Abstract
Pancreatic adenocarcinoma (PAAD) is characterized by high malignancy, frequent metastasis, and recurrence with an unfavorable prognosis. This study is aimed at constructing a prognostic model for tumor-infiltrating immune cells and a competing endogenous RNA (ceRNA) network in PAAD and analyzing susceptibilities of chemotherapy and immunotherapy of PAAD. Gene expression profiles and clinical information of PAAD were downloaded from The Cancer Genome Atlas (TCGA) database and divided into the tumor group and the normal group. A total of five PAAD survival-related key genes in the ceRNA network and three survival-related immune infiltrating cells were uncovered, and two survival risk models and nomograms were constructed. The efficiency and performance of the two models were verified using multi-index area under the curve analysis at different time points, decision curve analysis, and calibration curves. Co-expression analysis showed that LRRC1, MIR600HG, and RNF166 in the ceRNA network and tumor-infiltrating immune cells including CD8 T cells and M1 macrophages were likely related to the PAAD prognosis, and the expression of key ceRNA-related genes was experimently validated in tissues and cell lines by RT-qPCR. Patients with low risk scores for key genes in the ceRNA network displayed a positive response to anti-programmed death-1 (PD-1) treatment and greater sensitivity to chemotherapeutic drugs such as docetaxel, lapatinib, and paclitaxel. More importantly, our results suggested that the IC50 values of gemcitabine in PAAD were not significantly different between the high and low risk groups. The expression levels of immune checkpoints were significantly different in the high-risk and low-risk groups. The prognostic model, nomogram, and drug analysis may provide an essential reference for PAAD patient management in the clinic.
Highlights
Pancreatic adenocarcinoma (PAAD) is a highly malignant gastrointestinal tumor with a highly aggressive metastatic capacity, and its five-year survival rate is less than 10% (Siegel et al, 2021)
A total of 412 differentially expressed genes (DEGs) in PAAD were identified from The Cancer Genome Atlas (TCGA) database with the filter threshold of fold change (FC) > 2 and false discovery rate (FDR) < 0.01, including 360 differentially expressed mRNAs (147 downregulated and 213 upregulated; Figures 2A,B), 28 differentially expressed miRNAs (16 upregulated and 12 downregulated; Figures 2C,D), and 24 differentially expressed long non-coding RNA (lncRNA) (14 upregulated and 10 downregulated; Figures 2E,F)
Accurate prediction of prognosis allows for better assessment of patient adaptation to current treatments, including neoadjuvant therapy, surgery and radiotherapy, and immunotherapy
Summary
Pancreatic adenocarcinoma (PAAD) is a highly malignant gastrointestinal tumor with a highly aggressive metastatic capacity, and its five-year survival rate is less than 10% (Siegel et al, 2021). Early metastasis and drug resistance of PAAD are considered important reasons for its high mortality (Zhang et al, 2019; Chen et al, 2020a; Kong et al, 2020; Yang and Leung, 2020). Reducing the mortality of PAAD patients and improving their early diagnosis and prognosis urgently require understanding the effects of early-stage gene expression and immune cell infiltration on prognosis (Chou et al, 2016; Guo et al, 2020)
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