Abstract
Objective: The tumour microenvironment is one of the significant factors driving the carcinogenesis of Pancreatic adenocarcinoma (PAAD). However, the underlying mechanism of how the tumour microenvironment impacts the prognosis of PAAD is not completely clear.Results: The transcriptome and clinical data of 182 PAAD program cases were downloaded from the TCGA database. Three hundred thirty-three differentially expressed genes (DEGs) between high and low stromal groups and 314 DEGs between high and low immune score groups were identified using ESTIMATE score. Based on the 203 genes differentially expressed simultaneously in two score-related comparisons, we established an 8-mRNA signature to evaluate the prognosis of PAAD patients. Kaplan-Meier curves showed significantly worse survival for patients with high-risk scores in both the training and validation groups. The risk score was an independent prognostic factor and had a high predictive value for the prognosis of patients with PAAD. By searching the TCGA database, we showed that CA9, CXCL9, and GIMAP7 from the 8-mRNA signature were associated with the infiltration levels of immunocytes by regulating FOXO1 expression in PAAD.Conclusions: Unlike traditional methods of screening for differential genes in cancer and healthy tissues, we constructed a novel 8-mRNA signature to predict the prognosis of PAAD patients by applying ESTIMATE scoring to RNA-seq-based transcriptome data. Most importantly, we identified CA9, CXCL9, and GIMAP7 from the above eight genes as regulators of immunocyte infiltration by adjusting the expression of FOXO1 in PAAD. Thus, CA9, CXCL9, and GIMAP7 might be the ideal targets of immune therapy of PAAD.Methods: ESTIMATE scoring was used to determine the stromal and immune scores of transcriptome datasets downloaded from the TCGA database. An mRNA-based prognostic signature was built for the training cohort via the LASSO Cox regression model. The signature was verified using a validation cohort. Kaplan-Meier curves and log-rank analysis were used to identify survival differences. Western blot analysis and RT-qPCR analysis were carried out to analyze the expression of specific proteins and mRNAs. IHC was performed to assess the protein levels of Forkhead box-O 1 (FOXO1), Carbonic anhydrase 9 (CA9), C-X-C motif chemokine ligand 9 (CXCL9), and GTPase, IMAP family member 7 (GIMAP7) in the tissue microarray of PAAD.
Highlights
Pancreatic adenocarcinoma (PAAD) is one of the most devastating human malignant tumours in the world [1]
The ESTIMATE algorithm identifies differentially expressed genes (DEG) associated with stroma and immune scores We downloaded the transcriptome and clinical data of 182 PAAD program cases from the TCGA database
We identified an 8-mRNA signature to evaluate the overall survival time of PAAD patients based on the expression of the 8 mRNAs and their regression coefficients as follows: Risk score = (0.01579 × expression level of alcohol dehydrogenase 1B (ADH1B)) + (0.07838 × expression level of Carbonic anhydrase 9 (CA9)) + (-0.76361 × expression level of cadherin related family member 3 (CDHR3)) + (0.33812 × expression level of C-X-C motif chemokine ligand 9 (CXCL9)) + (-0.06606 × expression level of GIMAP7) + (-0.70384 × expression level of intercellular adhesion molecule 3 (ICAM3)) + (-0.11457 × expression level of LDLRAD1) + (-0.24179 × expression level of P2Y receptor family member 8 (P2RY8))
Summary
Pancreatic adenocarcinoma (PAAD) is one of the most devastating human malignant tumours in the world [1]. Because of its resistance to chemoradiotherapy and the trend of early metastasis, the 5-year survival rate of PAAD is less than 5% [2, 3]. The morbidity and mortality rates of PAAD are ninth and sixth, respectively, among Malignant tumours in China, which shows a rapid growth pattern that matches the trend in other countries [5]. A better understanding of the pathogenesis of cancer and the exploration of more therapeutic strategies is imperative for improving the prognosis of PAAD patients. PAAD is characterized by an intense stromal desmoplastic reaction around cancer cells [8], which plays an essential role in tumorigenesis and drug resistance [9]. The tumour microenvironment is one of the significant factors determining the prognosis of PAAD. The mechanism of how the tumour microenvironment engineers the carcinogenesis of PAAD is not entirely clear
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