In:
Frontiers in Oncology, Frontiers Media SA, Vol. 13 ( 2023-5-23)
Abstract:
Gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) are rare diseases encompassing pancreatic (PanNETs) and ileal NETs (SINETs), characterized by heterogeneous somatostatin receptors (SSTRs) expression. Treatments for inoperable GEP-NETs are limited, and SSTR-targeted Peptide Receptor Radionuclide Therapy (PRRT) achieves variable responses. Prognostic biomarkers for the management of GEP-NET patients are required. 18 F-FDG uptake is a prognostic indicator of aggressiveness in GEP-NETs. This study aims to identify circulating and measurable prognostic miRNAs associated with 18 F-FDG-PET/CT status, higher risk and lower response to PRRT. Methods Whole miRNOme NGS profiling was conducted on plasma samples obtained from well-differentiated advanced, metastatic, inoperable G1, G2 and G3 GEP-NET patients enrolled in the non-randomized LUX (NCT02736500) and LUNET (NCT02489604) clinical trials prior to PRRT (screening set, n= 24). Differential expression analysis was performed between 18 F-FDG positive (n=12) and negative (n=12) patients. Validation was conducted by Real Time quantitative PCR in two distinct well-differentiated GEP-NET validation cohorts, considering the primary site of origin (PanNETs n=38 and SINETs n=30). The Cox regression was applied to assess independent clinical parameters and imaging for progression-free survival (PFS) in PanNETs. In situ RNA hybridization combined with immunohistochemistry was performed to simultaneously detect miR and protein expression in the same tissue specimens. This novel semi-automated miR-protein protocol was applied in PanNET FFPE specimens (n=9). In vitro functional experiments were performed in PanNET models. Results While no miRNAs emerged to be deregulated in SINETs, hsa-miR-5096, hsa-let-7i-3p and hsa-miR-4311 were found to correlate with 18 F-FDG-PET/CT in PanNETs (p-value: & lt;0.005). Statistical analysis has shown that, hsa-miR-5096 can predict 6-month PFS (p-value: & lt;0.001) and 12-month Overall Survival upon PRRT treatment (p-value: & lt;0.05), as well as identify 18 F-FDG-PET/CT positive PanNETs with worse prognosis after PRRT (p-value: & lt;0.005). In addition, hsa-miR-5096 inversely correlated with both SSTR2 expression in PanNET tissue and with the 68 Gallium-DOTATOC captation values (p-value: & lt;0.05), and accordingly it was able to decrease SSTR2 when ectopically expressed in PanNET cells (p-value: & lt;0.01). Conclusions hsa-miR-5096 well performs as a biomarker for 18 F-FDG-PET/CT and as independent predictor of PFS. Moreover, exosome-mediated delivery of hsa-miR-5096 may promote SSTR2 heterogeneity and thus resistance to PRRT.
Type of Medium:
Online Resource
ISSN:
2234-943X
DOI:
10.3389/fonc.2023.1136331
DOI:
10.3389/fonc.2023.1136331.s001
DOI:
10.3389/fonc.2023.1136331.s002
Language:
Unknown
Publisher:
Frontiers Media SA
Publication Date:
2023
detail.hit.zdb_id:
2649216-7
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