Neoplastic Transformation of Human Mesenchymal Stromal Cells Mediated via LIN28B

• Published in: Scientific reports Vol. 9; no. 1; p. 8101
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 30-05-2019; Nature Publishing Group
• Subjects: 13/106; 38/61; 38/77; 38/89; 631/67/395; 631/80/83; Adipocytes; Antibiotics, Antineoplastic - pharmacology; Antibiotics, Antineoplastic - therapeutic use; Bone marrow; Cell Line; Cell Movement - genetics; Cell Proliferation - genetics; Cell Transformation, Neoplastic - genetics; Cohort Studies; Colonies; Datasets as Topic; Disease-Free Survival; Doxorubicin; Doxorubicin - pharmacology; Doxorubicin - therapeutic use; Drug Resistance, Neoplasm - genetics; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genetic transformation; Genomes; HMGA2 Protein - genetics; Humanities and Social Sciences; Humans; Kaplan-Meier Estimate; Mesenchymal stem cells; Mesenchymal Stem Cells - metabolism; Mesenchymal Stem Cells - pathology; Mesenchyme; Mesoderm; MicroRNAs - metabolism; miRNA; mRNA; multidisciplinary; Osteoblasts; Phenotypes; RNA-Binding Proteins - genetics; Sarcoma; Sarcoma - drug therapy; Sarcoma - genetics; Sarcoma - mortality; Sarcoma - pathology; Science; Science (multidisciplinary); Stem cell transplantation; Stem cells; Stromal cells; Therapeutic targets; Up-Regulation; Xenograft Model Antitumor Assays
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-44536-1

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.