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Research Article

GADD45B predicts lung squamous cell carcinoma survival and impacts immune infiltration, and T cell exhaustion

ORCID Icon, ORCID Icon, , , ORCID Icon &
Article: 2209706 | Received 11 Jun 2022, Accepted 05 Mar 2023, Published online: 11 May 2023

Figures & data

Table 1. Detailed information of databases applied in the present study.

Figure 1. Expression of GADD45B within different TCGA-derived cancers illustrated through TIMER. Significance levels: *p < 0.05, **p < 0.01, ***p < 0.001.

Figure 1. Expression of GADD45B within different TCGA-derived cancers illustrated through TIMER. Significance levels: *p < 0.05, **p < 0.01, ***p < 0.001.

Table 2. The effect of GADD45B level on cancer prognosis based on OncoLnc analysis.

Figure 2. Prognostic prediction performance of GADD45B in different cancers assessed through the GEPIA2 Plotter (a-g) and KM (h-k). (A) Survival heatmap regarding GADD45B levels within 33 TCGA-derived malignant tumours. The heatmap displays the log10 HRs with different colours. Blue and red squares indicate the lower and higher risks, respectively. The boxed rectangles represent the significance of the prognostic analysis. DFS and OS curved lines of LUSC (n = 482) (B), THCA (n = 510) (C), OS curves of HNSC (n = 518) (D), DFS curves of LUAD (n = 478) (E), OS curves of SARC (n = 262) (F), and OS curves of SKCM (n = 488) (G). DFS and OS curves of BC (n = 1879, n = 4929) (H), DFS and OS curves of LC (n = 1925, n = 982) (I), GC (n = 875, n = 640) (J), and OC (n = 1656, n = 1435) (K). OS-overall survival; RFS-relapse free survival; DFS-disease-free survival; PFS-progression-free survival.

Figure 2. Prognostic prediction performance of GADD45B in different cancers assessed through the GEPIA2 Plotter (a-g) and KM (h-k). (A) Survival heatmap regarding GADD45B levels within 33 TCGA-derived malignant tumours. The heatmap displays the log10 HRs with different colours. Blue and red squares indicate the lower and higher risks, respectively. The boxed rectangles represent the significance of the prognostic analysis. DFS and OS curved lines of LUSC (n = 482) (B), THCA (n = 510) (C), OS curves of HNSC (n = 518) (D), DFS curves of LUAD (n = 478) (E), OS curves of SARC (n = 262) (F), and OS curves of SKCM (n = 488) (G). DFS and OS curves of BC (n = 1879, n = 4929) (H), DFS and OS curves of LC (n = 1925, n = 982) (I), GC (n = 875, n = 640) (J), and OC (n = 1656, n = 1435) (K). OS-overall survival; RFS-relapse free survival; DFS-disease-free survival; PFS-progression-free survival.

Table 3. Prognostic prediction performance of GADD45B within different LUSC subtypes based on Kaplan-Meier Plotter.

Figure 3. Spearman’s relevance between GADD45B, immunomodulators, and lymphocytes (TISIDB). (A) Association of the abundance of TILs with the level of GADD45B (B) The three most significant TILs associated with GADD45B expression level. (C) Associations of immuno-inhibitor abundances with GADD45B expression level. (D) The three most significant immuno-inhibitors associated with GADD45B expression level. (E) Associations of immuno-stimulator abundances with GADD45B expression level. (F) The three most significant immuno-stimulators associated with GADD45B expression level. (G) Association of MHC molecules with GADD45B expression level. (H) The three most significant MHC molecules associated with GADD45B expression level. Blue or red boxes indicate negative or positive correlations, respectively. The correlation strength is in direct proportion to the colour intensity. MHC, major histocompatibility complex; TILs, tumour-infiltrating lymphocytes.

Figure 3. Spearman’s relevance between GADD45B, immunomodulators, and lymphocytes (TISIDB). (A) Association of the abundance of TILs with the level of GADD45B (B) The three most significant TILs associated with GADD45B expression level. (C) Associations of immuno-inhibitor abundances with GADD45B expression level. (D) The three most significant immuno-inhibitors associated with GADD45B expression level. (E) Associations of immuno-stimulator abundances with GADD45B expression level. (F) The three most significant immuno-stimulators associated with GADD45B expression level. (G) Association of MHC molecules with GADD45B expression level. (H) The three most significant MHC molecules associated with GADD45B expression level. Blue or red boxes indicate negative or positive correlations, respectively. The correlation strength is in direct proportion to the colour intensity. MHC, major histocompatibility complex; TILs, tumour-infiltrating lymphocytes.

Figure 4. Associations of GADD45B with degrees of immune infiltration within LUSC. (A) Associations of GADD45B expression level with immune infiltration degrees of CD8+ or CD4+ T cells, B cells, neutrophils, macrophages, and DCs and tumour purity. (B) TIMER plots showing the correlation of immune infiltrations or GADD45B expression with survival in LUSC, its sample contained 482 patients of which 205 died. (C) Tumour-infiltration degrees were associated with GADD45B SCNAs in LUSC. Significance levels: * p < 0.05; ** p < 0.01; *** p < 0.001.

