Abstract
Lung cancer is still one of the leading cause of death worldwide. The clinical variability of lung cancer is high and drives treatment decision. In this context, correct discrimination of pulmonary neuroendocrine tumors is still of critical relevance. The spectrum of neuroendocrine tumors is various, and each type has molecular and phenotypical differences. In order to advance in the discrimination of neuroendocrine from non-neuroendocrine lung tumors, we tested a series of 95 surgically resected and formalin-fixed paraffin embedded lung cancer tissues, and we analyzed the expression of miR205-5p and miR375-3p via TaqMan RT-qPCR. Via a robust mathematical approach, we excluded technical outliers increasing the data reproducibility. We found that miR375-3p levels are higher in low-grade neuroendocrine lung tumor samples compared to non-neuroendocrine lung tumors. However, miR375-3p is not able to distinguish among different types of neuroendocrine lung tumors. In this work, we provide a new molecular marker for distinguishing non-neuroendocrine from low-grade neuroendocrine lung tumors samples establishing an easy miRNA score to be used in clinical settings, enabling the pathologist to classify more accurately lung tumors biopsies, which may be ambiguously cataloged in routine examination.
Highlights
Pulmonary neuroendocrine (NE) tumors form a distinct group of neoplasms that share morphological, immunohistochemical, ultrastructural, and molecular features
New biomarkers are needed in order to distinguish NE from non-NE lung tumors. miRNAs are a promising new class of cancer biomarkers which may potentially affect all aspects of clinical care from early detection, diagnosis, and prognosis (Du et al, 2010; Mallick et al, 2010; Detassis et al, 2017), to the discernment of site of origin in patients presenting metastaticity from an unknown primary tumor (Rosenwald et al, 2010; Gao et al, 2011). miRNAs are short non-coding single-stranded RNAs acting at the posttranscriptional level, dampening gene expression and, in turn, modulating cell behavior (Bartel, 2009). miRNAs analysis has been already proposed for the classification of lung tumors (Del Vescovo and Denti, 2015)
We evaluated the Ct205 in a cohort of 21 AD, 14 squamous cell carcinomas (SQC), 6 atypical carcinoid (AT), and 21 typical carcinoid (TC) for a total of 35 non-NE and 27 NE samples
Summary
Pulmonary neuroendocrine (NE) tumors form a distinct group of neoplasms that share morphological, immunohistochemical, ultrastructural, and molecular features. The distinction of the different lung tumors is of primary relevance in selecting appropriate therapy (Melosky, 2018; Tsoukalas et al, 2018) For these reasons, new biomarkers are needed in order to distinguish NE from non-NE lung tumors. The basic helix-loop-helix protein, achaete-scute homologue 1 (ASH1), a master regulator of pulmonary NE cell development, is crucially involved in the pathogenesis of lung NE tumors. It is typically expressed by lung NE tumor (Demelash et al, 2012) and directly transactivates miR375-3p in cell lines and tumors (Nishikawa et al, 2011). In the present study we analyze miR375-3p expression in 95 surgically resected lung tumors, including 31 TC, 11 AT, 11 LCNEC, 4 SCLC, 22 AD, and 16 SQC and we demonstrate that, via an implemented statistical approach which has been recently developed and validated by our group (Ricci et al, 2015), miR375-3p is able to distinguish low-grade NE from non-NE lung tumors, but not LCNEC from SCLC tumors
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