Research Papers:

KRASG12 mutant induces the release of the WSTF/NRG3 complex, and contributes to an oncogenic paracrine signaling pathway

Yan Liu, Shu-Qing Wang, Yue-Hong Long, Su Chen, Yu-Feng Li and Jing-Hua Zhang _

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Oncotarget. 2016; 7:53153-53164. https://doi.org/10.18632/oncotarget.10625

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Yan Liu1,2,*, Shu-Qing Wang3,4,*, Yue-Hong Long1, Su Chen5, Yu-Feng Li2, Jing-Hua Zhang2

1College of Life Science, North China University of Science and Technology, Tangshan, 063000, China

2Cancer Institute, Tangshan People’s Hospital, Tangshan, 063001, China

3Hospital of the North China University of Science and Technology, Tangshan, 063000, China

4Department of Nephrology, Affiliated Kailuan General Hospital of North China University of Science and Technology, Tangshan, 063000, China

5School of Life Sciences and Technology, Department of Breast Surgery of Yangpu Hospital, Research Center for Translational Medicine at East Hospital, Tongji University, Shanghai, 200092, China

*These authors contributed equally to this work

Correspondence to:

Yan Liu, email: yanliu68@163.com

Jing-Hua Zhang, email: jhzhang_sc@sina.com

Keywords: RAS, WSTF, NRG3, paracrine signaling

Received: January 16, 2016     Accepted: July 06, 2016     Published: July 16, 2016


It remains unclear how the signals of mutant KRASG12 in the transformed cells spread to the surrounding non-mutated cells and changes the microenvironment to promote tumor formation. We identified that Williams–Beuren syndrome transcription factor (WSTF), a non-secretory protein, was released in complex with secretory protein-neuregulin-3 (NRG3). The KRASG12 mutant activates the transcription of NRG3. The WSTF/NRG3 in extracellular space could activate oncogenic pathways in normal colon cells carrying wild type KRAS and endow them with the ability to express NRG3 and release WSTF/NRG3. Extracellular WSTF/NRG3 promotes the formation of colon tumors. Blockade of extracellular WSTF could restore cetuximab sensitivity of colon cancer cells with mutant KRAS. The appearance of WSTF/NRG3 in serum and urine correlates with a colon tumor carrying a KRASG12 mutant. In summary, our demonstration provides a new pathway to our understanding of the biological development of complex diseases.

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