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.

MicroRNA Expression Profiling on Paired Primary and Lymph Node Metastatic Breast Cancer Revealed Distinct microRNA Profile Associated With LNM

“…Expression profiling of mRNA and miRNA was conducted as we previously described (30,31). Initially, total RNA (including miRNA) was labeled and subsequently was hybridized to the Agilent SurePrint G3 Human GE 8 × 60 k or Human 8 × 60 k v21 miRNA microarray chip (Agilent Technologies, Palo Alto, CA, USA).…”

Cancer Stem Cells in Soft-Tissue Sarcomas

“…LIN28 silencing changed the metabolism of cells and induced the loss of CSC traits [65]. Moreover, in sarcoma it has been reported that high expression of LIN28B and survival correlate inversely with each other [66]. Nevertheless, the value of LIN28B to discriminate CSCs populations and its relevance is poorly studied in STS.…”

“…Epigenetic modifiers, as mentioned before, seem to have an important role in sustaining a stem-like phenotype in STS. As an example, high expression of LIN28B has been associated with doxorubicin resistance and worse survival, pointing that this protein may be a relevant therapeutic target in STS [66]. Accordingly, the development of a new LIN28B-targeted therapy, including immunotherapy, might be a good approach in STS.…”

Tankyrase inhibitor XAV-939 enhances osteoblastogenesis and mineralization of human skeletal (mesenchymal) stem cells

“…A fluorescence-based apoptosis assay using the acridine orange/ethidium bromide (AO/EtBr) staining method was performed as previously described 68 after exposure of the cells to XAV-939 (3 µM) compared to DMSO-vehicle treated control cells. On day 3, cells were stained with dual fluorescent staining solution (1.0 µl) containing 100 µg/ml AO and 100 µg/ml EtBr (AO/EB, Sigma, St. Louis, MO, USA).…”