cells from primary tumors is the key event in metastasis, but specific determinants are widely unknown. Here, we show that DNp73, an inhibitor of the p53 tumor suppressor family, drives migration and invasion of nonmetastatic melanoma cells. Knockdown of endogenous DNp73 reduces this behavior in highly metastatic cell lines. Tumor xenografts expressing DNp73 show a higher ability to invade and metastasize, while growth remains unaffected. DNp73 facilitates an EMT-like phenotype with loss of E-cadherin and Slug upregulation. We provide mechanistic insight toward regulation of LIMA1/EPLIN by p73/DNp73 and demonstrate a direct link between the DNp73-EPLIN axis and IGF1R-AKT/STAT3 activation. These findings establish initiation of the invasion-metastasis cascade via EPLIN-dependent IGF1R regulation as major activity of DNp73.
UR - http://www.scopus.com/inward/record.url?scp=84885344813&partnerID=8YFLogxK
U2 - 10.1016/j.ccr.2013.08.023
DO - 10.1016/j.ccr.2013.08.023
M3 - Journal articles
C2 - 24135282
AN - SCOPUS:84885344813
SN - 1535-6108
VL - 24
SP - 512
EP - 527
JO - Cancer Cell
JF - Cancer Cell
IS - 4
ER -
