Endocrine Abstracts

Lung carcinoids are slow-proliferating neuroendocrine neoplasms commonly showing low mutational burden but a high heterogeneity and difficult clinical management. Despite valuable advances in their molecular characterization, some aspects remain still unknown. Recent studies have shown that alternative splicing is severely dysregulated in lung carcinoids, where it could promote tumoral features. In contrast, the role of some molecular systems closely related to splicing and other RNA processing mechanisms has been poorly explored in these rare tumors. An emerging example of this is the machinery that regulates the methylation of RNA (N6-methyladenosine or m6A), the most usual internal modification of RNA, which is largely understudied in this pathology. We hypothesized that m6A processing machinery may be altered in lung carcinoids and linked to splicing dysregulation, thus RNA metabolism would be severely modified in these tumors. Our main aim was to identify alterations in the m6A process coupled to RNA splicing changes that may interfere with lung carcinoid development and aggressiveness. To this end, we have carried out a pilot analysis on 16 atypical carcinoids, and, through biocomputational analyses, we have assessed the expression of 13 m6A regulators, exploring their putative associations with clinical features and splicing alterations. Remarkably, we observed a clear relationship between the expression levels of several m6A readers and patient survival, highlighting the relevance of these factors. Interestingly, we found a strong link between abnormal m6A-related gene expression and cellular functions and pathways associated with carcinoids tumorigenesis, development, and aggressiveness features. Among them, the more remarkable ones were related to key metabolic pathways, including cellular adhesion, ionic transport, and tumor-related features, such as proliferation, differentiation, and increased sensitivity to growth factors. Altogether, our preliminary results suggest that lung carcinoids also possess another level of RNA processing dysregulation involving m6A alteration, which would be linked to tumor development and aggressiveness and may be useful in the future to improve the clinical management of this disease.