TY - JOUR
T1 - ΔNp63 promotes pediatric neuroblastoma and osteosarcoma by regulating tumor angiogenesis
AU - Bid, Hemant K.
AU - Roberts, Ryan D.
AU - Cam, Maren
AU - Audino, Anthony
AU - Kurmasheva, Raushan T.
AU - Lin, Jiayuh
AU - Houghton, Peter J.
AU - Cam, Hakan
PY - 2014/1/1
Y1 - 2014/1/1
N2 - The tumor suppressor gene p53 and its family members p63/p73 are critical determinants of tumorigenesis. ΔNp63 is a splice variant of p63, which lacks the N-terminal transactivation domain. It is thought to antagonize p53-, p63-, and p73-dependent translation, thus blocking their tumor suppressor activity. In our studies of the pediatric solid tumors neuroblastoma and osteosarcoma, we find overexpression of ΔNp63; however, there is no correlation of ΔNp63 expression with p53 mutation status. Our data suggest that ΔNp63 itself endows cells with a gain-of-function that leads to malignant transformation, a function independent of any p53 antagonism. Here, we demonstrate that ΔNp63 overexpression, independent of p53, increases secretion of interleukin (IL)-6 and IL-8, leading to elevated phosphorylation of STAT3 (Tyr-705). We show that elevated phosphorylation of STAT3 leads to stabilization of hypoxia-inducible factor 1α (HIF-1α) protein, resulting in VEGF secretion. We also show human clinical data, which suggest a mechanistic role for ΔNp63 in osteosarcoma metastasis. In summary, our studies reveal the mechanism by which ΔNp63, as a master transcription factor, modulates tumor angiogenesis.
AB - The tumor suppressor gene p53 and its family members p63/p73 are critical determinants of tumorigenesis. ΔNp63 is a splice variant of p63, which lacks the N-terminal transactivation domain. It is thought to antagonize p53-, p63-, and p73-dependent translation, thus blocking their tumor suppressor activity. In our studies of the pediatric solid tumors neuroblastoma and osteosarcoma, we find overexpression of ΔNp63; however, there is no correlation of ΔNp63 expression with p53 mutation status. Our data suggest that ΔNp63 itself endows cells with a gain-of-function that leads to malignant transformation, a function independent of any p53 antagonism. Here, we demonstrate that ΔNp63 overexpression, independent of p53, increases secretion of interleukin (IL)-6 and IL-8, leading to elevated phosphorylation of STAT3 (Tyr-705). We show that elevated phosphorylation of STAT3 leads to stabilization of hypoxia-inducible factor 1α (HIF-1α) protein, resulting in VEGF secretion. We also show human clinical data, which suggest a mechanistic role for ΔNp63 in osteosarcoma metastasis. In summary, our studies reveal the mechanism by which ΔNp63, as a master transcription factor, modulates tumor angiogenesis.
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UR - http://www.scopus.com/inward/citedby.url?scp=84892692849&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-13-0894
DO - 10.1158/0008-5472.CAN-13-0894
M3 - Article
C2 - 24154873
AN - SCOPUS:84892692849
VL - 74
SP - 320
EP - 329
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 1
ER -