Insulin Receptor Substrate-1 Suppresses Transforming Growth Factor-β1–Mediated Epithelial-Mesenchymal Transition

Shi, Jian; Wang, Dongmei; Wang, Chunmei; Ying, Hanjie; Liu, Aihua; Zhang, Yonglian; Sun, Bing; Song, Jianguo

doi:10.1158/0008-5472.can-08-4470

Cited by 41 publications

(29 citation statements)

References 33 publications

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“…Because TGF-b-induced EMT has been implicated in lung tumour cell migration and metastasis 26,27 , it is important to know whether the profilin-2-Smad pathway is linked to TGF-binduced EMT. The overexpression of profilin-2 significantly enhanced the TGF-b1-induced expression of ZEB1, an EMT-inducing transcription factor.…”

Section: Resultsmentioning

confidence: 99%

Epigenetic regulation of Smad2 and Smad3 by profilin-2 promotes lung cancer growth and metastasis

et al. 2015

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Altered transforming growth factor-b (TGF-b) signalling has been implicated in tumour development and progression. However, the molecular mechanism behind this alteration is poorly understood. Here we show that profilin-2 (Pfn2) increases Smad2 and Smad3 expression via an epigenetic mechanism, and that profilin-2 and Smad expression correlate with an unfavourable prognosis of lung cancer patients. Profilin-2 overexpression promotes, whereas profilin-2 knockdown drastically reduces, lung cancer growth and metastasis. We show that profilin-2 suppresses the recruitment of HDAC1 to Smad2 and Smad3 promoters by preventing nuclear translocation of HDAC1 through protein-protein interaction at the C terminus of both proteins, leading to the transcriptional activation of Smad2 and Smad3. Increased Smad2 and Smad3 expression enhances TGF-b1-induced EMT and production of the angiogenic factors VEGF and CTGF. These findings reveal a new regulatory mechanism of TGF-b1/Smad signalling, and suggest a potential molecular target for the development of anticancer drugs.

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Section: Resultsmentioning

confidence: 99%

Epigenetic regulation of Smad2 and Smad3 by profilin-2 promotes lung cancer growth and metastasis

et al. 2015

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“…13 More importantly, TGFβ may induce a decrease in the IRS1 protein and phosphorylation levels, implying a potential role of IRS1 in TGFβ-mediated biological function 28 ( Fig. 2).…”

Section: Canonical Vs Non-canonical Akt Signaling Pathwaysmentioning

confidence: 97%

Genotoxic stress-mediated cell cycle activities for the decision of cellular fate

Erol¹

2011

Cell Cycle

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“…It induces EMT in human lung cancer cells [17] and increases lung cancer cell migration ability [18]. A549 cells undergo EMT in response to TGF-β1 treatment, as determined by cell morphology ( Figure 1A, left) and increased cell migration ability ( Figure 1A, middle and right).…”

Section: Foxa2 Expression Is Positively Correlated With Epithelial Idmentioning

confidence: 99%

FOXA2 functions as a suppressor of tumor metastasis by inhibition of epithelial-to-mesenchymal transition in human lung cancers

et al. 2010

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The forkhead box transcription factor A2 (FOXA2) is an important regulator in animal development and body homeostasis. However, whether FOXA2 is involved in transforming growth factor β1 (TGF-β1)-mediated epithelialto-mesenchymal transition (EMT) and tumor metastasis remains unknown. The present study showed that in human lung cancer cell lines, the abundance of FOXA2 positively correlates with epithelial phenotypes and negatively correlates with the mesenchymal phenotypes of cells, and TGF-β1 treatment decreased FOXA2 protein level. Consistently, knockdown of FOXA2 promoted EMT and invasion of lung cancer cells, whereas overexpression of FOXA2 reduced the invasion and suppressed TGF-β1-induced EMT. In addition, knockdown of FOXA2 induced slug expression, and ectopic expression of FOXA2 inhibited slug transcription. Furthermore, we identified that FOXA2 can bind to slug promoter through a conserved binding site, and that the DNA-binding region and transactivation region II of FOXA2 are required for repression of the slug promoter. These data demonstrate that FOXA2 functions as a suppressor of tumor metastasis by inhibition of EMT.

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Insulin Receptor Substrate-1 Suppresses Transforming Growth Factor-β1–Mediated Epithelial-Mesenchymal Transition

Cited by 41 publications

References 33 publications

Epigenetic regulation of Smad2 and Smad3 by profilin-2 promotes lung cancer growth and metastasis

Epigenetic regulation of Smad2 and Smad3 by profilin-2 promotes lung cancer growth and metastasis

Genotoxic stress-mediated cell cycle activities for the decision of cellular fate

FOXA2 functions as a suppressor of tumor metastasis by inhibition of epithelial-to-mesenchymal transition in human lung cancers

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