The Journal of Cell Biology · 2006 · 486 citations · 14 references
Life SciencesCell BiologyMolecular BiologyGene ExpressionMetastasisSignal TransductionCancer Cell SignalingEpithelial-mesenchymal TransitionEpithelial-to-mesenchymal TransitionGrowth Factor SignalingMetastatic Signaling PathwaysSignal Transduction In CancerDifferentiationEpithelial-mesenchymal TransformationEpithelial-mesenchymal Transition In CancerSmad Signaling PathwaySmad-mediated Signal TransductionTransforming Growth Factor-beta SignalingTumor Cell InvasivenessZinc Finger Proteins
Epithelial–mesenchymal transition (EMT) is a key process in development and cancer metastasis, often triggered by TGF‑β through Smad signaling, yet the precise molecular controls remain largely unknown. The study aims to map the pathway connecting TGF‑β signaling to epithelial differentiation through HMGA2 and key EMT regulators. The authors delineate a signaling cascade where TGF‑β activates Smad, induces HMGA2, which in turn regulates Snail, Slug, Twist, and Id2 to drive EMT. Transcriptomic and functional studies show that Smad‑induced HMGA2 drives irreversible EMT by up‑regulating Snail, Slug, Twist, and Id2, and that this network could be used as a combinatorial biomarker panel for EMT in cancer patients.
Epithelial–mesenchymal transition (EMT) occurs during embryogenesis, carcinoma invasiveness, and metastasis and can be elicited by transforming growth factor-β (TGF-β) 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-β, 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-β 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.
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Twist, a Master Regulator of Morphogenesis, Plays an Essential Role in Tumor Metastasis
Jing Yang, Sendurai A. Mani, Joana Liu Donaher et al. · Cell · 2004 · 3.8K citations · Full text
The transcriptional repressor Snail promotes mammary tumor recurrence
Susan E. Moody, Denise Perez, Tien-Chi Pan et al. · Cancer Cell · 2005 · 737 citations · Full text