Neoplastic Transformation of Human Mesenchymal Stromal Cells Mediated via LIN28B

Radhakrishnan Vishnubalaji, Ramesh Elango, Mashael Al-Toub, Muthurangan Manikandan, Ammar Al-Rikabi, Linda Harkness, Nicholas Ditzel, Muhammad Atteya, Rimi Hamam, Musaad Alfayez, Abdullah Aldahmash, Moustapha Kassem, Nehad M. Alajez*

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Resumé

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.

OriginalsprogEngelsk
Artikelnummer8101
TidsskriftScientific Reports
Vol/bind9
Antal sider14
ISSN2045-2322
DOI
StatusUdgivet - 1. dec. 2019

Fingeraftryk

Mesenchymal Stromal Cells
Sarcoma
Linear Energy Transfer
Mesoderm
Osteoblasts
MicroRNAs
Adipocytes
Disease-Free Survival
Neoplasms
Clone Cells
Messenger RNA

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Vishnubalaji, R., Elango, R., Al-Toub, M., Manikandan, M., Al-Rikabi, A., Harkness, L., ... Alajez, N. M. (2019). Neoplastic Transformation of Human Mesenchymal Stromal Cells Mediated via LIN28B. Scientific Reports, 9, [8101]. https://doi.org/10.1038/s41598-019-44536-1
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. I: Scientific Reports. 2019 ; Bind 9.
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title = "Neoplastic Transformation of Human Mesenchymal Stromal Cells Mediated via LIN28B",
abstract = "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.",
author = "Radhakrishnan Vishnubalaji and Ramesh Elango and Mashael Al-Toub and Muthurangan Manikandan and Ammar Al-Rikabi and Linda Harkness and Nicholas Ditzel and Muhammad Atteya and Rimi Hamam and Musaad Alfayez and Abdullah Aldahmash and Moustapha Kassem and Alajez, {Nehad M.}",
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Vishnubalaji, R, Elango, R, Al-Toub, M, Manikandan, M, Al-Rikabi, A, Harkness, L, Ditzel, N, Atteya, M, Hamam, R, Alfayez, M, Aldahmash, A, Kassem, M & Alajez, NM 2019, 'Neoplastic Transformation of Human Mesenchymal Stromal Cells Mediated via LIN28B', Scientific Reports, bind 9, 8101. https://doi.org/10.1038/s41598-019-44536-1

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.

I: Scientific Reports, Bind 9, 8101, 01.12.2019.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Neoplastic Transformation of Human Mesenchymal Stromal Cells Mediated via LIN28B

AU - Vishnubalaji, Radhakrishnan

AU - Elango, Ramesh

AU - Al-Toub, Mashael

AU - Manikandan, Muthurangan

AU - Al-Rikabi, Ammar

AU - Harkness, Linda

AU - Ditzel, Nicholas

AU - Atteya, Muhammad

AU - Hamam, Rimi

AU - Alfayez, Musaad

AU - Aldahmash, Abdullah

AU - Kassem, Moustapha

AU - Alajez, Nehad M.

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

AB - 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.

U2 - 10.1038/s41598-019-44536-1

DO - 10.1038/s41598-019-44536-1

M3 - Journal article

C2 - 31147574

AN - SCOPUS:85066465588

VL - 9

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

M1 - 8101

ER -

Vishnubalaji R, Elango R, Al-Toub M, Manikandan M, Al-Rikabi A, Harkness L et al. Neoplastic Transformation of Human Mesenchymal Stromal Cells Mediated via LIN28B. Scientific Reports. 2019 dec 1;9. 8101. https://doi.org/10.1038/s41598-019-44536-1