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HOX Transcript Antisense RNA HOTAIR Abrogates Vasculogenic Mimicry by Targeting the AngiomiR-204/FAK Axis in Triple Negative 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...

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Autores principales: Lozano-Romero, Allan, Astudillo-de la Vega, Horacio, Terrones-Gurrola, María Cruz del Rocío, Marchat, Laurence A., Hernández-Sotelo, Daniel, Salinas-Vera, Yarely M., Ramos-Payan, Rosalío, Silva-Cázares, Macrina B., Nuñez-Olvera, Stephanie I., Hernández-de la Cruz, Olga N., López-Camarillo, César
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7345118/
https://www.ncbi.nlm.nih.gov/pubmed/32466537
http://dx.doi.org/10.3390/ncrna6020019
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author Lozano-Romero, Allan
Astudillo-de la Vega, Horacio
Terrones-Gurrola, María Cruz del Rocío
Marchat, Laurence A.
Hernández-Sotelo, Daniel
Salinas-Vera, Yarely M.
Ramos-Payan, Rosalío
Silva-Cázares, Macrina B.
Nuñez-Olvera, Stephanie I.
Hernández-de la Cruz, Olga N.
López-Camarillo, César
author_facet Lozano-Romero, Allan
Astudillo-de la Vega, Horacio
Terrones-Gurrola, María Cruz del Rocío
Marchat, Laurence A.
Hernández-Sotelo, Daniel
Salinas-Vera, Yarely M.
Ramos-Payan, Rosalío
Silva-Cázares, Macrina B.
Nuñez-Olvera, Stephanie I.
Hernández-de la Cruz, Olga N.
López-Camarillo, César
author_sort Lozano-Romero, Allan
collection PubMed
description 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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spelling pubmed-73451182020-07-09 HOX Transcript Antisense RNA HOTAIR Abrogates Vasculogenic Mimicry by Targeting the AngiomiR-204/FAK Axis in Triple Negative Breast Cancer Cells Lozano-Romero, Allan Astudillo-de la Vega, Horacio Terrones-Gurrola, María Cruz del Rocío Marchat, Laurence A. Hernández-Sotelo, Daniel Salinas-Vera, Yarely M. Ramos-Payan, Rosalío Silva-Cázares, Macrina B. Nuñez-Olvera, Stephanie I. Hernández-de la Cruz, Olga N. López-Camarillo, César Noncoding RNA Article 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. MDPI 2020-05-26 /pmc/articles/PMC7345118/ /pubmed/32466537 http://dx.doi.org/10.3390/ncrna6020019 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Lozano-Romero, Allan
Astudillo-de la Vega, Horacio
Terrones-Gurrola, María Cruz del Rocío
Marchat, Laurence A.
Hernández-Sotelo, Daniel
Salinas-Vera, Yarely M.
Ramos-Payan, Rosalío
Silva-Cázares, Macrina B.
Nuñez-Olvera, Stephanie I.
Hernández-de la Cruz, Olga N.
López-Camarillo, César
HOX Transcript Antisense RNA HOTAIR Abrogates Vasculogenic Mimicry by Targeting the AngiomiR-204/FAK Axis in Triple Negative Breast Cancer Cells
title HOX Transcript Antisense RNA HOTAIR Abrogates Vasculogenic Mimicry by Targeting the AngiomiR-204/FAK Axis in Triple Negative Breast Cancer Cells
title_full HOX Transcript Antisense RNA HOTAIR Abrogates Vasculogenic Mimicry by Targeting the AngiomiR-204/FAK Axis in Triple Negative Breast Cancer Cells
title_fullStr HOX Transcript Antisense RNA HOTAIR Abrogates Vasculogenic Mimicry by Targeting the AngiomiR-204/FAK Axis in Triple Negative Breast Cancer Cells
title_full_unstemmed HOX Transcript Antisense RNA HOTAIR Abrogates Vasculogenic Mimicry by Targeting the AngiomiR-204/FAK Axis in Triple Negative Breast Cancer Cells
title_short HOX Transcript Antisense RNA HOTAIR Abrogates Vasculogenic Mimicry by Targeting the AngiomiR-204/FAK Axis in Triple Negative Breast Cancer Cells
title_sort hox transcript antisense rna hotair abrogates vasculogenic mimicry by targeting the angiomir-204/fak axis in triple negative breast cancer cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7345118/
https://www.ncbi.nlm.nih.gov/pubmed/32466537
http://dx.doi.org/10.3390/ncrna6020019
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