Zhou Yuan, Huang Borong, Zhang Qinqin, Yu Yaqun, Xiao Juan
Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, Affiliated Hospital of Guilin Medical University, Guilin, China.
Guangxi Health Commission Key Laboratory of Basic Research in Sphingolipid Metabolism Related Diseases, Affiliated Hospital of Guilin Medical University, Guilin, China.
Transl Cancer Res. 2024 Mar 31;13(3):1425-1442. doi: 10.21037/tcr-23-1365. Epub 2024 Mar 27.
Pancreatic adenocarcinoma (PAAD) is a lethal disease with a poor prognosis. Genes involved in acute pancreatitis (AP) or chronic pancreatitis (CP) might be important for PAAD development. This study sought to identify potential PAAD diagnosis markers and to establish a PAAD prognosis prediction model based on AP- and CP-related genes.
The significantly differentially expressed genes in both AP or CP and PAAD were obtained by a bioinformatics analysis. A risk-score model for predicting survival was constructed based on The Cancer Genome Atlas (TCGA) data and validated using an International Cancer Genome Consortium (ICGC) cohort. Protein expression and the effects of the genes in the risk models were validated by immunohistochemistry, or Cell Counting Kit-8 (CCK-8) and transwell assays. The study sample data included six AP tissue samples and five normal pancreatic tissue samples, six CP tissue samples and six normal pancreatic tissue samples from the Gene Expression Omnibus (GEO) expression profiling microarrays GSE109227 and GSE41418 data sets, respectively, and fragments per kilobase per million mapped fragments (FPKM) data from four normal controls and 150 PAAD cases from TCGA database, and 182 cancer patient samples with complete survival prognostic data from the ICGC database.
In total, 508 significantly differentially expressed genes were found in both AP or CP and PAAD. Trefoil factor 2 (), tubulointerstitial nephritis antigen (), trefoil factor 1 (), aquaporin 5 (), SAM pointed domain containing ETS transcription factor (), anterior gradient protein 2 (), apolipoprotein B messenger RNA editing enzyme catalytic subunit 1 (), kallikrein-related peptidase 6 (), dopa decarboxylase (), mucin 13 (), claudin 18 (), annexin A10 (), and tetraspanin 1 () were found to be present in PAAD and had the largest fold change. A risk-score model, comprising 19 genes, was constructed for prognostic prediction. A high-risk score indicated a poor prognosis. TINAG, DDC, SPDEF, and APOBEC1 proteins were increased in PAAD, while TINAG and DDC were correlated with the pathologic grade. Decreased TINAG, APOBEC1, transmembrane protein 94 (TMEM94), and kelch like family member 36 (KLHL36) expression inhibited PAAD cell proliferation, while decreased SPDEF, TMEM94, and KLHL36 expression significantly inhibited PAAD cell migration.
The AP and CP co-related genes were significantly correlated with PAAD. TINAG, DDC, SPDEF, and APOBEC1 could serve as new PAAD predictors. The risk model developed in this study could be used to predict the prognosis of PAAD patients.
胰腺腺癌（PAAD）是一种预后不良的致命疾病。参与急性胰腺炎（AP）或慢性胰腺炎（CP）的基因可能对PAAD的发生发展至关重要。本研究旨在识别潜在的PAAD诊断标志物，并基于与AP和CP相关的基因建立PAAD预后预测模型。
通过生物信息学分析获得AP或CP与PAAD中显著差异表达的基因。基于癌症基因组图谱（TCGA）数据构建预测生存的风险评分模型，并使用国际癌症基因组联盟（ICGC）队列进行验证。通过免疫组织化学、细胞计数试剂盒-8（CCK-8）和Transwell实验验证风险模型中基因的蛋白表达及作用。研究样本数据分别包括来自基因表达综合数据库（GEO）表达谱微阵列GSE109227和GSE41418数据集的6个AP组织样本和5个正常胰腺组织样本、6个CP组织样本和6个正常胰腺组织样本，以及来自TCGA数据库的4个正常对照和150例PAAD病例的每百万映射片段中每千碱基的片段数（FPKM）数据，和来自ICGC数据库的182例具有完整生存预后数据的癌症患者样本。
共发现508个在AP或CP与PAAD中均显著差异表达的基因。发现三叶因子2（）、肾小管间质性肾炎抗原（）、三叶因子1（）、水通道蛋白5（）、含SAM结构域的ETS转录因子（）、前梯度蛋白2（）、载脂蛋白B信使核糖核酸编辑酶催化亚基1（）、激肽释放酶相关肽酶6（）、多巴脱羧酶（）、粘蛋白13（）、紧密连接蛋白18（）、膜联蛋白A10（）和四跨膜蛋白1（）存在于PAAD中且具有最大的倍数变化。构建了一个包含19个基因的风险评分模型用于预后预测。高风险评分表明预后不良。PAAD中TINAG、DDC、SPDEF和APOBEC1蛋白增加，而TINAG和DDC与病理分级相关。TINAG、APOBEC1、跨膜蛋白94（TMEM94）和kelch样家族成员36（KLHL36）表达降低抑制PAAD细胞增殖，而SPDEF、TMEM94和KLHL36表达降低显著抑制PAAD细胞迁移。
AP和CP共同相关基因与PAAD显著相关。TINAG、DDC、SPDEF和APOBEC1可作为新PAAD预测指标。本研究建立的风险模型可用于预测PAAD患者的预后。
