S100A8/A9 Induced by Interaction with Macrophages in Esophageal Squamous Cell Carcinoma Promotes the Migration and Invasion of Cancer Cells via Akt and p38 MAPK Pathways

Tanigawa, Kazuyoshi; Tsukamoto, Shuntaro; Koma, Yoshiaki; Kitamura, Yu; Urakami, Satoshi; Shimizu, Masaki; Fujikawa, Masataka; Kodama, Takayuki; Nishio, Masaki; Shigeoka, Manabu; Kakeji, Yoshihiro; Yokozaki, Hiroshi

doi:10.1016/j.ajpath.2021.12.002

Cited by 22 publications

(24 citation statements)

References 62 publications

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“…Our genetic analysis indicated that S100s showed differential expression (upregulation or downregulation) between tumors and matched normal controls, furthermore, they have variable expression level across different cancer types. For example, almost all members of the S100 family were highly expressed in ESCA, consistent with previous studies demonstrating high expression of S100A7, S100A8, and S100A9 in esophageal squamous cell carcinoma (ESCC) [ 31 , 32 ], which predicted cancer cell migration and worse overall survival. Silencing of the S100 proteins in co-cultured ESCC cells was found to suppress migration and invasion via Akt and p38 MAPK signaling pathways, as reported in previous studies [ 32 ].…”

Section: Discussionsupporting

confidence: 89%

“…For example, almost all members of the S100 family were highly expressed in ESCA, consistent with previous studies demonstrating high expression of S100A7, S100A8, and S100A9 in esophageal squamous cell carcinoma (ESCC) [ 31 , 32 ], which predicted cancer cell migration and worse overall survival. Silencing of the S100 proteins in co-cultured ESCC cells was found to suppress migration and invasion via Akt and p38 MAPK signaling pathways, as reported in previous studies [ 32 ]. Another interesting finding was that S100s were risk factor than protective factor.…”

Section: Discussionsupporting

confidence: 89%

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The S100 family is a prognostic biomarker and correlated with immune cell infiltration in pan-cancer

Liang,

Huang,

Cai

et al. 2024

Discov Onc

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Background The S100 protein family is a group of small molecular EF-hand calcium-binding proteins that play critical roles in various biological processes, including promotion of growth, metastasis and immune evasion of tumor. However, the potential roles of S100 protein family expression in tumor microenvironment (TME) cell infiltration in pan-cancer remain elusive. Methods Herein, we conducted a comprehensive assessment of the expression patterns of the S100 protein family in pan-cancer, meticulously examining their correlation with characteristics of TME cell infiltration. The S100 score was constructed to quantify S100 family expression patterns of individual tumors. Results The S100 family was a potent risk factor in many cancers. Clustering analysis based on the transcriptome patterns of S100 protein family identified two cancer clusters with distinct immunophenotypes and clinical characteristics. Cluster A, with lower S100 expression, exhibited lower immune infiltration, whereas, Cluster B, with higher S100 expression, featured higher immune infiltration. Interestingly, Cluster B had a poorer prognosis, likely due to an immune-excluded phenotype resulting from stromal activation. The analysis revealed robust enrichment of the TGFb and EMT pathways in the cohort exhibiting high S100 score, alongside a positive correlation between the S100 score and Treg levels, suggesting the manifestation of an immune-excluded phenotype in this group. Moreover, S100 families were associated with the prognosis of 22 different cancers and a noteworthy association was observed between high S100 score and an unfavorable response to anti-PD-1/L1 immunotherapy. Consistent findings across two independent immunotherapy cohorts substantiated the advantageous therapeutic outcomes and clinical benefits in patients displaying lower S100score. Conclusion Our analysis demonstrated the role of S100 family in formation of TME diversity and complexity, enabling deeper cognition of TME infiltration characterization and the development of personalized immunotherapy strategies targeting S100 family for unique tumor types.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 89%

The S100 family is a prognostic biomarker and correlated with immune cell infiltration in pan-cancer

Liang,

Huang,

Cai

et al. 2024

Discov Onc

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“…The function of STK39 in promoting the progression of cholangiocarcinoma by activating the PI3K/ AKT signaling pathway has also been reported (34). S100A8 is a regulator of the EMT and AKT pathways and has been shown to promote migration, invasion, and metastasis in multiple cancers (35)(36)(37). All these proteins were significantly downregulated by the knockout of STT3A based on the results of the quantitative proteomic analysis in our study, indicating that they are potential target of STT3A.…”

Section: Discussionsupporting

confidence: 81%

Targeting STT3A produces an anti-tumor effect in lung adenocarcinoma by blocking the MAPK and PI3K/AKT signaling pathway

