Transforming growth factor-beta employs HMGA2 to elicit epithelial-mesenchymal transition.
Epithelial-mesenchymal transition (EMT) occurs during embryogenesis, carcinoma invasiveness, and metastasis and can be elicited by transforming growth factor-beta (TGF-beta) signaling via intracellular Smad transducers. The molecular mechanisms that control the onset of EMT remain largely unexplored. Transcriptomic analysis revealed that the high mobility group A2 (HMGA2) gene is induced by the Smad pathway during EMT. Endogenous HMGA2 mediates EMT by TGF-beta, whereas ectopic HMGA2 causes irreversible EMT characterized by severe E-cadherin suppression. HMGA2 provides transcriptional input for the expression control of four known regulators of EMT, the zinc-finger proteins Snail and Slug, the basic helix-loop-helix protein Twist, and inhibitor of differentiation 2. We delineate a pathway that links TGF-beta signaling to the control of epithelial differentiation via HMGA2 and a cohort of major regulators of tumor invasiveness and metastasis. This network of signaling/transcription factors that work sequentially to establish EMT suggests that combinatorial detection of these proteins could serve as a new tool for EMT analysis in cancer patients.
Thuault
Sylvie
S
Ludwig Institute for Cancer Research, Uppsala University, SE-751 24 Uppsala, Sweden, and Institut National de la Santé et de la Recherche Médicale, Hôpital E. Herriot, Lyon Cedex, France.
Valcourt
Ulrich
U
Petersen
Maj
M
Manfioletti
Guidalberto
G
Heldin
Carl-Henrik
CH
Moustakas
Aristidis
A
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D004847:Epithelial Cells / Q000166:cytology* / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D025743:HMGA2 Protein / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008648:Mesoderm / Q000166:cytology* / Q000187:drug effects*; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D025743:HMGA2 Protein; D012333:RNA, Messenger; D051785:Smad Proteins; D016212:Transforming Growth Factor beta