# Identification of miRNA/FGFR2 Axis in Well-Differentiated Gastroenteropancreatic Neuroendocrine Tumors

## TL;DR

This study identifies specific miRNAs and FGFR2 as potential biomarkers for improving the classification of well-differentiated GEP-NEN tumors.

## Contribution

The study discovers a miRNA/FGFR2 axis that differentiates G1 and G2 GEP-NENs, offering a novel biomarker approach for tumor grading.

## Key findings

- Four miRNAs are downregulated in G2 compared to G1 GEP-NENs.
- FGFR2 expression is significantly higher in G2 GEP-NENs.
- The miRNAs are linked to the FGF/FGFR signaling pathway via bioinformatic analysis.

## Abstract

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are rare tumors with different clinical and biological characteristics. Ki-67 staining and mitotic counts are the most commonly used prognostic markers, but these methods are time-consuming and lack reproducibility, highlighting the need for innovative approaches that improve histological evaluation and prognosis. In our previous study, we observed that the microRNA (miRNA) expression profile of GEP-NENs correlates with the three grades of GEP-NENs. This study aimed to characterize a group of miRNAs that discriminate well-differentiated GEP-NENs grading 1 (G1) and grading (G2). Fifty formalin-fixed and paraffin-embedded tissue specimens from well-differentiated GEP-NENs G1 and G2 tissues were used for this study. The expression levels of 21 miRNAs were examined using qRT-PCR, while FGFR2 and FGF1 protein expression were evaluated through immunohistochemistry (IHC). We identified four miRNAs (hsa-miR-133, hsa-miR-150-5p, hsa-miR-143-3p and hsa-miR-378a-3p) that are downregulated in G2 GEP-NENs compared to G1. Bioinformatic analysis revealed that these miRNAs play a key role in modulating the FGF/FGFR signaling pathway. Consistent with this observation, we found that fibroblast growth factor receptor 2 (FGFR2) expression is markedly higher in G2 NENs patients, whereas its expression remains low in G1 NENs. Our findings highlight the potential use of miRNAs to confirm the histological evaluation of GEP-NENs by employing them as biomarkers for improving histological evaluation and tumor classification.