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Identification of mitochondrial-related signature and molecular subtype for the prognosis of osteosarcoma - PubMed

  • ️Sun Jan 01 2023

Identification of mitochondrial-related signature and molecular subtype for the prognosis of osteosarcoma

Xiaokun Zhao et al. Aging (Albany NY). 2023.

Abstract

Mitochondria play a vital role in osteosarcoma. Therefore, the purpose of this study was to investigate the potential role of mitochondrial-related genes (MRGs) in osteosarcoma. Based on 92 differentially expressed MRGs, osteosarcoma samples were divided into two subtypes using the nonnegative matrix factorization (NMF). Ultimately, a univariate, least absolute shrinkage and selection operator (LASSO), and multivariate Cox analysis were performed to construct a prognostic risk model. The single-sample gene set enrichment analysis assessed the immune infiltration characteristics of osteosarcoma patients. Finally, we identified an osteosarcoma biomarker, malonyl-CoA decarboxylase (MLYCD), which showed downregulation. Osteosarcoma cells proliferation, migration, and invasion were effectively inhibited by the overexpression of MLYCD. Our findings will help us to further understand the molecular mechanisms of osteosarcoma and contribute to the discovery of new diagnostic biomarkers and therapeutic targets.

Keywords: biomarkers; mitochondrial; molecular subtype; osteosarcoma; prognostic signature.

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Conflict of interest statement

CONFLICTS OF INTEREST: No potential conflicts of interest were disclosed.

Figures

Figure 1
Figure 1

Flow chart of the program process.

Figure 2
Figure 2

Clustering based on NMF. (A) The heatmaps of differentially expressed mitochondrial genes. (B) The cophenetic correlation coefficient is used to reflect the stability of the cluster obtained from NMF. (C) RSS is used to reflect the clustering performance of the model. (D) Consensus map clustered via the NMF algorithm. (E) Kaplan–Meier curve analysis for the two subtypes. (F, G) Immune scores of cells of the tumor microenvironment (TME) showing significant differences.

Figure 3
Figure 3

Construction of mitochondrial-related gene signature. (A) Univariate analysis of potential prognostic factors. (B, C) Lasso regression for MRGs in univariate Cox regression. (D) The coefficients and P-value of the six MRGs. (E) Correlation diagram of six gene expression levels.

Figure 4
Figure 4

Prognostic analysis of the MRGs signature. (A) Kaplan–Meier survival curve analysis of patients in the high-risk group and low-risk group. (B) The AUC of time-dependent ROC curves. (C) The distributions of survival status and risk score. (D–I) Kaplan–Meier survival analysis of single genes in the TARGET cohort.

Figure 5
Figure 5

Validation of the MRGs signature in the GSE21257 dataset. (A) Kaplan–Meier survival curve analysis of patients in the high-risk group and low-risk group. (B) The distributions of survival status and risk score. (C) The AUC of time-dependent ROC curves. (D) PCA plot based on the MRGs signature.

Figure 6
Figure 6

Clinical correlation analyses. (A) Univariate Cox analysis. (B) Multivariate Cox analysis. (C) AUC value predicts clinical characteristics and risk score. (D) Heatmap and the clinical characteristics of the two groups. (E–G) Relationship between risk score and clinical pathological factors.

Figure 7
Figure 7

Nomogram and immune signature of the risk model. (A) Nomogram based on risk score, age, sex, and metastasis for predicting the 1-, 3-, and 5-year death rate. (B, C) Calibration plots of the nomogram for predicting the 3- and 5-year’ survival of osteosarcoma. (D) Relationship between risk score and immune cell infiltration and related functions via ssGSEA analysis. (E) Relationship between MRGs signature and immune cell infiltration and related functions via ssGSEA analysis.

Figure 8
Figure 8

The expression levels of MLYCD. (A, B) The MLYCD expression level in osteosarcoma and adjacent paired samples, based on the GSE99671 and GSE225588 cohort. (C) The qRT-PCR result of MLYCD in hFOB 1.19, 143B, MG63 cell lines. (D, E) The western blotting result of MLYCD in hFOB 1.19, 143B, MG63 cell lines. (F) The expressions of MLYCD in tumor and adjacent normal tissues. *P<0.05, **P<0.01 and ***P<0.001.

Figure 9
Figure 9

The effect of MLYCD on osteosarcoma cell proliferation, migration, and invasion. (A) Protein expression levels of MLYCD were measured by western blotting. (B–D) CCK-8 and colony-formation assays were used to assess osteosarcoma cell proliferation. (E, F) The wound healing assay was performed to estimate the effect of MLYCD overexpression on cell migration. (G–J) The transwell assay was conducted to assess the effect of MLYCD overexpression on osteosarcoma cell invasion and migration. Scale bar = 100um. *P<0.05, **P<0.01, and ***P<0.001.

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