Research Papers:

Sulfatide interacts with and activates integrin αVβ3 in human hepatocellular carcinoma cells

Rong Wang, Bing Qi, Yi Wei Dong, Qian Qian Cai, Nian Hui Deng, Qi Chen, Chao Li, Yu Tong Jin and Xing Zhong Wu _

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Oncotarget. 2016; 7:36563-36576. https://doi.org/10.18632/oncotarget.9095

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Rong Wang1,2,*, Bing Qi1,2,*, Yi Wei Dong1,2, Qian Qian Cai1,2, Nian Hui Deng3, Qi Chen3, Chao Li1, Yu Tong Jin1, Xing Zhong Wu1,2

1Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, PR. China

2Key Laboratory of Glycoconjugate Research, Ministry of Public Health, Shanghai, PR. China

3Yu Ying Children’s Hospital, Wenzhou Medical University, Wenzhou, PR. China

*These authors have contributed equally to this study

Correspondence to:

Xing Zhong Wu, e-mail: [email protected]

Keywords: integrin, sulfated cerebroside, clustering, signaling, hepatocellular carcinoma

Received: October 09, 2015    Accepted: April 16, 2016    Published: April 29, 2016


Integrin αVβ3 is a malignant driver of anchorage-independence and tumor angiogenesis, but its dysregulation in hepatocellular carcinoma (HCC) remains unclear. In this study, we observed that sulfatide significantly promoted integrin αV(ITGAV) expression and wound closure in HCC. We also noted that elevated sulfatide profoundly stimulated integrin αVβ3 clustering and signaling. In the cells with integrin αVβ3 clustering induced by sulfatide, integrin β3 subunit was phosphorylated. Simultaneously, focal adhesion kinase (FAK), Src and paxillin were also phosphorylated. Treatment with FAK inhibitor resulted in robust suppression of FAK-Y397 and Src-Y416 phosphorylation stimulated by sulfatide, but not suppression of integrin β3 phosphorylation. Src inhibitors repressed Src-Y416 and FAK Y861 and Y925 phosphorylation, but not FAK-Y397 and integrin β3 phosphorylation. After mutation of integrin β3 (Y773F and Y785F), FAK or Src phosphorylation failed to be stimulated by sulfatide. Moreover, β3 Y773 and Y785 phosphorylation was suppressed by insulin-like growth factor receptor knockdown even in cells stimulated by sulfatide. In assays of immunoprecipitation and immunostaining with integrin αV or β3 antibody, labeled sulfatide was found in the complex and co-localized with integrin αVβ3. Taken together, this study demonstrated that elevated sulfatide bound to integrin αVβ3 and induced clustering and phosphorylation of αVβ3 instead of matrix ligand binding, triggering outside-in signaling.

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