Mechanistic role of miR-375 in regulating PDPK1 to promote progression of small bowel neuroendocrine tumors: a silico analysis

Abstract

Background: The incidence of small bowel neuroendocrine tumors (SBNETs) is steadily increasing, new therapies are urgently needed to prolong the overall survival of patients.

Objective: This study aimed to identify diagnostic and therapeutic candidate markers for SBNETs.

Methods: Expression profiles of miRNAs were collected from GSE70534, and GSE103317, that of mRNAs were collected from GSE65286. Differentially expressed genes (DEmiRs, DEmRs) were analyzed between SBNETs and controls. Enrichment and coexpression analyses were carried out for DEmRs. XGBoost algorithm was used to screening feature miRNAs. Module genes in SBNETs-related pathways were selected to construct regulated network for feature miRNAs. Drug targeting prediction and immune environment evaluation were identified.

Results: A total of 57 common DEmiRs with the same direction of expression were identified. Hsa - miR - 375, hsa - miR - 107, hsa - miR - 1180, hsa - miR - 330 - 3p, and hsa - miR - 328 were identified as feature miRNAs. Among the target genes of feature miRNAs, PDPK1 was the correlation between PDPK1 and the target of Lutetium-177 (177Lu)-DOTATATE was the largest, which were regulated by miR - 375. Additionally, PDPK1 showed correlations with eosinophils, cytotoxic cells, and checkpoints in SBNETs.

Conclusions: Five feature miRNAs may have a good diagnostic role for the SBNETs. MiR - 375 regulated PDPK1 may serve as an effective therapeutic candidate marker for SBNETs.

Keywords: 177Lu-DOTATATE; PDPK1; Small bowel neuroendocrine tumors; miR − 375.

Fig. 1

The flowchart of this study. AUC area under the receiver operation characteristic curve; Differentially expressed mRNAs, DEmRs Differentially expressed miRNAs, DEmiRs ROC, receiver operation characteristic curve; XGBoost eXtreme Gradient Boosting

Fig. 2

Construction of diagnostic model and identification of feature miRNAs. A Volcano plot of differentially expressed miRNAs between SBNET and controls in GSE70534 dataset. B Volcano plot of differentially expressed miRNAs between SBNET and controls in GSE103317 dataset. C Intersection of up-regulated or down-regulated miRNAs in GSE70534 and GSE103317 datasets were considered as common DEmiRs. D The receiver operation characteristic (ROC) curves and precision-recall curves of XGBoost algorithm in GSE103317 dataset. E The attributes of top five features in the XGBoost model. SHAP, SHapley additive explanation. F SHAP values interacted with five features

Fig. 3

Biological functions and coexpression network of DEmRs. A Volcano plot of differentially expressed mRNAs between SBNET and controls in GSE65286 dataset. B Mainly biological processes of DEmRs involved. C Kyoto Encyclopedia of Genes and Genomes pathways of DEmRs involved. D Appropriate soft threshold parameters selection in WGCNA. E Dendrogram of coexpression network modules

Fig. 4

Diagnostic power of five feature miRNAs and prediction of their target genes. Heatmap A and box plots B of feature miRNAs expression in SBNET and controls in GSE70534 dataset. C ROC curves of five feature miRNAs. AUC, area under the receiver operation characteristic curve. D Regulatory networks of feature miRNAs and target genes, as well as involved pathways

Fig. 5

Intersected Kyoto Encyclopedia of Genes and Genomes pathways between enrichment analysis and gene set enrichment analysis results

Fig. 6

Target-drug interactions and immune evaluation. A Correlation between target genes of feature miRNAs and target genes of 177Lu-DOTATATE. B Binding sites between PDPK1 and miR − 375 predicted by Targetscan database. C Structural formula of 177Lu-DOTATATE. D The active site of SSTR1 docking to 177Lu-DOTATATE. E Differential levels of immune cells between SBNET and control. F Correlations between immune cells and PDPK1

Fig. 7

Immune checkpoints and PDPK1. (A) Correlations between immune checkpoints and PDPK1. (B) Differential levels of checkpoints between SBNET and control