Annexin-A1 Regulates MicroRNA-26b* and MicroRNA-562 to Directly Target NF-κB and Angiogenesis in Breast Cancer Cells

Abstract

Annexin 1 (ANXA1) is an endogenous anti-inflammatory protein implicated in cancer. ANXA1 was previously shown to be regulated by hsa-miR-196a. However, whether ANXA1 itself regulates microRNA (miR) expression is unknown. Therefore, we investigated the regulation of miR by ANXA1 in MCF7 breast cancer cells. MCF7-EV (Empty vector) and MCF7-V5 (ANXA1-V5 expressing cells) were subjected to a miR microarray. Microarray analysis revealed a number of miRNAs which were dysregulated in MCF7-V5 cells. 2 novel miRNAs (miR562 and miR26b*) were validated, cloned and functionally characterized. As ANXA1 constitutively activates NF-κB activity to modulate breast cancer metastasis, we found that miR26b* and miR562 directly targeted the canonical NF-κB pathway by targeting the 3′ UTR and inhibiting expression of Rel A (p65) and NF-κB1 (p105) respectively. MiR562 inhibited wound healing, which was reversed when ANXA1 was overexpressed. Overexpression of either miR562 or miR26b* in MCF-7 cells enhanced endothelial tube formation when cocultured with human umbilical cord endothelial cells while conversely, treatment of MCF7 cells with either anti-miR562 or anti-miR26b* inhibited endothelial tube formation after co-culture. Further analysis of miR562 revealed that miR562-transfected cell conditioned media enhances endothelial cell tube formation, indicating that miR562 increased angiogenic secreted factors from MCF-7 breast tumor cells. TNFα was increased upon overexpression of miR562, which was reversed when ANXA1 was co-transfected In conclusion, this data suggests that ANXA1-regulated miR26b* and miR562 may play a role in wound healing and tumor-induced endothelial cell tube formation by targeting NF-κB expression and point towards a potential therapeutic target for breast cancer.

Annexin A1 is involved in resistance to 5-FU in colon cancer cells

“…Consistent with our findings, a recent study has also revealed that upregulated ANXA1 was associated with resistance to various chemotherapeutic agents (10). ANXA1 activates NF-κB, which is known as the association of resistance to 5-FU, resulting in progression of metastasis (12). The investigation of resistance mechanisms to chemotherapies is strongly required to develop anticancer therapies with high efficacy and minimum risk of adverse events.…”

Annexin A12–26 Treatment Improves Skin Heterologous Transplantation by Modulating Inflammation and Angiogenesis Processes

“…Assuredly, systemic administration of AnxA1 2–26 enhanced the number of new vessels in the transplanted tissue and enhanced local gene and protein expression of VEGF-A, showing a pro-angiogenic action of the peptide. The direct role of AnxA1 on angiogenesis has not been described, as data regarding AnxA1 on angiogenesis were obtained in in vivo and in vitro tumorigenesis conditions, and data suggest that the tumor microenvironment is determinant to angiogenic actions of AnxA1 ( Oh et al, 2004 ; Yi and Schnitzer, 2009 ; Anbalagan et al, 2014 ). Remarkably, our in vivo data showed the ability of AnxA1 2–26 to induce angiogenesis in the subcutaneous tissue, equivalent to that caused by VEGF-A.…”

Bioinformatic analysis of microRNA-mRNA expression profiles of bladder tissue induced by bladder outlet obstruction in a rat model

“…miRNA profiling has previously been reported in tumor classification, diagnostics and therapeutics. miR-26b profiling has specifically been reported in angiogenesis in breast cancer cells (24) and epithelial-mesenchymal transi-and epithelial-mesenchymal transition in hepatocellular carcinoma (25). Additionally, miR-26b is downregulated in carcinoma-associated fibroblasts from estrogen receptor-positive breast cancers leading to enhanced cell migration and invasion (26).…”