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

Dansaem Lim,Aram Lee,Jin Gu Cho,Eunsik Yun,Byung Su Kwon,Young Joo Lee,Jongmin Kim,Hong-Yeoul Ryu,Sukjoon Yoon,Woochul Chang,Myeong-Sok Lee

doi:10.3390/genes12010009

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.

Highlights

Breast cancer is the most commonly occurring cancer in women and one of the leading causes of death in women after menopause [1]
To investigate the involvement of AXL in Vasculogenic mimicry (VM) formation in breast cancer cells, VM formation and AXL expression were examined in seven breast cancer cell lines
We evaluated the expression level of AXL in seven breast cancer cell lines to investigate the correlation with VM formation

Summary

Introduction

Breast cancer is the most commonly occurring cancer in women and one of the leading causes of death in women after menopause [1]. (ii) human epidermal growth factor receptor-2 (HER2) positive, and PR and/or ER positive or negative, and (iii) triple negative breast cancer (TNBC) [2,3,4]. TNBC refers to tumors without the expression of PR, ER, and HER2, and is associated with a more frequent relapse and higher mortality than the different types of breast cancer [4]. TNBC accounts for about 15–20% of all breast cancers and 5% of all cancer-related deaths [5]. Since TNBC patients cannot be treated with drugs targeting ER and HER2, they have an increased risk of low survival and disease progression [6,7]. Because current therapies for TNBC have limited effects, investigating TNBC tumor progression and development, as well as the causal agents for the phenotypic heterogeneity, is important for the development of new treatment options [3]

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Results

Conclusion