The oncoprotein HBXIP enhances angiogenesis and growth of breast cancer through modulating FGF8 and VEGF.
Tumor angiogenesis plays an important role in the development of cancer. Previously, we reported that hepatitis B X-interacting protein (HBXIP) functioned as an oncoprotein in breast cancer. However, the role of HBXIP in angiogenesis in breast cancer remains poorly understood. In the present study, we show that the oncoprotein HBXIP plays crucial roles in the event. We observed that the expression levels of HBXIP were positively correlated with those of fibroblast growth factor 8 (FGF8) or vascular endothelial growth factor (VEGF) in clinical breast cancer tissues. Then, we demonstrated that HBXIP was able to upregulate FGF8 through activation of its promoter involving direct binding to cAMP response element-binding protein (CREB) in breast cancer cells and thereby increased its secretion. Strikingly, we identified another pathway that HBXIP upregulated FGF8 and VEGF through inhibiting miRNA-503, which directly targeted 3' untranslated region of FGF8 or VEGF mRNA in the cells. Moreover, we revealed that HBXIP-induced FGF8 could upregulate VEGF expression through activating phosphoinositide 3-kinase (PI3K)/Akt/hypoxia-inducible factor 1-alpha (HIF1α) signaling and increase its secretion. In function, matrigel angiogenesis assay and hemoglobin content analysis uncovered that HBXIP-enhanced FGF8/VEGF boosted tumor angiogenesis and growth in breast cancer in vitro and in vivo in a paracrine/autocrine manner. Thus, we conclude that HBXIP enhances angiogenesis and growth of breast cancer through modulating FGF8 and VEGF. Our finding provides new insights into the mechanism of tumor angiogenesis in breast cancer. Therapeutically, HBXIP may serve as a novel target of tumor angiogenesis.
Department of Biochemistry.
Fabao
F
Liu
Xiaona
X
You
Yue
Y
Wang
Qian
Q
Liu
Yunxia
Y
Liu
Shuqin
S
Zhang
Lingyi
L
Chen
Xiaodong
X
Zhang
Lihong
L
Ye
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005260:Female; D051524:Fibroblast Growth Factor 8 / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D015533:Transcriptional Activation; D047368:Tumor Burden / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C110719:LAMTOR5 protein, human; C545473:MIRN503 microRNA, human; D035683:MicroRNAs; D042461:Vascular Endothelial Growth Factor A; D051524:Fibroblast Growth Factor 8; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt