Cooperative multi-targeting of signaling networks by angiomiR-204 inhibits vasculogenic mimicry in breast cancer cells

HOX transcript antisense RNA (HOTAIR) is an oncogenic long non-coding RNA frequently overexpressed in cancer. HOTAIR can enhance the malignant behavior of tumors by sponging microRNAs with tumor suppressor functions. Vasculogenic mimicry is a hypoxia-activated process in which tumor cells form three-dimensional (3D) channel-like networks, resembling endothelial blood vessels, to obtain nutrients. However, the role of HOTAIR in vasculogenic mimicry and the underlying mechanisms are unknown in human cancers. In the current study, we investigated the relevance of HOTAIR in hypoxia-induced vasculogenic mimicry in metastatic MDA-MB-231 and invasive Hs-578t triple negative breast cancer cells. Analysis of The Cancer Genome Atlas (TCGA) database using cBioPortal confirmed that HOTAIR was upregulated in clinical breast tumors relative to normal mammary tissues. Our quantitative RT-PCR assays showed a significant increase in HOTAIR levels after 48 h hypoxia relative to normoxia in breast cancer cell lines. Remarkably, knockdown of HOTAIR significantly abolished the hypoxia-induced vasculogenic mimicry which was accompanied by a reduction in the number of 3D channel-like networks and branch points. Likewise, HOTAIR silencing leads to reduced cell migration abilities of cancer cells. Bioinformatic analysis predicted that HOTAIR has a potential binding site for tumor suppressor miR-204. Luciferase reporter assays confirmed that HOTAIR is a competitive endogenous sponge of miR-204. Congruently, forced inhibition of HOTAIR in cells resulted in augmented miR-204 levels in breast cancer cells. Further bioinformatic analysis suggested that miR-204 can bind to the 3′ untranslated region of focal adhesion kinase 1 (FAK) transcript involved in cell migration. Western blot and luciferase reporter assays confirmed that FAK is a novel target of miR-204. Finally, silencing of HOTAIR resulted in low levels of cytoplasmic FAK protein and alterations in the organization of cellular cytoskeleton and focal adhesions. In summary, our results showed, for the first time, that HOTAIR mitigates cell migration and vasculogenic mimicry by targeting the miR-204/FAK axis in triple negative breast cancer cells.

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A Novel Phosphopeptide Microarray Based Interactome Map in Breast Cancer Cells Reveals Phosphoprotein-GRB2 Cell Signaling Networks

PLoS ONE ◽

10.1371/journal.pone.0067634 ◽

2013 ◽

Vol 8 (6) ◽

pp. e67634 ◽

Cited By ~ 9

Author(s):

Srinivasan Krishnamoorthy ◽

Zhonghua Liu ◽

Ailing Hong ◽

Ruijuan Zhu ◽

Haosi Chen ◽

...

Keyword(s):

Breast Cancer ◽

Cell Signaling ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Signaling Networks ◽

Cell Signaling Networks

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Effects of miR‑93 on epithelial‑to‑mesenchymal transition and vasculogenic mimicry in triple‑negative breast cancer cells

Molecular Medicine Reports ◽

10.3892/mmr.2020.11668 ◽

2020 ◽

Vol 23 (1) ◽

pp. 1-1

Author(s):

Gaili An ◽

Feng Lu ◽

Shangke Huang ◽

Jun Bai ◽

Li He ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Triple Negative Breast Cancer ◽

Breast Cancer Cells ◽

Epithelial To Mesenchymal Transition ◽

Triple Negative ◽

Vasculogenic Mimicry ◽

Mesenchymal Transition

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Regulation of IL-6 signaling by miR-125a and let-7e in endothelial cells controls vasculogenic mimicry formation of breast cancer cells

BMB Reports ◽

10.5483/bmbrep.2019.52.3.308 ◽

2019 ◽

Vol 52 (3) ◽

pp. 214-219 ◽

Cited By ~ 13

Author(s):

Youngsook Park ◽

Jongmin Kim

Keyword(s):

Breast Cancer ◽

Endothelial Cells ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Vasculogenic Mimicry

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Extracellular Vesicle Transfer from Endothelial Cells Drives VE-Cadherin Expression in Breast Cancer Cells, Thereby Causing Heterotypic Cell Contacts

Cancers ◽

10.3390/cancers12082138 ◽

2020 ◽

Vol 12 (8) ◽

pp. 2138 ◽

Cited By ~ 1

Author(s):

Maryam Rezaei ◽

Ana C. Martins Cavaco ◽

Martin Stehling ◽

Astrid Nottebaum ◽

Katrin Brockhaus ◽

...

Keyword(s):

Breast Cancer ◽

Endothelial Cells ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Vasculogenic Mimicry ◽

Transcriptional Level ◽

Breast Cancers ◽

Intimate Contact ◽

Cadherin Switch ◽

Gene Assay

Cadherins mediate cohesive contacts between isotypic cells by homophilic interaction and prevent contact between heterotypic cells. Breast cancer cells neighboring endothelial cells (ECs) atypically express vascular endothelial (VE)-cadherin. To understand this EC-induced VE-cadherin expression in breast cancer cells, MCF7 and MDA-MB-231 cells expressing different endogenous cadherins were co-cultured with ECs and analyzed for VE-cadherin at the transcriptional level and by confocal microscopy, flow cytometry, and immunoblotting. After losing their endogenous cadherins and neo-expression of VE-cadherin, these cells integrated into an EC monolayer without compromising the barrier function instantly. However, they induced the death of nearby ECs. EC-derived extracellular vesicles (EVs) contained soluble and membrane-anchored forms of VE-cadherin. Only the latter was re-utilized by the cancer cells. In a reporter gene assay, EC-adjacent cancer cells also showed a juxtacrine but no paracrine activation of the endogenous VE-cadherin gene. This cadherin switch enabled intimate contact between cancer and endothelial cells in a chicken chorioallantoic membrane tumor model showing vasculogenic mimicry (VM). This EV-mediated, EC-induced cadherin switch in breast cancer cells and the neo-expression of VE-cadherin mechanistically explain the mutual communication in the tumor microenvironment. Hence, it may be a target to tackle VM, which is often found in breast cancers of poor prognosis.

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