Shi Wenjie, Li Chen, Wartmann Thomas, Kahlert Christoph, Du Renfei, Perrakis Aristotelis, Brunner Thomas, Croner Roland S, Kahlert Ulf D
Molecular and Experimental Surgery, University Clinic for General-, Visceral-, Vascular- and Trans-Plantation Surgery, Medical Faculty University Hospital Magdeburg, Otto-von Guericke University, 39120 Magdeburg, Germany.
University Hospital for Gynecology, Pius-Hospital, University Medicine Oldenburg, Carl von Ossietzky University Oldenburg, 26121 Oldenburg, Germany.
J Pers Med. 2022 Mar 16;12(3):478. doi: 10.3390/jpm12030478.
Background: Transient receptor potential channels (TRPs) have been demonstrated to take on functions in pancreatic adenocarcinoma (PAAD) biology. However, little data are available that validate the potential of TRP in a clinical translational setting. Methods: A TRPs-related gene signature was constructed based on the Cox regression using a TCGA-PAAD cohort and receiver operating characteristic (ROC) was used to evaluate the predictive ability of this model. Core genes of the signature were screened by a protein-to-protein interaction (PPI) network, and expression validated by two independent datasets. The mutation analysis and gene set enrichment analysis (GSEA) were conducted. Virtual interventions screening was performed to discover substance candidates for the identified target genes. Results: A four TRPs-related gene signature, which contained MCOLN1, PKD1, TRPC3, and TRPC7, was developed and the area under the curve (AUC) was 0.758. Kaplan−Meier analysis revealed that patients with elevated signature score classify as a high-risk group featuring significantly shorter recurrence free survival (RFS) time, compared to the low-risk patients (p < 0.001). The gene prediction model also had a good predictive capability for predicting shortened overall survival (OS) and disease-specific survival (DSS) (AUC = 0.680 and AUC = 0.739, respectively). GSEA enrichment revealed the core genes of the signature, TRPC3 and TRPC7, were involved in several cancer-related pathways. TRPC3 mRNA is elevated in cancer tissue compared to control tissue and augmented in tumors with lymph node invasion compared to tumors without signs of lymph node invasion. Virtual substance screening of FDA approved compounds indicates that four small molecular compounds might be potentially selective not only for TRPC3 protein but also as a potential binding partner to TRPC7 protein. Conclusions: Our computational pipeline constructed a four TRP-related gene signature that enables us to predict clinical prognostic value of hitherto unrecognized biomarkers for PAAD. Sensory ion channels TRPC3 and TRPC7 could be the potential therapeutic targets in pancreatic cancer and TRPC3 might be involved in dysregulating mitochondrial functions during PAAD genesis.
瞬时受体电位通道（TRPs）已被证明在胰腺腺癌（PAAD）生物学中发挥作用。然而，在临床转化背景下验证TRP潜力的数据很少。方法：使用TCGA-PAAD队列基于Cox回归构建TRPs相关基因特征，并使用受试者工作特征（ROC）评估该模型的预测能力。通过蛋白质-蛋白质相互作用（PPI）网络筛选特征的核心基因，并通过两个独立数据集验证表达。进行突变分析和基因集富集分析（GSEA）。进行虚拟干预筛选以发现已鉴定靶基因的物质候选物。结果：开发了一个包含MCOLN1、PKD1、TRPC3和TRPC7的四个TRPs相关基因特征，曲线下面积（AUC）为0.758。Kaplan-Meier分析显示，与低风险患者相比，特征评分升高的患者分类为高风险组，其无复发生存（RFS）时间明显缩短（p < 0.001）。基因预测模型在预测总生存（OS）缩短和疾病特异性生存（DSS）方面也具有良好的预测能力（AUC分别为0.680和0.739）。GSEA富集显示特征的核心基因TRPC3和TRPC7参与了几个癌症相关途径。与对照组织相比，癌症组织中TRPC3 mRNA升高，与无淋巴结浸润迹象的肿瘤相比，有淋巴结浸润的肿瘤中TRPC3 mRNA增加。FDA批准化合物的虚拟物质筛选表明，四种小分子化合物可能不仅对TRPC3蛋白具有潜在选择性，而且作为TRPC7蛋白的潜在结合伴侣。结论：我们的计算流程构建了一个四个TRP相关基因特征，使我们能够预测PAAD迄今未被认识的生物标志物的临床预后价值。感觉离子通道TRPC3和TRPC7可能是胰腺癌的潜在治疗靶点，TRPC3可能在PAAD发生过程中参与线粒体功能失调。
