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.