MicroRNA 34a–AXL Axis Regulates Vasculogenic Mimicry Formation in Breast Cancer Cells

Abstract

Targeting the tumor vasculature is an attractive strategy for cancer treatment. However, the tumor vasculature is heterogeneous, and the mechanisms involved in the neovascularization of tumors are highly complex. Vasculogenic mimicry (VM) refers to the formation of vessel-like structures by tumor cells, which can contribute to tumor neovascularization, and is closely related to metastasis and a poor prognosis. Here, we report a novel function of AXL receptor tyrosine kinase (AXL) in the regulation of VM formation in breast cancer cells. MDA-MB-231 cells exhibited VM formation on Matrigel cultures, whereas MCF-7 cells did not. Moreover, AXL expression was positively correlated with VM formation. Pharmacological inhibition or AXL knockdown strongly suppressed VM formation in MDA-MB-231 cells, whereas the overexpression of AXL in MCF-7 cells promoted VM formation. In addition, AXL knockdown regulated epithelial–mesenchymal transition (EMT) features, increasing cell invasion and migration in MDA-MB-231 cells. Finally, the overexpression of microRNA-34a (miR-34a), which is a well-described EMT-inhibiting miRNA and targets AXL, inhibited VM formation, migration, and invasion in MDA-MB 231 cells. These results identify a miR-34a–AXL axis that is critical for the regulation of VM formation and may serve as a therapeutic target to inhibit tumor neovascularization.

Metastatic breast tumors downregulate miR-145 regulating the hypoxia-induced vasculogenic mimicry

“…Metastasis remains as one of the more devastating cancer hallmarks, which account for most of cancer-related deaths. Notably, VM has been established a s a novel marker of poor prognosis in breast cancer patients, as it promotes resistance to therapy [ [20] , [21] ], and tumor progression [22] . Although the molecular mechanisms for VM development have been the objective of intense research, little is known about its regulation by ncRNAs.…”

MicroRNAs: A Link between Mammary Gland Development and Breast Cancer

“…We found two miRNAs, miR-34 and miR-193b, to be involved in the regulation of angiogenesis in both pubertal and cancer processes. MiR-34 is a tumour suppressive miRNA which has been found to reduce vasculogenic mimicry in breast cancer by targeting AXL tyrosine kinase [63]. Overexpression of miR-34a was also found to reduce invasion and migration.…”

Vasculogenic Mimicry in Breast Cancer: Clinical Relevance and Drivers

“…The signaling of AXL receptor tyrosine kinase promotes cancer stem cell-like phenotypes, drug resistance, metastasis, and EMT. Overexpression of this receptor promotes the regulation of VM formation in breast cancer cells [ 73 ] through miRNA-34a that targets the 3’-untranslated region (UTR) [ 85 , 86 ]. In this sense, it was demonstrated that miRNA-34a overexpression downregulated AXL receptor expression resulting in the inhibition of VM formation, migration, and invasion in MDA-MB 231 cells [ 28 ].…”