Comprehensive characterization of extracellular matrix-related genes in PAAD identified a novel prognostic panel related to clinical outcomes and immune microenvironment: A silico analysis with in vivo and vitro validation.
Comprehensive characterization of extracellular matrix-related genes in PAAD identified a novel prognostic panel related to clinical outcomes and immune microenvironment: A silico analysis with in vivo and vitro validation.
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DOI：
10.3389/fimmu.2022.985911
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发表时间：
2022
影响因子：
7.3
通讯作者：
Shang, Dong
中科院分区：
文献类型：
--
作者：
Chen, Xu;Yuan, Qihang;Liu, Jifeng;Xia, Shilin;Shi, Xueying;Su, Yuxin;Wang, Zhizhou;Li, Shuang;Shang, Dong
关键词：
细胞外基质（ECM）是肿瘤微环境的重要组成部分，其与基质细胞和肿瘤细胞相互作用以刺激癌细胞增殖、迁移、侵袭和经历血管生成的能力。然而，ECM相关基因（ECMGs）在胰腺癌（PAAD）中的重要功能尚未得到系统评价。因此，在泛癌，特别是PAAD中，需要对ECMG进行全面的评价。首先，通过整合表达谱、预后值、突变信息、甲基化水平和途径调控关系，探索了ECMG的泛癌症概述。7个ECMG（LAMB 3、LAMA 3、ITGB 6、ITGB 4、ITGA 2、LAMC 2和COL 11 A1）是PAAD的中枢基因，在PAAD中表达明显上调，与肿瘤分期和预后密切相关。根据ECMG表达和ECM评分将PAAD患者分为3组。聚类2是伴随着最低ECM评分的具有最佳预后的亚型，进一步验证了ECM对PAAD的病理生理过程的显著贡献。在三种ECM亚型中观察到癌基因和抑癌基因表达、免疫微环境和化疗敏感性的显著差异。在应用各种生物信息学方法后，开发并验证了一种新的和稳健的基于ECM相关mRNA-lncRNA的预后面板（ECM-APP），用于准确预测PAAD患者的临床结局。将PAAD患者随机分为训练组、内部验证组和外部验证组;同时，根据ECM相关mRNA和lncRNA的表达特征，将每位患者分为高风险（预后不良）和低风险（预后良好）人群。肿瘤突变负荷和免疫微环境的差异可能是导致高风险和低风险人群中肿瘤发生差异的原因。总的来说，我们的研究结果确定并验证了7个ECMG与PAAD的发生和进展显著相关。基于ECM的分子分类和预后面板有助于PAAD患者的预后评估和个性化干预。
The extracellular matrix (ECM) is a vital component of the tumor microenvironment, which interplays with stromal and tumor cells to stimulate the capacity of cancer cells to proliferate, migrate, invade, and undergo angiogenesis. Nevertheless, the crucial functions of ECM-related genes (ECMGs) in pancreatic adenocarcinoma (PAAD) have not been systematically evaluated. Hence, a comprehensive evaluation of the ECMGs is required in pan-cancer, especially in PAAD. First, a pan-cancer overview of ECMGs was explored through the integration of expression profiles, prognostic values, mutation information, methylation levels, and pathway-regulation relationships. Seven ECMGs (i.e. LAMB3, LAMA3, ITGB6, ITGB4, ITGA2, LAMC2, and COL11A1) were identified to be hub genes of PAAD, which were obviously up-regulated in PAAD and considerably linked to tumor stage as well as prognosis. Subsequently, patients with PAAD were divided into 3 clusters premised on ECMG expression and ECM scores. Cluster 2 was the subtype with the best prognosis accompanied by the lowest ECM scores, further verifying ECM’s significant contribution to the pathophysiological processes of PAAD. Significant differences were observed for oncogene and tumor suppressor gene expression, immune microenvironment, and chemotherapy sensitivity across three ECM subtypes. After applying a variety of bioinformatics methods, a novel and robust ECM-associated mRNA-lncRNA-based prognostic panel (ECM-APP) was developed and validated for accurately predicting clinical outcomes of patients with PAAD. Patients with PAAD were randomly categorized into the train, internal validation, and external validation cohorts; meanwhile, each patient was allocated into high-risk (unfavorable prognosis) and low-risk (favorable prognosis) populations premised on the expression traits of ECM-related mRNAs and lncRNAs. The discrepancy in the tumor mutation burden and immune microenvironment might be responsible for the difference in prognoses across the high-risk and low-risk populations. Overall, our findings identified and validated seven ECMGs remarkably linked to the onset and progression of PAAD. ECM-based molecular classification and prognostic panel aid in the prognostic assessment and personalized intervention of patients with PAAD.
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影响因子：
3.9
作者：
Che X;Su W;Li X;Liu N;Wang Q;Wu G
通讯作者：
Wu G
影响因子：
3.3
作者：
通讯作者：
--
影响因子：
64.5
作者：
Binnewies, Mikhail;Mujal, Adriana M.;Krummel, Matthew F.
通讯作者：
Krummel, Matthew F.
DOI：
10.1016/j.urolonc.2017.08.016
发表时间：
2017-12-01
影响因子：
2.7
作者：
Jeh, Seong Uk;Park, Jung Je;Hwa, Jeong Seok
通讯作者：
Hwa, Jeong Seok
DOI：
10.1038/nrg2485
发表时间：
2009-01
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
通讯作者：
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