Metformin reduces SATB2-mediated osteosarcoma stem cell-like phenotype and tumor growth via inhibition of N-cadherin/NF-kB signaling

OBJECTIVE: To investigate the role of SATB2 in stem cell-like properties of osteosarcoma and identify new strategies to eliminate cancer stem cells of osteosarcoma.

MATERIALS AND METHODS: Osteosarcoma cancer stem cells were derived by sarcosphere generation or chemo drug enrichment. SATB2 and pluripotency-associated gene expression in osteosarcoma CSCs were analyzed using qRT-PCR and Western blotting. The sphere formation assay, cell counting kit-8 assay and anti-chemotherapy proteins were used to measure the effects of altered SATB2, N-cadherin expression or metformin treatment in CSCs. Nude mice were injected with SATB2-deficient U2OS/MTX cells to assess the role of SATB2 in osteosarcoma growth and chemoresistance in vivo. Bioinformatics analyses were performed to identify SATB2 downstream target genes and immunochemistry to determine the correlation between SATB2 expression and patient outcome. Western blotting and luciferase reporter assays were used to examine the effects of N-cadherin and SATB2 inhibition on the NF-kB pathway.

RESULTS: SATB2 was upregulated in osteosarcoma stem cells. Knockdown of SATB2 decreased sarcosphere formation, cell proliferation and stem cell-like gene expression in vitro, meanwhile reduced tumor growth and chemoresistance in vivo. High SATB2 expression in osteosarcoma patient samples was associated with poor clinical outcome. N-cadherin was one critical downstream target gene of SATB2 that mediated the stem cell-like phenotype. Reduction of SATB2 or N-cadherin resulted in NF-kB inactivation, which led to impaired osteosarcoma sphere formation and tumor cell proliferation. Metformin treatment of osteosarcoma cells enhanced the effects of chemotherapy via suppression of N-cadherin.

CONCLUSIONS: SATB2 plays an important role in regulating osteosarcoma stem cell-like properties and tumor growth. The combination of conventional chemotherapy and metformin may be a promising therapeutic strategy for osteosarcoma patients.

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