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Silencing KIF18B enhances radiosensitivity: identification of a promising therapeutic target in sarcoma
Wensi Liu1, Zhaojin Yu1, Haichao Tang1
1Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, 110122, P. R. China; Liaoning Key Laboratory of molecular targeted anti-tumour drug development and evaluation; Liaoning Cancer immune peptide drug Engineering Technology Research Center; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumours, Ministry of Education; China Medical University, Shenyang, 110122, P. R. China.
Background:
Sarcomas are rare heterogeneous tumours, derived from primitive mesenchymal stem cells, with more than 100 distinct subtypes. Radioresistance remains a major clinical challenge for sarcomas, demanding urgent for effective biomarkers of radiosensitivity.
Methods:
The radiosensitive gene Kinesin family member 18B (KIF18B) was mined through bioinformatics with integrating of 15 Gene Expression Omnibus (GEO) datasets and The Cancer Genome Atlas (TCGA) database. We used radiotherapy-sh-KIF18B combination to observe the anti-tumour effect in sarcoma cells and subcutaneous or orthotopic xenograft models. The KIF18B-sensitive drug T0901317 (T09) was further mined to act as radiosensitizer using the Genomics of Drug Sensitivity in Cancer (GDSC) database.
Findings:
KIF18B mRNA was significantly up-regulated in most of the subtypes of bone and soft tissue sarcoma. Multivariate Cox regression analysis showed that KIF18B high expression was an independent risk factor for prognosis in sarcoma patients with radiotherapy. Silencing KIF18B or using T09 significantly improved the radiosensitivity of sarcoma cells, delayed tumour growth in subcutaneous and orthotopic xenograft model, and elongated mice survival time. Furthermore, we predicted that T09 might bind to the structural region of KIF18B to exert radiosensitization.
Interpretation:
These results indicated that sarcomas with low expression of KIF18B may benefit from radiotherapy. Moreover, the radiosensitivity of sarcomas with overexpressed KIF18B could be effectively improved by silencing KIF18B or using T09, which may provide promising strategies for radiotherapy treatment of sarcoma.
Fundings:
A full list of funding can be found in the Funding Sources section.
Insights
Kinesin family member 18B (KIF18B) is a biomarker for sarcoma radiosensitivity. Silencing KIF18B or using drug T09 enhances radiotherapy efficacy in sarcoma, offering new treatment strategies.
Area of Science:
- Oncology
- Genetics
- Biochemistry
Background:
- Sarcomas are rare, heterogeneous cancers with over 100 subtypes.
- Radioresistance is a significant clinical challenge in sarcoma treatment.
- Effective biomarkers for predicting radiosensitivity are urgently needed.
Purpose of the Study:
- To identify biomarkers for sarcoma radiosensitivity.
- To investigate Kinesin family member 18B (KIF18B) as a potential biomarker.
- To explore therapeutic strategies involving KIF18B and radiosensitizers.
Main Methods:
- Bioinformatic analysis integrating 15 Gene Expression Omnibus (GEO) datasets and The Cancer Genome Atlas (TCGA).
- Experimental validation using radiotherapy combined with KIF18B silencing in sarcoma cell and xenograft models.
- Identification of KIF18B-sensitive drug T0901317 (T09) as a radiosensitizer using the Genomics of Drug Sensitivity in Cancer (GDSC) database.
Main Results:
- KIF18B mRNA was significantly upregulated in most sarcoma subtypes.
- High KIF18B expression independently predicted poor prognosis in sarcoma patients receiving radiotherapy.
- Silencing KIF18B or administering T09 improved sarcoma radiosensitivity, inhibited tumor growth, and prolonged survival in preclinical models.
- T09 is predicted to bind KIF18B, mediating radiosensitization.
Conclusions:
- Sarcomas with low KIF18B expression may respond well to radiotherapy.
- Overexpressed KIF18B in sarcomas can be targeted by KIF18B silencing or T09 to enhance radiosensitivity.
- These findings suggest promising therapeutic strategies for sarcoma radiotherapy.
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