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Neoplastic Transformation of Human Mesenchymal Stromal Cells Mediated via LIN28B

Bone marrow stromal (Mesenchymal) stem cells (MSCs) are multipotent bone cells capable of differentiating into mesoderm-type cells, such as osteoblasts and adipocytes. Existing evidence suggests that transformation of MSCs gives rise to sarcoma. In order to identify the molecular mechanism leading t...

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Autores principales: Vishnubalaji, Radhakrishnan, Elango, Ramesh, Al-Toub, Mashael, Manikandan, Muthurangan, Al-Rikabi, Ammar, Harkness, Linda, Ditzel, Nicholas, Atteya, Muhammad, Hamam, Rimi, Alfayez, Musaad, Aldahmash, Abdullah, Kassem, Moustapha, Alajez, Nehad M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6542832/
https://www.ncbi.nlm.nih.gov/pubmed/31147574
http://dx.doi.org/10.1038/s41598-019-44536-1
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author Vishnubalaji, Radhakrishnan
Elango, Ramesh
Al-Toub, Mashael
Manikandan, Muthurangan
Al-Rikabi, Ammar
Harkness, Linda
Ditzel, Nicholas
Atteya, Muhammad
Hamam, Rimi
Alfayez, Musaad
Aldahmash, Abdullah
Kassem, Moustapha
Alajez, Nehad M.
author_facet Vishnubalaji, Radhakrishnan
Elango, Ramesh
Al-Toub, Mashael
Manikandan, Muthurangan
Al-Rikabi, Ammar
Harkness, Linda
Ditzel, Nicholas
Atteya, Muhammad
Hamam, Rimi
Alfayez, Musaad
Aldahmash, Abdullah
Kassem, Moustapha
Alajez, Nehad M.
author_sort Vishnubalaji, Radhakrishnan
collection PubMed
description Bone marrow stromal (Mesenchymal) stem cells (MSCs) are multipotent bone cells capable of differentiating into mesoderm-type cells, such as osteoblasts and adipocytes. Existing evidence suggests that transformation of MSCs gives rise to sarcoma. In order to identify the molecular mechanism leading to spontaneous transformation of human bone marrow MSCs (hBMSCs), we performed comprehensive microRNA (miRNA) and mRNA profiling in the transformed hBMSC-Tum line compared to the parental clone. As a result, we identified multiple dysregulated molecular networks associated with the hBMSC transformed phenotype. LIN28B was upregulated 177.0-fold in hBMSC-Tum, which was associated with marked reduction in LET-7 expression and upregulated expression of its target HMGA2. Targeted depletion of LIN28B or exogenous expression of LET-7b suppressed hBMSC-Tum proliferation, colony formation, and migration. On the other hand, forced expression of LIN28B promoted malignant transformation of parental hBMSC cells as shown by enhanced in vitro colony formation, doxorubicin resistance, and in vivo tumor formation in immunocompromised mice. Analysis of LIN28B and HMGA2 expression levels in cohorts from The Cancer Genome Atlas sarcoma dataset revealed a strong inverse-relationship between elevated expression and overall survival (OS) in 260 patients (p = 0.005) and disease-free survival (DFS) in 231 patients (p = 0.02), suggesting LIN28B and HMGA2 are important regulators of sarcoma biology. Our results highlight an important role for the LIN28B/LET-7 axis in human sarcoma pathogenesis and suggest that the therapeutic targeting of LIN28B may be relevant for patients with sarcoma.
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spelling pubmed-65428322019-06-07 Neoplastic Transformation of Human Mesenchymal Stromal Cells Mediated via LIN28B Vishnubalaji, Radhakrishnan Elango, Ramesh Al-Toub, Mashael Manikandan, Muthurangan Al-Rikabi, Ammar Harkness, Linda Ditzel, Nicholas Atteya, Muhammad Hamam, Rimi Alfayez, Musaad Aldahmash, Abdullah Kassem, Moustapha Alajez, Nehad M. Sci Rep Article Bone marrow stromal (Mesenchymal) stem cells (MSCs) are multipotent bone cells capable of differentiating into mesoderm-type cells, such as osteoblasts and adipocytes. Existing evidence suggests that transformation of MSCs gives rise to sarcoma. In order to identify the molecular mechanism leading to spontaneous transformation of human bone marrow MSCs (hBMSCs), we performed comprehensive microRNA (miRNA) and mRNA profiling in the transformed hBMSC-Tum line compared to the parental clone. As a result, we identified multiple dysregulated molecular networks associated with the hBMSC transformed phenotype. LIN28B was upregulated 177.0-fold in hBMSC-Tum, which was associated with marked reduction in LET-7 expression and upregulated expression of its target HMGA2. Targeted depletion of LIN28B or exogenous expression of LET-7b suppressed hBMSC-Tum proliferation, colony formation, and migration. On the other hand, forced expression of LIN28B promoted malignant transformation of parental hBMSC cells as shown by enhanced in vitro colony formation, doxorubicin resistance, and in vivo tumor formation in immunocompromised mice. Analysis of LIN28B and HMGA2 expression levels in cohorts from The Cancer Genome Atlas sarcoma dataset revealed a strong inverse-relationship between elevated expression and overall survival (OS) in 260 patients (p = 0.005) and disease-free survival (DFS) in 231 patients (p = 0.02), suggesting LIN28B and HMGA2 are important regulators of sarcoma biology. Our results highlight an important role for the LIN28B/LET-7 axis in human sarcoma pathogenesis and suggest that the therapeutic targeting of LIN28B may be relevant for patients with sarcoma. Nature Publishing Group UK 2019-05-30 /pmc/articles/PMC6542832/ /pubmed/31147574 http://dx.doi.org/10.1038/s41598-019-44536-1 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Vishnubalaji, Radhakrishnan
Elango, Ramesh
Al-Toub, Mashael
Manikandan, Muthurangan
Al-Rikabi, Ammar
Harkness, Linda
Ditzel, Nicholas
Atteya, Muhammad
Hamam, Rimi
Alfayez, Musaad
Aldahmash, Abdullah
Kassem, Moustapha
Alajez, Nehad M.
Neoplastic Transformation of Human Mesenchymal Stromal Cells Mediated via LIN28B
title Neoplastic Transformation of Human Mesenchymal Stromal Cells Mediated via LIN28B
title_full Neoplastic Transformation of Human Mesenchymal Stromal Cells Mediated via LIN28B
title_fullStr Neoplastic Transformation of Human Mesenchymal Stromal Cells Mediated via LIN28B
title_full_unstemmed Neoplastic Transformation of Human Mesenchymal Stromal Cells Mediated via LIN28B
title_short Neoplastic Transformation of Human Mesenchymal Stromal Cells Mediated via LIN28B
title_sort neoplastic transformation of human mesenchymal stromal cells mediated via lin28b
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6542832/
https://www.ncbi.nlm.nih.gov/pubmed/31147574
http://dx.doi.org/10.1038/s41598-019-44536-1
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