Cheng¹,

Liang²,

Xin³

et al. 2022

Transl Lung Cancer Res

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Background: Glycosylation is crucial for the stability and biological functions of proteins. The aberrant glycosylation of critical proteins plays an important role in multiple cancers, including lung adenocarcinoma (LUAD). STT3 oligosaccharyltransferase complex catalytic subunit A (STT3A) is a major isoform of N-linked glycosyltransferase that catalyzes the glycosylation of various proteins. However, the functions of STT3A in LUAD are still unclear. Methods:The expression profiles of STT3A were initially analyzed in public data sets and then validated by quantitative real-time polymerase chain reaction, Western blot and immunohistochemistry assays in clinical LUAD samples. The overall survival (OS) between patients with high and low STT3A expression was compared using a Kaplan-Meier curve with a log-rank analysis. STT3A was knocked-out using CRISPR/ Cas9 and inhibited by NGI-1. Cell Counting Kit-8, colony formation assay, wound-healing, transwell assay, and flow cytometry were performed to assess the cellular functions of STT3A in vitro. A mice xenograft model was established to investigate the effects of STT3A on tumor growth in vivo. Further, the downstream signaling pathways of STT3A were screened by mass spectrometry with a bioinformatics analysis, and the activation of the target pathways were subsequently validated by Western blot.Results: The expression of STT3A was frequently upregulated in LUAD tissues than normal lung tissues.The high expression of STT3A was significantly associated with poor OS in LUAD patients. The knockout or inhibition of STT3A suppressed proliferation, migration, and invasion, and arrested the cell cycle of LUAD cell lines in vitro. Similarly, the knockout or inhibition of STT3A suppressed tumor growth in vivo.In terms of molecular mechanism, STT3A may promote LUAD progression by activating the mitogenactivated protein kinase (MAPK) and phosphatidylinositol-3-kinase and protein kinase B (PI3K/AKT) pathways and regulating the epithelial-mesenchymal transition.Conclusions: STT3A promotes LUAD progression via the MAPK and PI3K/AKT signaling pathways and could serve as a novel prognostic biomarker and potential therapeutic target for LUAD patients.

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“…S100a8 also participates in several signaling pathways in tumor cells and contributes to tumor development, growth, and metastasis by interfering with tumor metabolism and regulating the tumor microenvironment[ 20 ]. For instance, coculturing ESCC cells with macrophages enhances S100A8/9 expression and release by ESCC cells, promoting ESCC progression through the Akt and p38 MAPK signaling pathways[ 21 ]. S100A8 is highly expressed in colorectal cancer and promotes epithelial–mesenchymal transition and metastasis via the transforming growth factor-β/USF2 axis[ 22 ].…”

Section: Discussionmentioning

confidence: 99%

Transcriptome sequencing reveals novel biomarkers and immune cell infiltration in esophageal tumorigenesis

Sun,

Chen,

Huang

et al. 2024

World J Gastrointest Oncol

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BACKGROUND Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies worldwide, and its development comprises a multistep process from intraepithelial neoplasia (IN) to carcinoma (CA). However, the critical regulators and underlying molecular mechanisms remain largely unknown. AIM To explore the genes and infiltrating immune cells in the microenvironment that are associated with the multistage progression of ESCC to facilitate diagnosis and early intervention. METHODS A mouse model mimicking the multistage development of ESCC was established by providing warter containing 4-nitroquinoline 1-oxide (4NQO) to C57BL/6 mice. Moreover, we established a control group without 4NQO treatment of mice. Then, transcriptome sequencing was performed for esophageal tissues from patients with different pathological statuses, including low-grade IN (LGIN), high-grade IN (HGIN), and CA, and controlled normal tissue (NOR) samples. Differentially expressed genes (DEGs) were identified in the LGIN, HGIN, and CA groups, and the biological functions of the DEGs were analyzed via Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. The CIBERSORT algorithm was used to detect the pattern of immune cell infiltration. Immunohistochemistry (IHC) was also conducted to validate our results. Finally, the Luminex multiplex cytokine analysis was utilized to measure the serum cytokine levels in the mice. RESULTS Compared with those in the NOR group, a total of 681541, and 840 DEGs were obtained in the LGIN, HGIN, and CA groups, respectively. Using the intersection of the three sets of DEGs, we identified 86 genes as key genes involved in the development of ESCC. Enrichment analysis revealed that these genes were enriched mainly in the keratinization, epidermal cell differentiation, and interleukin (IL)-17 signaling pathways. CIBERSORT analysis revealed that, compared with those in the NOR group, M0 and M1 macrophages in the 4NQO group showed stronger infiltration, which was validated by IHC. Serum cytokine analysis revealed that, compared with those in the NOR group, IL-1β and IL-6 were upregulated, while IL-10 was downregulated in the LGIN, HGIN, and CA groups. Moreover, the expression of the representative key genes, such as S100a8 and Krt6b, was verified in external human samples, and the results of immunohistochemical staining were consistent with the findings in mice. CONCLUSION We identified a set of key genes represented by S100a8 and Krt6b and investigated their potential biological functions. In addition, we found that macrophage infiltration and abnormal alterations in the levels of inflammation-associated cytokines, such as IL-1β, IL-6, and IL-10, in the peripheral blood may be closely associated with the development of ESCC.

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S100A8/A9 Induced by Interaction with Macrophages in Esophageal Squamous Cell Carcinoma Promotes the Migration and Invasion of Cancer Cells via Akt and p38 MAPK Pathways

Cited by 22 publications

References 62 publications

The S100 family is a prognostic biomarker and correlated with immune cell infiltration in pan-cancer

The S100 family is a prognostic biomarker and correlated with immune cell infiltration in pan-cancer

Targeting STT3A produces an anti-tumor effect in lung adenocarcinoma by blocking the MAPK and PI3K/AKT signaling pathway

Transcriptome sequencing reveals novel biomarkers and immune cell infiltration in esophageal tumorigenesis

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