Investigating microRNA-375 as a Tissue and Circulating Marker for Neuroendocrine Cells and Neoplasms

Abstract

Neuroendocrine neoplasia is an enigmatic disease that is currently without reliable diagnostic markers. Normal neuroendocrine cells are difficult to recognize upon routine H&E staining, requiring several IHC markers to confirm their cell-type. A lack of a single, specific marker has led to difficulties in successfully diagnosing neuroendocrine neoplasms (NENs), leading to poor patient outcomes. This has contributed to nearly 50% of cases becoming metastatic in the disease course. microRNAs (miRNA) are small non-coding RNA that negatively regulate gene expression through messenger RNA destabilization. Due to their disease specificity, miRNAs are being increasingly researched as potential candidate diagnostic markers. miRNA-375 (miR-375) was previously shown to be more highly expressed in NEN tissue compared to site matched controls using RNA sequencing. In this study, we investigate the potential for miR-375 to be used as a marker for neuroendocrine cell differentiation as well as neuroendocrine neoplasia. We first visualized miR-375 expression in healthy tissues from varying anatomical sites using chromogenic in situ hybridization. We found that miR-375 was only specific to candidate neuroendocrine cells, scattered throughout many tissues. The presence of miR-375 was then compared in neuroendocrine tumor tissue in organs of the gastroenteropancreatic system with non-neuroendocrine cancer from the same region. miR-375 was present in NEN tissue and absent in control tissues. Finally, we compared the plasma abundance of miR-375 in the circulation of lung-NEN patients to patients with non-NEN lung cancer and non-neoplastic lung disease. miR-375 abundance was found to be higher in the plasma of lung NEN patients compared to controls. With the results from this study, miR-375 has the potential to a be a promising candidate marker for future NEN diagnostics.