S100P 作为胰腺癌免疫抑制微环境的潜在生物标志物：生物信息学分析和体外研究。
S100P as a potential biomarker for immunosuppressive microenvironment in pancreatic cancer: a bioinformatics analysis and in vitro study.
机构信息
Department of gastroenterology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.
Department of Pharmacy, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.
出版信息
BMC Cancer. 2023 Oct 18;23(1):997. doi: 10.1186/s12885-023-11490-1.
BACKGROUND
Immunosuppression is a significant factor contributing to the poor prognosis of cancer. S100P, a member of the S100 protein family, has been implicated in various cancers. However, its role in the tumor microenvironment (TME) of pancreatic cancer remains unclear. This study aimed to investigate the potential impact of S100P on TME characteristics in patients with pancreatic cancer.
METHODS
Multiple data (including microarray, RNA-Seq, and scRNA-Seq) were obtained from public databases. The expression pattern of S100P was comprehensively evaluated in RNA-Seq data and validated in four different microarray datasets. Prognostic value was assessed through Kaplan-Meier plotter and Cox regression analyses. Immune infiltration levels were determined using the ESTIMATE and ssGSEA algorithms and validated at the single-cell level. Spearman correlation test was used to examine the correlation between S100P expression and immune checkpoint genes, and tumor mutation burden (TMB). DNA methylation analysis was performed to investigate the change in mRNA expression. Reverse transcription PCR (RT-PCR) and immunohistochemical (IHC) were utilized to validate the expression using five cell lines and 60 pancreatic cancer tissues.
RESULTS
This study found that S100P was differentially expressed in pancreatic cancer and was associated with poor prognosis (P < 0.05). Notably, S100P exhibited a significant negative-correlation with immune cell infiltration, particularly CD8 + T cells. Furthermore, a close association between S100P and immunotherapy was observed, as it strongly correlated with TMB and the expression levels of TIGIT, HAVCR2, CTLA4, and BTLA (P < 0.05). Intriguingly, higher S100P expression demonstrated a negative correlation with methylation levels (cg14323984, cg27027375, cg14900031, cg14140379, cg25083732, cg07210669, cg26233331, and cg22266967), which were associated with CD8 + T cells. In vitro RT-PCR validated upregulated S100P expression across all five pancreatic cancer cell lines, and IHC confirmed high S100P levels in pancreatic cancer tissues (P < 0.05).
CONCLUSION
These findings suggest that S100P could serve as a promising biomarker for immunosuppressive microenvironment, which may provide a novel therapeutic way for pancreatic cancer.
背景
免疫抑制是癌症预后不良的一个重要因素。S100P 是 S100 蛋白家族的成员之一，与多种癌症有关。然而，其在胰腺癌肿瘤微环境（TME）中的作用尚不清楚。本研究旨在探讨 S100P 对胰腺癌患者 TME 特征的潜在影响。
方法
从公共数据库中获取了多个数据（包括微阵列、RNA-Seq 和 scRNA-Seq）。在 RNA-Seq 数据中综合评估 S100P 的表达模式，并在四个不同的微阵列数据集进行验证。通过 Kaplan-Meier 绘图器和 Cox 回归分析评估预后价值。使用 ESTIMATE 和 ssGSEA 算法确定免疫浸润水平，并在单细胞水平进行验证。使用 Spearman 相关检验检测 S100P 表达与免疫检查点基因和肿瘤突变负荷（TMB）之间的相关性。进行 DNA 甲基化分析以研究 mRNA 表达的变化。使用五个细胞系和 60 个胰腺癌组织进行逆转录 PCR（RT-PCR）和免疫组织化学（IHC）验证表达。
结果
本研究发现 S100P 在胰腺癌中表达差异，并与预后不良相关（P<0.05）。值得注意的是，S100P 与免疫细胞浸润呈显著负相关，特别是 CD8+T 细胞。此外，还观察到 S100P 与免疫治疗之间存在密切关联，因为它与 TMB 和 TIGIT、HAVCR2、CTLA4 和 BTLA 的表达水平强烈相关（P<0.05）。有趣的是，较高的 S100P 表达与甲基化水平呈负相关（cg14323984、cg27027375、cg14900031、cg14140379、cg25083732、cg07210669、cg26233331 和 cg22266967），这与 CD8+T 细胞有关。体外 RT-PCR 验证了所有五个胰腺癌细胞系中 S100P 表达上调，免疫组织化学证实了胰腺癌组织中 S100P 水平较高（P<0.05）。
结论
这些发现表明，S100P 可作为免疫抑制微环境的有前途的生物标志物，为胰腺癌提供了一种新的治疗方法。
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