Figure 4. Associations of GADD45B with degrees of immune infiltration within LUSC. (A) Associations of GADD45B expression level with immune infiltration degrees of CD8+ or CD4+ T cells, B cells, neutrophils, macrophages, and DCs and tumour purity. (B) TIMER plots showing the correlation of immune infiltrations or GADD45B expression with survival in LUSC, its sample contained 482 patients of which 205 died. (C) Tumour-infiltration degrees were associated with GADD45B SCNAs in LUSC. Significance levels: * p < 0.05; ** p < 0.01; *** p < 0.001.

Table 4. Relationships between GADD45B and TIIC markers based on the TIMER in LUSC.

Table 5. The correlation of GADD45B with TIIC gene markers in LUSC and normal samples using GEPIA2.

Figure 5. GADD45B expression in LUSC. (A) GADD45B expression in different TISIDB-derived LUSC immune subtypes. (B) GADD45B expression in different TISIDB-derived LUSC molecular subtypes. (C) GADD45B expression in different GEPIA2-derived LUSC stages. GADD45B gene expression data were calculated relative to log counts per million mapped reads (log2 CPM) in (A, B) and log2 (TPM + 1) in (C). (D) HPA-based immunohistochemistry of GADD45B. GADD45B in normal tissue: https://www. proteinatlas.org/ENSG00000099860-GADD45B/tissue/lung; GADD45B in tumour tissue: https://www.proteinatlas.org/ENSG00000099860-GADD45B/pathology/lung+ cancer#img. T: GADD45B pcarotein expression in cancer samples (high staining, strong intensity, quantity >75%); N: GADD45B protein expression in non-carcinoma samples (low staining, weak intensity, quantity 75%-25%). (E) GADD45B mRNA expression is correlated with the histological and sample types (n = 758).

Figure 5. GADD45B expression in LUSC. (A) GADD45B expression in different TISIDB-derived LUSC immune subtypes. (B) GADD45B expression in different TISIDB-derived LUSC molecular subtypes. (C) GADD45B expression in different GEPIA2-derived LUSC stages. GADD45B gene expression data were calculated relative to log counts per million mapped reads (log2 CPM) in (A, B) and log2 (TPM + 1) in (C). (D) HPA-based immunohistochemistry of GADD45B. GADD45B in normal tissue: https://www. proteinatlas.org/ENSG00000099860-GADD45B/tissue/lung; GADD45B in tumour tissue: https://www.proteinatlas.org/ENSG00000099860-GADD45B/pathology/lung+ cancer#img. T: GADD45B pcarotein expression in cancer samples (high staining, strong intensity, quantity >75%); N: GADD45B protein expression in non-carcinoma samples (low staining, weak intensity, quantity 75%-25%). (E) GADD45B mRNA expression is correlated with the histological and sample types (n = 758).

Figure 6. Co-expression and potential function analyses of GADD45B in LUSC (LinkedOmics). (A) GADD45B-related genes in LUSC identified through the Pearson test. Green and red dots separately represent genes with notably negative and positive correlations with GADD45B. (B and C) Heatmaps presenting the 50 most significantly correlated (both positive and negative) GADD45B-related genes in LUSC. (D and E) Markedly associated GO: BP annotations along with KEGG pathway analysis for GADD45B in LUSC. (F and G) Survival heatmaps revealing the 50 most significantly correlated (both positive and negative) GADD45B-related genes in LUSC. Survival heatmaps revealing the log10 HRs of different genes. Blue and red squares denote decreased and increased risks, respectively. Blocks with frames indicate significant positive and negative consequences of the prognostic factors analysis (p < 0.05). (H) GADD45B and its predicted miRNAs (GADD45B is displayed as blue rounds and targeted miRNAs as yellow rounds. The mutual effect between GADD45B and its interrelated miRNAs is presented as lines). GO: Gene Ontology; KEGG: Kyoto Encyclopaedia of Genes and Genomes; FDR: false discovery rate.

Figure 6. Co-expression and potential function analyses of GADD45B in LUSC (LinkedOmics). (A) GADD45B-related genes in LUSC identified through the Pearson test. Green and red dots separately represent genes with notably negative and positive correlations with GADD45B. (B and C) Heatmaps presenting the 50 most significantly correlated (both positive and negative) GADD45B-related genes in LUSC. (D and E) Markedly associated GO: BP annotations along with KEGG pathway analysis for GADD45B in LUSC. (F and G) Survival heatmaps revealing the 50 most significantly correlated (both positive and negative) GADD45B-related genes in LUSC. Survival heatmaps revealing the log10 HRs of different genes. Blue and red squares denote decreased and increased risks, respectively. Blocks with frames indicate significant positive and negative consequences of the prognostic factors analysis (p < 0.05). (H) GADD45B and its predicted miRNAs (GADD45B is displayed as blue rounds and targeted miRNAs as yellow rounds. The mutual effect between GADD45B and its interrelated miRNAs is presented as lines). GO: Gene Ontology; KEGG: Kyoto Encyclopaedia of Genes and Genomes; FDR: false discovery rate.

Figure 7. NSCLC pathway that is regulated by the alteration of GADD45B.

Figure 7. NSCLC pathway that is regulated by the alteration of GADD45B.
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Data availability statement

Data supporting our findings are already included in the manuscript.