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Targeting mutant TP53 as a potential therapeutic strategy for the treatment of osteosarcoma.
Tang, Fan; Min, Li; Seebacher, Nicole A; Li, Xiaoyang; Zhou, Yubin; Hornicek, Francis J; Wei, Yuquan; Tu, Chongqi; Duan, Zhenfeng.
Afiliação
  • Tang F; Department of Orthopedics, West China Hospital of Sichuan University, Chengdu, Sichuan, 610041, P. R. China.
  • Min L; State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan, 610041, P. R. China.
  • Seebacher NA; Sarcoma Biology Laboratory, Department of Orthopaedic Surgery, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, 90095.
  • Li X; Department of Orthopedics, West China Hospital of Sichuan University, Chengdu, Sichuan, 610041, P. R. China.
  • Zhou Y; Sarcoma Biology Laboratory, Department of Orthopaedic Surgery, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, 90095.
  • Hornicek FJ; Sarcoma Biology Laboratory, Department of Orthopaedic Surgery, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, 90095.
  • Wei Y; Sarcoma Biology Laboratory, Department of Orthopaedic Surgery, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, 90095.
  • Tu C; Sarcoma Biology Laboratory, Department of Orthopaedic Surgery, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, 90095.
  • Duan Z; Sarcoma Biology Laboratory, Department of Orthopaedic Surgery, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, 90095.
J Orthop Res ; 37(3): 789-798, 2019 03.
Article em En | MEDLINE | ID: mdl-30667081
ABSTRACT
Mutant TP53 is a promising therapeutic target in cancers. Considering the current challenges facing the clinical treatment of cancer, as well as the urgent need to identify novel therapeutic targets in osteosarcomas, we aimed to evaluate the clinical significance of mutant TP53 in osteosarcoma patients and to explore the therapeutic effect of targeting mutant TP53 in osteosarcomas. We performed a meta-analysis to investigate the relationship between mutant TP53 and the overall survival of patients with osteosarcoma. A CRISPR-Cas9 system and a TP53 inhibitor, NSC59984, were also used to specifically knock-out and inhibit mutant TP53 in the human osteosarcoma cell lines, KHOS, and KHOSR2. The meta-analysis demonstrated that mutations in the TP53 gene could be used to predict a poor 2-year survival in osteosarcoma patients. We also demonstrated that the expression of mutant TP53 in human osteosarcoma cell lines can be efficiently knocked-out using CRISPR-Cas9, and this decreased the proliferation, migration, and tumor formation activity of these osteosarcoma cells. Moreover, drug sensitivity to doxorubicin was increased in these TP53 knock-out osteosarcoma cells. NSC59984 also showed similar anti-tumor effects as CRISPR-Cas9 targeted TP53 in the osteosarcoma cells in vitro. We have also demonstrated that the knock-out or inhibition of mutant TP53 decreased the expression of the oncogene IGF-1R, anti-apoptotic proteins Bcl-2, and Survivin in osteosarcoma cells. Collectively, these results suggest that mutant TP53 is a promising therapeutic target in osteosarcomas. Therefore, further studies exploring novel strategies to target mutant TP53 may help improve the treatment outcomes of osteosarcoma patients in the clinic. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Piperazinas / Neoplasias Ósseas / Terapia Genética / Osteossarcoma / Genes p53 / Nitrofuranos Tipo de estudo: Prognostic_studies / Systematic_reviews Limite: Humans Idioma: En Ano de publicação: 2019 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Piperazinas / Neoplasias Ósseas / Terapia Genética / Osteossarcoma / Genes p53 / Nitrofuranos Tipo de estudo: Prognostic_studies / Systematic_reviews Limite: Humans Idioma: En Ano de publicação: 2019 Tipo de documento: Article