The effect of HMGB1 on the clinicopathological and prognostic features of non-small cell lung cancer - PubMed (original) (raw)

The effect of HMGB1 on the clinicopathological and prognostic features of non-small cell lung cancer

Anlin Feng et al. Oncotarget. 2016.

Abstract

Several studies have assessed the diagnostic and prognostic values of high mobility group protein box 1 (HMGB1) expression in non-small cell lung cancer (NSCLC), but these results remain controversial. The purpose of this study was to perform a meta-analysis of the gene microarray analyses of datasets from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) to evaluate the association of HMGB1 expression with the clinicopathological and prognostic features of patients with NSCLC. Furthermore, we investigated the underlying molecular mechanisms by bioinformatics analysis. Twenty relevant articles involving 2651 patients were included in this meta-analysis; the HMGB1 expression in NSCLC tissues was significantly higher than that in the healthy non-cancer control tissues. We also found an indication by microarray analysis and meta-analysis that HMGB1 expression was associated with the cancer TNM Staging System. In terms of prognostic features, a survival analysis from KM-Plotter tool revealed that the high HMGB1 expression group exhibited poorer survival in lung adenocarcinoma (ADC) and overall NSCLC patients. The survival and disease-free analyses from TCGA datasets also showed that HMGB1 mainly affected the development of patients with ADC. Therefore, we focused on how HMGB1 affected the prognosis and development of ADC using bioinformatics analyses and detected that the mitogen-activated protein kinases (MAPK), apoptosis and cell cycle signaling pathways were the key pathways that varied during HMGB1 up-regulation in ADC. Moreover, various genes such as PLCG2, the phosphatidylinositol-4, 5-bisphosphate 3-kinase superfamily (PI3Ks), protein kinase C (PKC) and DGKZ were selected as hub genes in the gene regulatory network. Our results indicated that HMGB1 is a potential biomarker to predict progression and survival of NSCLC, especially of ADC types.

Keywords: ADC; HMGB1; NSCLC; biomarker; prognosis.

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Figures

Figure 1

Figure 1. Schematic flow diagram of article selection

Figure 2

Figure 2. The results of the meta-analysis

A. Forest plot for HMGB1 in NSCLC and normal lung tissues. B. Forest plot for HMGB1 in NSCLC and para-tumor tissues. C. Forest plot for HMGB1 in lung ADC and SCC. D. Association between HMGB1 expression and NSCLC lymph node metastasis.

Figure 3

Figure 3. The expression of HMGB1 in various histologic types and TNM stages in NSCLC

A. The expression of HMGB1 in ADC and SCC (GSE30219). B-D. The expression of HMGB1 in different TNM stages (GSE30219). E. The expression of HMGB1 in ADC and SCC (GSE41271). F. The expression of HMGB1 in different final stages (GSE41271).

Figure 4

Figure 4. HMGB1 expression is correlated with the survival rate of NSCLC patients

A. Overall survival rate was analyzed in 1928 NSCLC patients in relation to HMGB1 expression. B. Overall survival rate was analyzed in 866 ADC patients in relation to HMGB1 expression. C. Overall survival rate was analyzed in 675 SCC patients in relation to HMGB1 expression. D-E. Overall survival and disease-free time rate were analyzed in 576 lung ADC patients in relation to HMGB1 expression. F-G. Overall survival and disease-free time rate were analyzed in 504 cases of lung SCC.

Figure 5

Figure 5. The bioinformatics analysis of molecular mechanisms of HMGB1 in ADC

A-B. Significantly over-represented biological processes in DEGs. C-D. Significantly over-represented pathways in DEGs. E. Pathway network. The dots represent pathways; the size of the dots represents the value of the degree of expression; the red and blue color of the dots denote up-regulated and down-regulated pathways, respectively; the yellow color of dots indicates that this pathway contains both up-regulated and down-regulated genes; and the direction of the arrow indicates upstream and downstream. F. Gene regulatory network. The dots represent genes; the size of the dots represents the value of betweenness centrality; the red and blue color of the dots denote up-regulated and down-regulated genes, respectively; the direction of the arrow denotes the upstream and downstream relationship; and the dotted lines denote indirect interaction. G. Network view of the PLCG2/HMGB1 neighborhood, PLCG2 and HMGB1 are seed genes (indicated with thick border). Darker red indicates increased frequency of alteration in ADC. H. Network view of the PIK3CG/PIK3R5/PIK3R1/HMGB1 neighborhood, PIK3CG, PIK3R5, PIK3R1 and HMGB1 are seed genes (indicated with thick border). I. Network Figure S view of the PRKCA/PRKCB/HMGB1 neighborhood, PRKCA, PRKCB and HMGB1 are seed genes (indicated with thick border). J. Network view of the DGKZ/HMGB1 neighborhood, DGKZ and HMGB1 are seed genes (indicated with thick border).

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