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. 2021 Oct 27:14:5183-5195.
doi: 10.2147/OTT.S336225. eCollection 2021.

Identification of HOXD10 as a Marker of Poor Prognosis in Glioblastoma Multiforme

Yanxin Li  1 , Ke Ma  2 , Qi Xie  3 , Xianwei Zhang  3 , Xiulei Zhang  4 , Kui Chen  1 , Lingfei Kong  3 , Rongjun Qian  1
Affiliations

Identification of HOXD10 as a Marker of Poor Prognosis in Glioblastoma Multiforme

Yanxin Li et al. Onco Targets Ther. .

Abstract

Purpose: HOXD10 is a tumor modulator that can either be a tumor-suppressor or a tumor-promoting gene. However, the role of HOXD10 in glioblastoma multiforme (GBM) remains unclear.

Methods: Immunohistochemistry (IHC) was applied to detect protein expression of HOXD10 in GBM and normal brain tissue patients. Clinicopathological characteristics with GBM were recorded, and a Kaplan-Meier curve was plotted. Additionally, the mRNA expression of HOXD10 and its effect on prognosis were analyzed using the online tool GEPIA and the Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), and the Gene Expression Omnibus (GEO) databases. Based on the mRNA expression of HOXD10, GBM patients from TCGA database were divided into low- and high-HOXD10 expression groups to analyze the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, and construct a lncRNA-miRNA-mRNA network and a protein-protein interaction (PPI) network.

Results: The mRNA expression of HOXD10 was up-regulated in GBM according to GEPIA, while the protein expression of HOXD10 in GBM was down-regulated according to IHC analysis of samples from patients collected from our hospital. Correlation analysis showed that HOXD10 expression was significantly related to IDH1 status. Univariate analysis revealed that low HOXD10 expression, complete surgical resection, postoperative radiotherapy, postoperative temozolomide chemotherapy and IDH1 mutation were all beneficial prognostic factors. Further multivariate analysis revealed that only complete surgical resection and postoperative radiotherapy were independent prognostic factors. GO and KEGG enrichment analyses indicated that HOXD10 expression is mainly involved in cytokine-cytokine receptor interactions. In the ceRNA network, 89 nodes, containing 45 mRNAs, 39 miRNAs and five lncRNAs associated with prognosis were involved. The PPI network revealed a tight interaction between HOXD10 and HOXD8, HOXD9, HOXD11, HOXD13 and HOXB3.

Conclusion: Based on our experimental data, although HOXD10 expression is low in GBM compared with normal brain tissue, GBM patients with high HOXD10 expression have a worse prognosis. HOXD10 may play different or even opposite roles in different stages of GBM occurrence and development. For patients with GBM, HOXD10 may be a valid predictor of prognosis.

Keywords: GBM; HOXD10; ceRNA; prognosis; protein-protein interaction.

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Conflict of interest statement

The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
(A) The mRNA expression of HOXD10 is significantly upregulated in GBM compared with normal brain tissues. *P < 0.05. (B–F) High mRNA expression of HOXD10 in GBM predicted poor prognosis based on database analyses. (B), TCGA database; (C and D), CGGA database; (E and F), GEO database.
Figure 2
Figure 2
Representative immunohistochemical staining of HOXD10 in GBM and normal brain tissues. (A), HOXD10 was negative in normal brain tissue (X400). (B), HOXD10 was positive in normal brain tissue (X400). (C), HOXD10 was negative in GBM (X400). (D), HOXD10 was positive in GBM (X400).
Figure 3
Figure 3
Univariate and multivariate survival analyses. (A), Complete surgical resection can improve the survival time of GBM patients. (B), Postoperative TMZ chemotherapy can improve the survival time of GBM patients. (C), Postoperative radiation therapy can improve the survival time of GBM patients. (D), GBM patients with IDH1 mutation had a longer survival time. (E), GBM patients with high HOXD10 protein expression had a shorter survival time. (F), Complete surgical resection can improve the PFS of GBM patients. (G), Tumors that invade multiple lobes were more likely to recur after surgery. (H), Postoperative radiation therapy can prolong the PFS of GBM patients.
Figure 4
Figure 4
Differential analysis of gene expression profiles in high- and low-HOXD10 expression groups and pathway enrichment analysis. (A), Volcano plot showing the differentially expressed genes. (B), Bubble chart of the results of GO enrichment analysis. (C), Bar plot of the results of KEGG enrichment analysis.
Figure 5
Figure 5
Survival analysis of differentially expressed lncRNAs. (A–D and F), High expression of HOTAIR, HOXC-AS3, HOXC12-AS, LINC01305 and LINC01539 were poor prognostic factors. (E), High expression of MIR663AHG was good prognostic factor.
Figure 6
Figure 6
Construction of a ceRNA network. (A), The ceRNA network was constructed based on the up-regulation of lncRNAs screened by HOXD10 expression level and related to the survival of GBM patients. (B), The ceRNA network was constructed based on down-regulated lncRNAs screened by HOXD10 expression level and related to the survival of GBM patients.
Figure 7
Figure 7
Protein–protein interaction (PPI) network analysis. After eliminating disconnected nodes, 71 genes were involved in the PPI. The network was visualized with Cytoscape 3.6.1.
See this image and copyright information in PMC

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