Slit-Robo GTPase-Activating Protein 2 as a metastasis suppressor in osteosarcoma
Tracy A. MarkoGhaidan A. ShamsanElizabeth N. EdwardsPaige E. HazeltonSusan K. RatheIngrid CornaxPaula OvernJyotika VarshneyBrandon J. DiessnerBranden S. MoriarityM. Gerard O’SullivanDavid J. OddeDavid A. Largaespada
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Abstract:
Osteosarcoma is the most common primary bone tumor, with metastatic disease responsible for most treatment failure and patient death. A forward genetic screen utilizing Sleeping Beauty mutagenesis in mice previously identified potential genetic drivers of osteosarcoma metastasis, including Slit-Robo GTPase-Activating Protein 2 (Srgap2). This study evaluates the potential role of SRGAP2 in metastases-associated properties of osteosarcoma cell lines through Srgap2 knockout via the CRISPR/Cas9 nuclease system and conditional overexpression in the murine osteosarcoma cell lines K12 and K7M2. Proliferation, migration, and anchorage independent growth were evaluated. RNA sequencing and immunohistochemistry of human osteosarcoma tissue samples were used to further evaluate the potential role of the Slit-Robo pathway in osteosarcoma. The effects of Srgap2 expression modulation in the murine OS cell lines support the hypothesis that SRGAP2 may have a role as a suppressor of metastases in osteosarcoma. Additionally, SRGAP2 and other genes in the Slit-Robo pathway have altered transcript levels in a subset of mouse and human osteosarcoma, and SRGAP2 protein expression is reduced or absent in a subset of primary tumor samples. SRGAP2 and other axon guidance proteins likely play a role in osteosarcoma metastasis, with loss of SRGAP2 potentially contributing to a more aggressive phenotype.Long noncoding RNA activated by transforming growth factor-β (lncRNA-ATB) is a novel lncRNA, which is recently reported to have critical roles in carcinogenesis and progression of several cancers. However, the expression, clinical values, biological roles, and underlying molecular mechanisms of lncRNA-ATB in osteosarcoma are still known. In this study, we measured lncRNA-ATB expression in serum and osteosarcoma tissues of osteosarcoma patients, analyzed its diagnostic and prognostic values. Serum lncRNA-ATB is increased in osteosarcoma patients and could accurately discriminate osteosarcoma patients from healthy controls. LncRNA-ATB is also upregulated in osteosarcoma tissues and cell lines, and positively associated with Enneking stage, metastasis and recurrence. Increased lncRNA-ATB level indicates poor recurrence-free survival and overall survival. Functional experiments demonstrated that overexpression of lncRNA-ATB enhances osteosarcoma cells proliferation, migration, and invasion, and while depletion of lncRNA-ATB inhibits osteosarcoma cells proliferation, migration, and invasion. Mechanistically, we found that lncRNA-ATB inhibits miR-200s, and upregulates miR-200s target genes ZEB1 and ZEB2. Additionally, the roles of lncRNA-ATB on osteosarcoma cells proliferation, migration, and invasion in vitro, and osteosarcoma tumor growth in vivo are dependent on the regulation of miR-200s. Taken together, this study suggests that lncRNA-ATB may be a potential diagnostic and prognostic biomarker and a therapeutic target for osteosarcoma.
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Objective to find resistant and sensitive osteosarcoma tumor tissue samples,so that to prepare for further looking for differences in protein.Methods Obtain the tissue of patients with osteosarcoma,osteosarcoma cells isolated and cultured in vitro drug sensitivity test cells,so as to identify drug-resistant and sensitive osteosarcoma tissue samples.Results Detection curve of osteosarcoma cells to various chemotherapy drugs and Found resistant and sensitive osteosarcoma tissue samples.Conclusion Osteosarcoma has different sensitivity to various chemotherapeutic drugs,Cisplatin is further appropriate drugs to look for differences in protein research.
Chemosensitivity assay
Chemotherapeutic drugs
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Introduction: Osteosarcoma usually originates in the metaphyseal region of long bone, but may also arise in the diaphyseal of long bone. Diaphyseal osteosarcoma is a rare cases account for <10% of all osteosarcoma. In some cases two or more osteosarcoma lesions are seen in the same patient, at the same time (Synchronous osteosarcoma). It’s unusual condition of osteosarcoma, they are found at a frequency of about 1–3% osteosarcoma cases.
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Over several years, scientists investigating cancer have focused their efforts on elucidating the mechanisms underlying cancer metastasis, with the aim of finding a way to inhibit this process. These mechanisms, however, only explain the process of cancer metastasis, but do not explain why cancer would metastasize in the first place. Cancer metastasizes due to several factors, namely attack by the immune system, lack of oxygen and necessary nutrients, large amounts of lactic acid produced by glycolysis and increased cell death. Therefore, the majority of the presently available treatments for cancer also bear the potential to induce metastasis. Thus, it is crucial in medical practice to minimize the risk of cancer metastasis during a time when there are no effective means to inhibit this process.
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Cases of unusual osteosarcoma comprising parosteal osteosarcoma, intraosseous well differentiated osteosarcoma, postradiation osteosarcoma, epithelioid osteosarcoma, and MFH-like osteosarcoma were reported. They were apparently differed from conventional osteosarcoma in the point of biologic activity and prognosis. Osteosarcoma is, therefore, considered as a heterogeneic tumor. It is important to make an exact diagnosis and to make an appropriate treatment depending on the diagnosis.
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