OSR1 phosphorylates the Smad2/3 linker region and induces TGF-β1 autocrine to promote EMT and metastasis in breast cancer

Abstract

Oxidative stress-responsive kinase 1 (OSR1) plays a critical role in multiple carcinogenic signal pathways, and its overexpression has been found in various types of cancer; however, the pathophysiological role of OSR1 in breast cancer has not been evaluated. This study aims to elaborate on the role of OSR1 in breast cancer metastasis and the specific regulatory mechanism. Our results showed that OSR1 mRNA and protein were upregulated in both human breast cancer samples and cell lines. Moreover, phosphorylated OSR1 (p-OSR1) was an independent poor prognostic indicator in patients with breast cancer. OSR1 upregulation induced epithelial-to-mesenchymal transition (EMT) in normal and malignant mammary epithelial cells with the increasing metastatic capacity. In contrast, deleting OSR1 in aggressive breast cancer cells inhibited these phenotypes. OSR1 is the critical activator for transcription factors of EMT. Mechanistically, we found that OSR1 can directly interact and phosphorylate the linker region of Smad2 at Thr220 and Smad3 at Thr179. Phosphorylated Smad2/3 translocated into the nucleus to enhance transforming growth factor-β1 (TGF-β1) autocrine signalling and increase the transcription of EMT regulators. Importantly, interruption of the OSR1-Smad2/3-TGF-β1 signalling axis elicited a robust anti-EMT and anti-metastatic effect in vitro and in vivo. Taken together, we conclude that OSR1-mediated Smad2/3-TGF-β1 signalling promotes EMT and metastasis representing a promising therapeutic target in breast cancer treatment.

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Fig. 1: OSR1 expression in breast cancer and its association with patient outcome.
Fig. 2: OSR1 enhances the proliferation of breast cancer cells in vitro and in vivo.
Fig. 3: OSR1 promotes the migration and invasion of breast cancer cells in vitro and in vivo.
Fig. 4: OSR1 induces EMT in breast cancer cells.
Fig. 5: OSR1 interacts and phosphorylates Smad2/3 to enhance TGF-β1 signalling.
Fig. 6: OSR1 enhances TGF-β1 expression in an autocrine manner.
Fig. 7: OSR1-Smad2/3-TGF-β1 signalling axis promotes EMT and metastasis in vitro and in vivo.
Fig. 8: Proposed possible mechanisms of OSR1 to facilitate EMT and metastasis in breast cancer.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81670595, 81970568), Shanghai Natural Science Funds (16ZR1428200), and the Excellent Youth Medical Talents Program of Shanghai General Hospital (06N1702011).

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Correspondence to Junming Xu.

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Li, Y., Li, L., Qin, J. et al. OSR1 phosphorylates the Smad2/3 linker region and induces TGF-β1 autocrine to promote EMT and metastasis in breast cancer. Oncogene (2020). https://doi.org/10.1038/s41388-020-01499-2

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