Leukemia inhibitory factor triggers activation of signal transducer and activator of transcription 3, proliferation, invasiveness, and altered protease expression in choriocarcinoma cells.
Extravillous trophoblast cells resemble cancer cells with regard to their intrinsic invasiveness. They invade decidual tissue, but, unlike tumor cells, shut down their invasive properties, when they become inappropriate. Stimuli involved in the modulation of invasion, as well as their underlying signaling mechanisms require further clarification. We were especially interested in discovering signals capable of stimulating invasion in otherwise low-invasive cells involved in reproduction. Using the choriocarcinoma cell line Jeg-3 as a model, we have addressed the potential role of cytokine/growth factor-driven activation of signal transducer and activator of transcription 3 (STAT3) in this process. Jeg-3 cells were treated with various factors known to induce trophoblast proliferation, differentiation, migration, or invasiveness (insulin-like-growth-factor-II (IGF-II), hepatocyte growth factor (HGF), interleukin-6 (IL-6), and leukemia inhibitory factor (LIF)). Only LIF elicited strong tyrosine phosphorylation and specific DNA-binding activity of STAT3. It induced a significant acceleration of cell proliferation and promoted the capability of Jeg-3 cells to invade into an artificial extracellular matrix. Moreover, LIF influenced the expression pattern of proteases and protease inhibitors with potential relevance for invasiveness (downregulation of mRNA for tissue inhibitor of metalloproteinase 1 (TIMP-1) and upregulation of mRNA for caspase-4). In conjunction with earlier work, in which we found that STAT3 DNA-binding activity was increased in invasive cells (choriocarcinoma, first trimester trophoblasts) and absent in non-invasive cells (term trophoblasts), these findings suggest a connection between LIF-driven STAT3 activity and invasiveness of choriocarcinoma and trophoblast cells.
Fitzgerald
Justine S
JS
Department of Obstetrics, Friedrich-Schiller-University Jena, Bachstrasse 18, 07740 Jena, Germany.
Tsareva
Svetlana A
SA
Poehlmann
Tobias G
TG
Berod
Luciana
L
Meissner
Anja
A
Corvinus
Florian M
FM
Wiederanders
Bernd
B
Pfitzner
Edith
E
Markert
Udo R
UR
Friedrich
Karlheinz
K
D020169:Caspases / Q000378:metabolism; D053471:Caspases, Initiator; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002822:Choriocarcinoma / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D053605:Leukemia Inhibitory Factor; D009361:Neoplasm Invasiveness; D020411:Oligonucleotide Array Sequence Analysis; D010447:Peptide Hydrolases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011247:Pregnancy; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
D015850:Interleukin-6; C507837:LIF protein, human; D053605:Leukemia Inhibitory Factor; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D014443:Tyrosine; D010447:Peptide Hydrolases; C093516:CASP4 protein, human; D020169:Caspases; D053471:Caspases, Initiator