Sensory Ion Channel Candidates Inform on the Clinical Course of Pancreatic Cancer and Present Potential Targets for Repurposing of FDA-Approved Agents

Wenjie Shi; Chen Li; Thomas Wartmann; Christoph Kahlert; Renfei Du; Aristotelis Perrakis; Thomas Brunner; Roland S Croner; Ulf D Kahlert

doi:10.3390/jpm12030478

Sensory Ion Channel Candidates Inform on the Clinical Course of Pancreatic Cancer and Present Potential Targets for Repurposing of FDA-Approved Agents

J Pers Med. 2022 Mar 16;12(3):478. doi: 10.3390/jpm12030478.

Authors

Wenjie Shi^{1

2}, Chen Li³, Thomas Wartmann¹, Christoph Kahlert⁴, Renfei Du⁵, Aristotelis Perrakis¹, Thomas Brunner⁶, Roland S Croner¹, Ulf D Kahlert¹

Affiliations

¹ 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.
² University Hospital for Gynecology, Pius-Hospital, University Medicine Oldenburg, Carl von Ossietzky University Oldenburg, 26121 Oldenburg, Germany.
³ Department of Biology, Chemistry, Pharmacy, Free University of Berlin, 14195 Berlin, Germany.
⁴ Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische University Dresden, 01307 Dresden, Germany.
⁵ Clinic for Neurosurgery, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, 40225 Düsseldorf, Germany.
⁶ Department of Radiation Oncology, Otto-von Guericke University, Leipziger Str. 44, 39120 Magdeburg, Germany.

Abstract

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.

Keywords: TRP; TRPC3; TRPC7; biomarker; pancreatic cancer; sensory ion channels.