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. 2023 Jun 19;14(10):1837-1847.
doi: 10.7150/jca.83910. eCollection 2023.

Protein expression of S100A2 reveals it association with patient prognosis and immune infiltration profile in colorectal cancer

Phimmada Hatthakarnkul  1   2 , Aula Ammar  1 , Kathryn A F Pennel  1 , Leah Officer-Jones  3 , Silvia Cusumano  3 , Jean A Quinn  1 , Amna Ahmed Mohemmed Matly  1 , Peter G Alexander  4 , Jennifer Hay  5 , Ditte Andersen  6 , Gerard Lynch  1 , Hester C van Wyk  4 , Noori Maka  4 , Donald C McMillan  4 , John Le Quesne  3   1 , Chanitra Thuwajit  7 , Joanne Edwards  1
Affiliations

Protein expression of S100A2 reveals it association with patient prognosis and immune infiltration profile in colorectal cancer

Phimmada Hatthakarnkul et al. J Cancer. .

Abstract

Purpose: Colorectal cancer (CRC) is the third most diagnosed cancer worldwide. Despite a well-established knowledge of tumour development, biomarkers to predict patient outcomes are still required. S100 calcium-binding protein A2 (S100A2) has been purposed as a potential marker in many types of cancer, however, the prognostic value of S100A2 in CRC is rarely reported.

Material and methods: In this study, immunohistochemistry (IHC) was performed to identify the prognostic role of S100A2 protein expression in the tumour core of the tissue microarrays (TMAs) in colorectal cancer patients (n=787). Bulk RNA transcriptomic data was used to identify significant genes compared between low and high cytoplasmic S100A2 groups. Multiplex immunofluorescence (mIF) was performed to further study and confirm the immune infiltration in tumours with low and high cytoplasmic S100A2.

Results: Low cytoplasmic protein expression of S100A2 in the tumour core was associated with poor survival (HR 0.539, 95%CI 0.394-0.737, P<0.001) and other adverse tumour phenotypes. RNA transcriptomic analysis showed a gene significantly associated with the low cytoplasmic S100A2 group (AKT3, TAGLN, MYLK, FGD6 and ETFDH), which correlated with tumour development and progression. GSEA analysis identifies the enriched anti-tumour and immune activity group of genes in high cytoplasmic S100A2. Additionally, mIF staining showed that high CD3+FOXP3+ and CD163+ inversely associated with low cytoplasmic S100A2 (P<0.001, P=0.009 respectively).

Conclusion: Our finding demonstrates a prognostic value of S100A2 together with the correlation with immune infiltration in CRC.

Keywords: S100A2; colorectal cancer; inflammatory.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

Figures

Figure 1
Figure 1
Cytoplasmic S100A2 staining; Weak (A), Medium (B), and Strong (C) expression in CRC TMAs.
Figure 2
Figure 2
Kaplan-Meier survival analysis based on cytoplasmic S100A2 expression for cancer specific survival (CSS) in CRC patients.
Figure 3
Figure 3
(A) Hierarchical clustering of the top 50 most differentially expressed genes between low (Grey) and high (Amber) S100A2 protein expression. (B) Volcano plot showing the distribution of gene expression fold changes and p values between patients with high and low S100A2; Red means up-regulated in cases with low S100A2 and blue means up-regulated in cases with high S100A2.
Figure 4
Figure 4
(A) Enrichment analysis by tumour with low and high cytoplasmic S100A2 in CRC from GSEA software (B) Enrichment plots using gene set immune signature (c7.all.v2022.1.Hs.symbols.gmt database).
Figure 5
Figure 5
Multiplex staining of immune markers in CRC TMAs. (A) Panel of CD3, FOXP3, CD68, aSMA and PanCK and (B) Panel of CD163, CD66b, KI67 and PanCK. Magnification 4.87X. Magnification for zoom-in image 20X. Images generate on Visiopharm.
Figure 6
Figure 6
Bar charts showing the percentage of (A) CD3FOXP3 and (B) CD66b and (C) CD68 and (D) CD163 relative to S100A2 status in CRC.
Figure 7
Figure 7
Proposed mechanism of S100A2 for regulating P53 to induce tumour-related signalling, created with BioRender.
See this image and copyright information in PMC

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