Identification of MicroRNAs Differentially Expressed in Lung Carcinoid Subtypes and Progression

Abstract

Aim: To extensively explore microRNA expression profiles in lung carcinoids in correlation with clinical and pathological features. Methods: A PCR-based array was employed in the screening phase to analyze 752 microRNAs in a discovery set of 12 lung carcinoids, including 6 typical (3 with lymph node metastasis) and 6 atypical (3 with lymph node metastasis). The results were validated by means of real-time PCR in 37 carcinoids, including 22 typical (4 with lymph node metastasis) and 15 atypical (7 with lymph node metastasis), and 19 high-grade neuroendocrine carcinomas. Results: Unsupervised cluster analysis segregated the pilot cases into 3 distinct groups. Twenty-four microRNAs were differentially regulated in atypical versus typical carcinoids, and 29 in metastatic versus nonmetastatic cases. Eleven microRNAs were selected for validation. All but 1 were significantly different among lung neuroendocrine tumor histotypes. Moreover, 5 (miR-129-5p, miR-409-3p, miR-409-5p, miR-185 and miR-497) were significantly upregulated in typical compared to atypical carcinoids. MiR-409-3p, miR-409-5p and miR-431-5p were also significantly downregulated in carcinoids metastatic to the lymph nodes. Predictive in silico analysis of specific target genes showed that these 3 latter microRNAs linked to metastatic potential are implicated in several cellular functions and highlighted several novel genes which may be worth exploring. Conclusions: Our findings demonstrate that lung carcinoids have distinct microRNA expression profiles as compared to high-grade neuroendocrine carcinomas and that specific microRNAs might have potential implications as diagnostic tools or clinical biomarkers.

Genetic and epigenetic drivers of neuroendocrine tumours (NET)

“…It has been shown that miR-409-3p inhibit cell migration and/or invasion in fibrosarcoma (Weng et al 2012), bladder cancer ) and gastric cancer (Zheng et al 2012) cells. In addition, miR-21 upregulation was correlated with metastatic disease (Lee et al 2014, Rapa et al 2015, which was also observed in PanNET (Roldo et al 2006). This miR was shown to deregulate PTEN (Meng et al 2007), involved in the mTOR pathway and ANP32A/SMARCA4 (Schramedei et al 2011), two proteins that are involved in chromatin remodelling.…”

“…Different studies have examined miRNA expression in pulmonary carcinoids using different profiling platforms comparing normal lung tissue and tumour, carcinoids and high-grade NEC as well as localized and metastatic disease (Lee et al 2012, Deng et al 2014, Mairinger et al 2014, Rapa et al 2015. Although these studies are difficult to merge, some recurrent deregulated miRNAs in lung NET progression were identified, including miR-129-5p, miR-409-3p and miR-155.…”

“…Although these studies are difficult to merge, some recurrent deregulated miRNAs in lung NET progression were identified, including miR-129-5p, miR-409-3p and miR-155. miR-409-3p was found to be downmodulated in carcinoids with lymph node metastases (Rapa et al 2015). It has been shown that miR-409-3p inhibit cell migration and/or invasion in fibrosarcoma (Weng et al 2012), bladder cancer ) and gastric cancer (Zheng et al 2012) cells.…”

GEP- NETS UPDATE: Genetics of neuroendocrine tumors

“…There were the averages of 13 protein-altering mutations per sample (128). Differential expression of miRNAs in typical vs atypical lung carcinoids has also been reported (130).…”

Circulating tumor cells and miRNAs as prognostic markers in neuroendocrine neoplasms

“…All but one miRNA (miR-431-5p) were found to be upregulated in the carcinoid group as compared to high-grade neuroendocrine carcinomas. Moreover, when evaluating the association between the 11 selected miRNAs and clinical and carcinoid pathological characteristics, four miRNAs (miR-129-5p, miR-129*, miR-22 and miR-141) were found downregulated in high-stage tumors, four miRNAs (miR-129-5p, miR-409-3p, miR-409-5p and miR-431-5p) were found downregulated in cases with vascular invasion and three miRNAs (miR-409-3p, miR-409-5p and miR-431-5p) were found downregulated in tumors with lymph node metastases (Rapa et al 2015). Similarly, miRNA expression pattern in GEP NENs has been extensively investigated (Ruebel et al 2010, Matthaei et al 2012, Li et al 2013a, Dossing et al 2014, Miller et al 2016), but few studies evaluated a possible prognostic role of miRNAs in GEP NEN.…”