Abstract
Vascular endothelial growth factor A (VEGF-A), a fundamental component of angiogenesis, provides nutrients and oxygen to solid tumors, and enhances tumor cell survival, invasion, and migration. Nuclear factor 90 (NF90), a double-stranded RNA-binding protein, is strongly expressed in several human cancers, promotes tumor growth by reducing apoptosis, and increasing cell cycle process. The mechanisms by which cervical cancer cells inducing VEGF-A expression and angiogenesis upon NF90 upregulation remain to be fully established. We demonstrated that NF90 is upregulated in human cervical cancer specimens and the expression of NF90 is paralleled with that of VEGF-A under hypoxia. The expressions of hypoxia inducible factor-1α (HIF-1α) and VEGF-A are downregulated upon NF90 knockdown, which can be rescued by ectopic expression of NF90. Suppression of NF90 decreases the tube formation and cell migration of HUVECs. Moreover, the PI3K/Akt signaling pathway participates in the regulation. Knockdown of NF90 also reduces the tumor growth and angiogenesis of cervical cancer cell line in the mouse xenograft model. Taken together, suppression of NF90 in cervical cancer cell lines can decrease VEGF-A expression, inhibit angiogenesis, and reduce tumorigenic capacity in vivo.
Highlights
Nuclear factor 90 (NF90), originally identified as a post-transcriptional regulator of interleukin-2 (IL-2) promoter[1], is conserved in vertebrates, and is one of the major products of alternative splicing of the interleukin enhancer-binding factor-3 (ILF3) gene[2]
We investigated the protein levels of NF90, NF110, and nuclear factor 45 (NF45) in 14 paired cervical cancer tissues and Knockdown of NF90 decreases hypoxia inducible factor-1α (HIF-1α)/Vascular endothelial growth factor A (VEGF-A) protein expressions in cervical cancer cell lines
As NF90 and the larger alternative splice variant NF110 might have distinct functions, the protein expression of NF110 has been observed during the following experiments. qRT-PCR and western blotting showed that the NF90 shRNA3 selectively represses the expression of NF90 mRNA (Supplementary Fig. 2) and protein (Fig. 3a)
Summary
NF90 ( known as DRBP76), originally identified as a post-transcriptional regulator of interleukin-2 (IL-2) promoter[1], is conserved in vertebrates, and is one of the major products of alternative splicing of the interleukin enhancer-binding factor-3 (ILF3) gene[2]. NF110 ( known as ILF3), an alternative splice form of ILF3, has a distinct N-terminal with NF90, and overexpressed in malignant nasopharyngeal carcinoma cells[3]. NF90 forms a heterodimeric complex with nuclear factor 45 (NF45), a product of interleukin enhancer-binding factor-2. ILF3 maintains sustained uPA expression in the breast cancer cells and promotes breast tumorigenicity[27]. NF90 bounds to the 3′untranslated regions (3'-UTRs) of cyclin E1
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