A ubiquitin-related gene signature for predicting prognosis and constructing molecular subtypes in osteosarcoma

Nan Wei; Gong Chao-Yang; Zhou Wen-Ming; Lei Ze-Yuan; Shi Yong-Qiang; Zhang Shun-Bai; Zhang Kai; Ma Yan-Chao; Zhang Hai-Hong

doi:10.3389/fphar.2022.904448

A ubiquitin-related gene signature for predicting prognosis and constructing molecular subtypes in osteosarcoma

Front Pharmacol. 2022 Aug 17:13:904448. doi: 10.3389/fphar.2022.904448. eCollection 2022.

Authors

Nan Wei^{1

2}, Gong Chao-Yang^{1

2}, Zhou Wen-Ming^{1

2}, Lei Ze-Yuan^{1

2}, Shi Yong-Qiang^{1

2}, Zhang Shun-Bai^{1

2}, Zhang Kai^{1

2}, Ma Yan-Chao^{1

2}, Zhang Hai-Hong^{1

2}

Affiliations

¹ Orthopaedics Key Laboratory of Gansu Province, Lanzhou, China.
² Lanzhou University Second Hospital, Lanzhou, China.

Abstract

Background: Ubiquitination is medicated by three classes of enzymes and has been proven to involve in multiple cancer biological processes. Moreover, dysregulation of ubiquitination has received a growing body of attention in osteosarcoma (OS) tumorigenesis and treatment. Therefore, our study aimed to identify a ubiquitin-related gene signature for predicting prognosis and immune landscape and constructing OS molecular subtypes. Methods: Therapeutically Applicable Research to Generate Effective Treatments (TARGET) was regarded as the training set through univariate Cox regression, Lasso Cox regression, and multivariate Cox regression. The GSE21257 and GSE39055 served as the validation set to verify the predictive value of the signature. CIBERSORT was performed to show immune infiltration and the immune microenvironment. The NMF algorithm was used to construct OS molecular subtypes. Results: In this study, we developed a ubiquitin-related gene signature including seven genes (UBE2L3, CORO6, DCAF8, DNAI1, FBXL5, UHRF2, and WDR53), and the gene signature had a good performance in predicting prognosis for OS patients (AUC values at 1/3/5 years were 0.957, 0.890, and 0.919). Multivariate Cox regression indicated that the risk score model and prognosis stage were also independent prognostic prediction factors. Moreover, analyses of immune cells and immune-related functions showed a significant difference in different risk score groups and the three clusters. The drug sensitivity suggested that IC50 of proteasome inhibitor (MG-132) showed a notable significance between the risk score groups (p < 0.05). Through the NMF algorithm, we obtained the three clusters, and cluster 3 showed better survival outcomes. The expression of ubiquitin-related genes (CORO6, UBE2L3, FBXL5, DNAI1, and DCAF8) showed an obvious significance in normal and osteosarcoma tissues. Conclusion: We developed a novel ubiquitin-related gene signature which showed better predictive prognostic ability for OS and provided additional information on chemotherapy and immunotherapy. The OS molecular subtypes would also give a useful guide for individualized therapy.

Keywords: immune; molecular subtypes; osteosarcoma; ubiquitin; ubiquitination.