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Transforming growth factor-beta employs HMGA2 to elicit epithelial-mesenchymal transition.

ABSTRACT: 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.

SUBMITTER: Thuault S

PROVIDER: S-EPMC2064178 | biostudies-literature | 2006 Jul

REPOSITORIES: biostudies-literature

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Transforming growth factor-beta employs HMGA2 to elicit epithelial-mesenchymal transition.

Thuault Sylvie S Valcourt Ulrich U Petersen Maj M Manfioletti Guidalberto G Heldin Carl-Henrik CH Moustakas Aristidis A

The Journal of cell biology 20060710 2

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 irrev ...[more]

PMID: 16831886

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Project description:Transforming growth factor-? (TGF-?) and epidermal growth factor (EGF) have critical roles in regulating the metastasis of aggressive breast cancers, yet the impact of epithelial-mesenchymal transition (EMT) induced by TGF-? in altering the response of breast cancer cells to EGF remains unknown. We show in this study that murine metastatic 4T1 breast cancer cells formed compact and dense spheroids when cultured under three-dimensional (3D) conditions, which was in sharp contrast to the branching phenotypes exhibited by their nonmetastatic counterparts. Using the human MCF10A series, we show that epithelial-type and nonmetastatic breast cancer cells were unable to invade to EGF, whereas their mesenchymal-type and metastatic counterparts readily invaded to EGF. Furthermore, EMT induced by TGF-? was sufficient to manifest dense spheroid morphologies, a phenotype that increased primary tumor exit and invasion to EGF. Post-EMT invasion to EGF was dependent on increased activation of EGF receptor (EGFR) and p38 mitogen-activated protein kinase, all of which could be abrogated either by pharmacologic (PF-562271) or by genetic (shRNA) targeting of focal adhesion kinase (FAK). Mechanistically, EMT induced by TGF-? increased cell-surface levels of EGFR and prevented its physical interaction with E-cadherin, leading instead to the formation of oncogenic signaling complexes with T?R-II. Elevated EGFR expression was sufficient to transform normal mammary epithelial cells, and to progress their 3D morphology from that of hollow acini to branched structures characteristic of nonmetastatic breast cancer cells. Importantly, we show that TGF-? stimulation of EMT enabled this EGFR-driven breast cancer model to abandon their inherent branching architecture and form large, undifferentiated masses that were hyperinvasive to EGF and showed increased pulmonary tumor growth upon tail vein injection. Finally, chemotherapeutic targeting of FAK was sufficient to revert the aggressive behaviors of these structures. Collectively, this investigation has identified a novel EMT-based approach to neutralize the oncogenic activities of EGF and TGF-? in aggressive and invasive forms of breast cancer.

Project description:PurposeTransforming growth factor-β (TGF-β) is considered to be essential to induce epithelial-to-mesenchymal transition (EMT) which plays central roles in wound healing in ocular fibrotic complication. The present study investigates whether small interference RNAs (siRNAs) targeting the type II receptor of TGF-β (TβRII) could be used to minimize the TGF-β action.MethodsTGF-β receptor type II (TβRII) specific siRNAs designed from the Nakamura human gene sequence were used to transfect the cultured lens epithelial cells (LECs). The optimal transfection of scramble siRNA-Cy3 labeled duplexes in cultured LECs were examined by laser scanning confocal microscope and flow cytometry. TβRII protein expression and transcript levels were analyzed by immunofluorescence, western blotting, and real time PCR, respectively. Western blotting was performed to examine protein expression of fibronectin and alpha-smooth muscle actin (α-SMA). Scratch assay was used to determine cell migration. Cell morphology was observed after transfection by inverted microscope.ResultsThe optimal transfection rate of scramble siRNA-Cy3 labeled duplexes was efficient in that nearly to 50% in cultured LECs. TβRII specific siRNAs significantly reduced the receptor transcript and protein expression in cultured LECs. The gene knockdown inhibited LECs transdifferentiation, as it abrogated the expression of fibronectin and α-SMA, and retarded cell migration on the scratch assay. In addition, after transfection with TβRII specific siRNA, the cultured LECs did not show fibroblast-like shape which was one of the feature signs of EMT. Wound scratch assays indicated that the number of cultured LECs migrated into the wounded area was significantly lower in TβRII specific siRNA treated group (12.8 ± 3.27/7.85 mm(2)), compared with normal (57.8 ± 3.06/7.85 mm(2)) and scrambled RNA transfected group (50.8 ± 3.64/7.85 mm(2); p<0.0001).ConclusionsOur results provided additional evidence to support that TGF-β pathway was involved in the development of EMT of human posterior capsule opacification, while how TβRII was involved should be further investigated.

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Transforming growth factor-beta employs HMGA2 to elicit epithelial-mesenchymal transition.

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Transforming growth factor-beta employs HMGA2 to elicit epithelial-mesenchymal transition.

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