| Osteosarcoma is the most common malignant bone tumor in children andadolescents which derived from mesenchymal tissue. The invasion, and metastasisoccur quite often, the outcaome of which is the death or disability of patients. Theunderlying mechanism for its occurrence has not been fully understood yet. Thereexist no effective prevention and treatment. It accurs frequently in children andadolescents, who has long expected survival time, therefore long time chemotherapyis required which often results in the toxic effects to the patient and induces cellsresistance to chemotherapy that seriously restrict the long-term application ofchemotherapy. Therefore, research on the molecular mechanism to maintainmalignant phenotype of osteosarcoma and to mediate the resistance tochemotherapeutic drugs. The genetherapy which aim at increasing sensitivity of thecells to chemotherapeutic drug is the key to improve the curative effect.SATB1is a nuclear matrix binding protein, which binds with the nuclear matrixadhesion area, participate in cell chromosome remodeling, histone acetylation andmethylation process, control expression of the target genes through epigeneticregulation. In normal tissue, SATB1expression mainly in thymus cells, regulate T celldevelopment and mature, and mediate function of cell immunity. SATB1does notexpress in normal adult tissue with the exception of thymus, bone marrow and nervetissue. Recent studies show that, in some breast cancer, malignant tumor of digestive,respiratory and urogenital system, SATB1expression increased, suggesting that itplay an important role in the progress of these malignant tumors, It is also shown thatin the drug resistance breast cancer cell line (MCF-7/ADR) SATB1expression ishigh. Silence SATB1in these cells decrease the resistance of the cells to the drugs.Conversely, MCF-7cells are low resistance to the drug, and the expression of SATB1in the cells is low as well. Overexpression of SATB1in these cells mediated by transfection of plasmid DNA, increase the cell metastasis and the resistance tochemotherapeutic drugs, indicating the correlation between high expression of SATB1in breast cancer cells with high metastasis and resistance to chemotherapeutic drugs.But little is known on role of SATB1in osteosarcoma cells.This study start with analyzing the mRNA levels of SATB1in the cell lines ofhuman malignant tumor, the results showed that the SATB1expression is different.The highest expression of SATB1occurs in human osteosarcoma U2OS cells. Toexplore the role of SATB1in maintaining malignant phenotype of the cell, the studywas carried out wih silencing SATB1expression by RNA interference technology,analyzing change on biological behavior of the cell. The results showed thatinterference plasmid (SATB1-shRNA) stability transfection significantly knockdownSATB1expression in U2OS cell. Knockdown of SATB1significantly improve themalignant phenotype and increase sensitivity to chemotherapeutic drugs arsenictrioxide in U2OS. The effects of knockdown SATB1in U2OS cells include:(1)reducing proliferation and promoting apoptosis, respectively by inhibiting CTGF,JunB, Survivin and Bcl-2expression;(2) reducing cell migration and invasion byup-regulating TIMP-3and downregulating MMP-2, MMP-9and Vimentin expression;(3) increasing sensitivity of the cells to arsenic trioxide by down-regulating expressionof ABCG2and ABCC1;(4)depressing cell tumorigenic ability and invasion. Theresults show that SATB1plays an important role in maintaining malignant phenotypeof human osteosarcoma U2OS cells and resistance of the cells to chemotherapeuticdrugs arsenic trioxide, provide a theoretical basis for the potential application of genetherapy targeted to SATB1associated with chemotherapeutic drugs in treating humanosteosarcoma. These conclusions were supported by the further studies on the clinicalspecimens of osteosarcoma in which the expression levels of SATB1are related withmalignancy of tumor. |
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