Transcriptome and pan-cancer system analysis identify PM2.5-induced stanniocalcin 2 as a potential prognostic and immunological biomarker for cancers

Abstract

Epidemiological studies have shown that air pollution and particulate matter (PM) are closely related to the occurrence of cancer. However, the potential prognostic and immunological biomarkers for air pollution related cancers are lacking. In this study, we proved PM2.5 exposure was correlated with lung cancer through transcriptome analysis. Importantly, we identified STC2 as a key gene regulated by PM2.5, whose expression in epithelial cells was significantly increased after PM2.5 treatment and validated by using RT-qPCR and immunofluorescence. Kaplan-Meier OS curves suggested that high STC2 expression positively correlated with a poor prognosis in lung cancer. Furthermore, we discovered that STC2 was associated with multiple cancers and pathways in cancer. Next, Pan-Cancer Expression Landscape of STC2 showed that STC2 exhibited inconsistent expression across 26 types of human cancer, lower in KIRP in cancer versus adjacent normal tissues, and significantly higher in another cancers. Cox regression results suggested that STC2 expression was positively or negatively associated with prognosis in different cancers. Moreover, STC2 expression was associated with clinical phenotypes including age, gender, stage and grade. Mutation features of STC2 were also analyzed, in which the highest alteration frequency of STC2 was presented in KIRC with amplification. Meanwhile, the effects of copy number variation (CNV) on STC2 expression were investigated across various tumor types, suggesting that STC2 expression was significantly correlated with CNV in tumors. Additionally, STC2 was closely related to tumor heterogeneity, tumor stemness and tumor immune microenvironment like immune cell infiltration. In the meantime, we analyzed methylation modifications and immunological correlation of STC2. The results demonstrated that STC2 expression positively correlated with most RNA methylation genes and immunomodulators across tumors. Taken together, the findings revealed that PM2.5-induced STC2 might be a potential prognostic and immunological biomarker for cancers related to air pollution.

Keywords: PM2.5; biomarker; cancer; prognosis; stanniocalcin 2 (STC2).

FIGURE 1

PM2.5 exposure is associated with lung cancer. (A,D,G,J) Volcano plots showing DEGs from our own RNA-seq data and public datasets (GSE155616, GSE158954, and GSE 128199); (B,E,H,K) Heatmaps showing top 10 DEGs. (C,F,I,L) GSEA analysis showing PM2.5 exposure was associated with lung cancer.

FIGURE 2

STC2 is a key gene regulated by PM2.5 and associated with multiple cancers. (A) Venn plot showing PM2.5 induced STC2 in different gene sets; (B) Immunofluorescence imaging showing the expression level of STC2 in different group; (C) qPCR showing the relative expression of STC2 in different group; (D) GSEA analysis showing high STC2 expression associated with lung cancer; (E,F) Kaplan-Meier OS curves showing high STC2 expression positively correlated with a poor prognosis in lung cancer; (G,H) STC2 expression was associated with a variety of cancers.

FIGURE 3

Pan-Cancer Expression Landscape of STC2. (A) STC2 expression across 26 types of human cancer; (B) Cox regression showing the correlation between STC2 expression and OS; (C,D) Two presentative Kaplan-Meier OS curves (KIPAN and HNSC). *: p-value < 0.05; **: p-value < 0.01, ***: p-value < 0.001, ****: p-value < 0.0001.

FIGURE 4

Correlation between STC2 Expression and Clinical phenotypes. (A) The relationship between STC2 expression and age; (B) The relationship between STC2 expression and gender. *: p-value < 0.05; **: p-value < 0.01, ***: p-value < 0.001.

FIGURE 5

Correlation between STC2 Expression and Clinical phenotypes. (A) The relationship between STC2 expression and Stage; (B) The relationship between STC2 expression and Grade. *: p-value < 0.05; **: p-value < 0.01, ***: p-value < 0.001, ****: p-value < 0.0001.

FIGURE 6

Correlation between STC2 Expression and Clinical phenotypes. (A–C) The relationship between STC2 expression and TMN staging. *: p-value < 0.05; **: p-value < 0.01, ***: p-value < 0.001, ****: p-value < 0.0001.

FIGURE 7

STC2 expression correlated with immune infiltration. (A) TIMER analysis showing the correlation between STC2 expression and immune cells infiltration; (B) CIBERSORT showing the correlation between STC2 expression and immune cells infiltration; (C) EPIC showing the correlation between STC2 expression and immune cells infiltration; (D) MCPcounter showing the correlation between STC2 expression and immune cells infiltration.

FIGURE 8

STC2 expression correlated with immune infiltration. (A) Correlation between STC2 expression and stromal score in six cancer types; (B) Correlation between STC2 expression and immune score in six cancer types; (C) Correlation between STC2 expression and estimate score in six cancer types.

FIGURE 9

Mutation features of STC2. (A) Mutation features of STC2 in different tumor samples; (B) The types, sites and case percentage of STC2 genetic alteration; (C) The effects of copy number variation (CNV) on STC2 expression. *: p-value < 0.05; **: p-value < 0.01, ****: p-value < 0.0001.

FIGURE 10

Correlation between the STC2 Expression and tumor heterogeneity. (A) Correlations between STC2 expression and TMB; (B) Correlations between STC2 expression and MSI; (C) Correlations between STC2 expression and tumor purity; (D) Correlations between STC2 expression and ploidy.

FIGURE 11

Correlation between STC2 expression and tumor stemness. (A–F) Relationship between STC2 expression and DNAss, RNAss, EREG-METHss, EREG-EXPss, DMPss and ENHss.

FIGURE 12

Correlation between STC2 expression and RNA methylation modifications. (A) Relationship between the expression of STC2 and three types of RNA methylation modifications; (B) Relationship between STC2 and immune checkpoints genes; (C,D) Immunological correlation of STC2.