Heavy ions can enhance TGFβ mediated epithelial to mesenchymal transition.
TGFβ is a key modulator of the Epithelial-Mesenchymal Transition (EMT), a process important in cancer progression and metastasis, which leads to the suppression of epithelial genes and expression of mesenchymal proteins. Ionizing radiation was found to specifically induce expression of the TGF-β1 isoform, which can modulate late post-radiation changes and increase the risk of tumor development and metastasis. Interactions between TGFβ induced EMT and DNA damage responses have not been fully elucidated, particularly at low doses and following different radiation quality exposures. Further characterization of the relationship between radiation quality, EMT and cancer development is warranted. We investigated whether space radiation induced TGFβ dependent EMT, using hTERT immortalized human esophageal epithelial cells (EPC2-hTERT) and non-transformed mink lung epithelial cells (Mv1Lu). We have observed morphologic and molecular alterations in EPC2 and Mv1Lu cells consistent with EMT after pre-treatment with TGFβ1. This effect could be efficiently inhibited in both cell lines by the use of a TGFβRI inhibitor. High-energy silicon or iron nuclei were each able to cause a mild induction of EMT, with the inclusion of TGFβ1 inducing a greatly enhanced EMT phenotype even when cells were irradiated with doses as low as 0.1 Gy. A further enhancement of EMT was achieved at a higher dose of 2 Gy. TGFβRI inhibitor was able to reverse the EMT induced by the combination of TGFβ1 and radiation. These studies indicate that heavy ions, even at a low dose, may trigger the process of TGFβ1-induced EMT, and suggest further studies are needed to determine whether the chronic exposures received in space may potentiate this process in astronauts, leading to an increased risk of cancer.
USRA, Division of Life Sciences, Houston, TX 77058, USA.
Minli
M
Wang
Megumi
M
Hada
Janice
J
Huff
Janice M
JM
Pluth
Jennifer
J
Anderson
Peter
P
O'Neill
Francis A
FA
Cucinotta
D000818:Animals; D002461:Cell Line, Transformed / Q000187:drug effects / Q000528:radiation effects; D004307:Dose-Response Relationship, Radiation; D004847:Epithelial Cells / Q000187:drug effects / Q000528:radiation effects*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000528:radiation effects*; D004947:Esophagus / Q000166:cytology; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D020450:Heavy Ions / Q000009:adverse effects*; D006801:Humans; D007501:Iron; D008168:Lung / Q000166:cytology; D008907:Mink; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011621:Pteridines / Q000494:pharmacology; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D011994:Recombinant Proteins / Q000494:pharmacology; D012825:Silicon; D051899:Smad2 Protein / Q000378:metabolism; D051906:Smad7 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*; D051176:beta Catenin / Q000378:metabolism
D016326:Extracellular Matrix Proteins; D011621:Pteridines; D018125:Receptors, Transforming Growth Factor beta; D011994:Recombinant Proteins; C511004:SD-208; D051899:Smad2 Protein; D051906:Smad7 Protein; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; D051176:beta Catenin; D007501:Iron; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D012825:Silicon