The oncoprotein HBXIP enhances angiogenesis and growth of breast cancer through modulating FGF8 and VEGF

Abstract

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.

HBXIP and LSD1 Scaffolded by lncRNA Hotair Mediate Transcriptional Activation by c-Myc

“…Moreover, we revealed that HBXIP was able to interact with the E-box in the promoters of c-Myc-induced genes. It further supports that HBXIP is a coactivator of transcriptional factor c-Myc, which is consistent with our reports that HBXIP is able to coactivate transcription factors, such as TF-IID, STAT3, SP1, CREB, and E2F1, in breast cancer cells (15)(16)(17)(18)(19)(20).…”

“…HBXIP functions as an oncogenic transcriptional co-activator in breast cancer (19,35). Either HBXIP or c-Myc contains a leucine-zipper domain (5,15).…”

“…MDA-MB-463, MDA-MB-231, and HEK293T cells were cultured in DMEM (Invitrogen) supplemented with 10% FCS. The siRNAs targeting HBXIP mRNA were reported previously (16,19). The siRNAs targeting c-Myc mRNA, Hotair, and LSD1 mRNA were listed in Supplementary Table S1 (28).…”

“…We have reported that expression of HBXIP is obviously enriched in breast cancer tissues. HBXIP acts as an oncogenic transcriptional coactivator of multiple transcription factors, such as TF-IID, STAT3, SP1, CREB, and E2F1, in the promotion of breast cancer growth and metastasis (15)(16)(17)(18)(19)(20). However, whether HBXIP serves as a coactivator of oncogenic transcriptional factor c-Myc in breast cancer remains poorly understood.…”

Oncoprotein HBXIP Modulates Abnormal Lipid Metabolism and Growth of Breast Cancer Cells by Activating the LXRs/SREBP-1c/FAS Signaling Cascade

“…It has been reported that HBXIP is required for mTORC1 activation by amino acid in cell growth (14). Importantly, our study has revealed that HBXIP requires the interaction with c-Fos and phosphorylation of both proteins for nuclear import (15) and acts as a coactivator for transcription factors including CREB, TFIID, Sp1, E2F1, and STAT4 in the development of breast cancer (15)(16)(17)(18). Therefore, we supposed that HBXIP might play a crucial role in abnormal lipid metabolism of breast cancer.…”