Abstract
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.
Highlights
Hepatocellular carcinoma (HCC) is one of the most malignant diseases worldwide, especially in Asia, where there is a high prevalence of chronic viral hepatitis infection
As compared to DMSO control, galactocerebroside, lactocerebroside and ganglioside, sulfatide interestingly enhanced the expression of integrin αV subunit (Figure 1A) in both human hepatocellular carcinoma cells (SMMC-7721 and BEL-7404), but not integrin β1, 3 or 5
Integrin αVβ3 mediates the interaction with extracellular matrix as an adhesion molecule, but overexpressed integrin αVβ3 initiates endothelial cell survival in anchorage independence and tumor metastasis without ECM ligand binding [5]
Summary
Hepatocellular carcinoma (HCC) is one of the most malignant diseases worldwide, especially in Asia, where there is a high prevalence of chronic viral hepatitis infection. Some integrins inhibit tumor cell proliferation via inducing apoptosis or cell death [2], Integrin αVβ3 is required for tumor angiogenesis [3] and anchorage-independent proliferation of cancer cells [4, 5]. Expression of integrin αVβ3 is upregulated in the vasculature associated with solid tumors [3, 4], indicating that integrin αVβ3 is involved in angiogenesis [6] and tumor metastasis [5, 7, 8]. Integrin αVβ3 is especially expressed on the most aggressive protruding tumor www.impactjournals.com/oncotarget cells that invade normal tissue, in many cancers such as melanoma and carcinomas of pancreas [5]. The antagonists of integrin αVβ3 obviously inhibited the tumor aggressiveness by inducing apoptosis of proliferative angiogenic vascular cells [4]
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