STAT3alpha is oncogenic for endometrial carcinoma cells and mediates the oncogenic effects of autocrine human growth hormone.
We herein demonstrate an oncogenic role for signal transducer and activator of transcription (STAT)-3alpha (the full length STAT3 isoform), which also mediates autocrine human GH (hGH)-stimulated oncogenicity, in human endometrial carcinoma (EC) cells. Autocrine hGH stimulated Y705 phosphorylation of STAT3 and STAT3-mediated transcriptional activity in a SRC and Janus-2 Kinase dependent manner in human EC cell lines. Forced expression of a constitutively active variant of STAT3alpha increased proliferation, anchorage-independent, three-dimensional (3D) Matrigel, and xenograft growth and promoted epithelial-mesenchymal transition, migration, and invasion of EC cells. Conversely, the oncogenic capacity of EC cells was significantly impaired by treatment with JSI-124, an inhibitor of STAT3 phosphorylation and activity, small interfering RNA-mediated depletion of STAT3alpha, or a dominant-negative variant of STAT3alpha. Furthermore, the enhanced EC cell oncogenicity stimulated by autocrine hGH, was also abrogated by functional inhibition or small interfering RNA-mediated depletion of STAT3alpha. STAT3alpha may therefore be a common mediator of oncogenic signaling pathways stimulating progression of EC.
Tang
Jian-Zhong
JZ
Liggins Institute, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1142, New Zealand.
Kong
Xiang-Jun
XJ
Banerjee
Arindam
A
Muniraj
Nethaji
N
Pandey
Vijay
V
Steiner
Michael
M
Perry
Jo K
JK
Zhu
Tao
T
Liu
Dong-Xu
DX
Lobie
Peter E
PE
D000818:Animals; D019898:Autocrine Communication / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D016889:Endometrial Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D019382:Human Growth Hormone / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D008856:Microscopy, Fluorescence; D009361:Neoplasm Invasiveness; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D034622:RNA Interference; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D014183:Transplantation, Heterologous; D014315:Triterpenes / Q000494:pharmacology
D008565:Membrane Proteins; D050796:STAT3 Transcription Factor; D014315:Triterpenes; C405010:delta-hGHR; D019382:Human Growth Hormone; C038106:cucurbitacin I