Altered miRNAs Expression Correlates With Gastroenteropancreatic Neuroendocrine Tumors Grades

Abstract

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare and heterogeneous tumors that present a wide spectrum of different clinical and biological characteristics. Currently, tumor grading, determined by Ki-67 staining and mitotic counts, represents the most reliable predictor of prognosis. This time-consuming approach fails to reach high reproducibility standards thus requiring novel approaches to support histological evaluation and prognosis. In this study, starting from a microarray analysis of paraffin-embedded tissue specimens, we defined the miRNAs signature for poorly differentiated NETs (G3) compared to well-differentiated NETs (G1 and G2) consisting of 56 deregulated miRNAs. We identified 8 miRNAs that were expressed in all GEP-NETs grades but at different level. Among these miRNAs, miR-96-5p expression level was progressively higher from grade 1 to grade 3; inversely, its target FoxO1 expression decreased from grade 1 to grade 3. Our results reveal that the miRNAs expression profile of GEP-NET is correlated with the tumor grade, showing a potential advantage of miRNA quantification that could aid clinicians in the classification of common GEP-NETs subtypes. These findings could reliably support the histological evaluation of GEP-NETs paving the way toward personalized treatment approaches.

MiRNA Expression in Neuroendocrine Neoplasms of Frequent Localizations

“…Accordingly, the FoxO1 gene has been shown to have reduced expression in grade 3 gastric NENs. FoxO1 expression was found in tumors at G1 and G2, which is consistent with a more favorable prognosis in these patients [19]. These results demonstrate the potential value of miRNA quantification for the classification of gastric NEN subtypes.…”

“…It was found that the expression level of miRNA-96-5p progressively increased from 1 to 3 degrees of gastric NEN. These data demonstrate the important role of miRNA as a biomarker in the classification of gastric NENs [19].…”

“…In one of the most recent studies [19], eight miRNAs were found that were expressed in all classes of gastric NEN (miRNA-10b-5p, miRNA-130b-3p, miRNA-192-5p, miRNA-194-5p, miRNA-210-3p, miRNA-214-3p, miRNA-7-5p and miRNA-96-5p), but the level of their expression was different for different classes of gastric NENs. Among these miRNAs was miRNA-96-5p, the expression level of which increased with a change in the degree of differentiation of gastric NEN tumors from G1 to G3.…”

“…Among these miRNAs was miRNA-96-5p, the expression level of which increased with a change in the degree of differentiation of gastric NEN tumors from G1 to G3. It was also shown that miRNA-96-5p controls the expression of the FoxO1 gene [19]. The transcription factor FoxO1 (Forkhead box O, FOXO) is a downstream target in the IGF-1R PI3K/Akt pathway involved in several physiological and pathological processes, including cancer development.…”

MicroRNAs and Treatment with Somatostatin Analogs in Gastro- Entero-Pancreatic Neuroendocrine Neoplasms: Challenges in Personalized Medicine

“…Not unexpectedly, the expression pattern of miRNA-96 is heterogenous as well and it functions either as an oncomiR by promoting cellular growth, invasiveness and metastasis in breast cancer [104], pancreatic cancer [105] and hepatocarcinoma [106] or as a tumor suppressor in renal cell carcinoma [107], colorectal cancer [108] and lymphoma [109]. Regarding NENs, it seems that miRNA-96 mostly acts as an oncogene; its levels increase with tumor grade [63] and its regulation is influenced by SSAs therapy. It was shown to directly target at the 3'UTRs of AKT1S1 mRNA, leading to its downregulation and thus induction of mTOR activities [110,111].…”