Abstract
BackgroundExtensive research has increased our understanding of the molecular alterations needed for non-small cell lung cancer (NSCLC) development. Deregulation of a pathway including MYCN, HMGA2 and CDKN2A, with the participation of DICER1, is of importance in several solid tumours, and may also be of significance in the pathogenesis of NSCLC.MethodsGene expression of MYCN, HMGA2, CDKN2A and DICER1 were investigated with RT-qPCR in surgically resected NSCLC tumour tissue from 175 patients. Expression of the let-7 microRNA family was performed in 78 adenocarcinomas and 16 matching normal lung tissue samples using microarrays. The protein levels of HMGA2 were determined by immunohistochemistry in 156 tumour samples and the protein expression was correlated with gene expression. Associations between clinical data, including time to recurrence, and expression of mRNA, protein and microRNAs were analysed.ResultsCompared to adenocarcinomas, squamous cell carcinomas had a median 5-fold increase in mRNA expression of HMGA2 (p = 0.003). A positive correlation (r = 0.513, p < 0.010) between HMGA2 mRNA expression and HMGA2 protein expression was seen. At the protein level, 90 % of the squamous cell carcinomas expressed high levels of the HMGA2 protein compared to 47 % of the adenocarcinomas (p < 0.0001). MYCN was positively correlated with HMGA2 (p < 0.010) and DICER1 mRNA expression (p < 0.010), and the expression of the let-7 microRNAs seemed to be correlated with the genes studied. MYCN expression was associated with time to recurrence in multivariate survival analyses (p = 0.020).ConclusionsA significant difference in HMGA2 mRNA expression between the histological subtypes of NSCLC was seen with a higher expression in the squamous cell carcinomas. This was also found at the protein level, and we found a good correlation between the mRNA and the protein expression of HMGA2. Moreover, the expression of MYCN, HMGA2, and DICER1 seems to be correlated to each other and the expression of the let7-genes impacted by their expression. MYCN gene expression seems to be of importance in time to recurrence in this patient cohort with resected NSCLC.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2104-9) contains supplementary material, which is available to authorized users.
Highlights
Extensive research has increased our understanding of the molecular alterations needed for non-small cell lung cancer (NSCLC) development
In this study we explore the significance of MYCN, High mobility group AT-hook 2 (HMGA2), Cyclin-dependent kinase inhibitor 2A (CDKN2A) and DICER1 in NSCLC tumours by gene expression analysis
90.9 Gene expression 1.7 We discovered a significant difference in the median values of HMGA2 mRNA expression according to tumour 30.9 histology (p = 0.003) with a considerably higher median fold change value in the squamous cell carcinoma group 1.7 (70.6 fold) compared to adenocarcinomas (13.1 fold) and 66.3 others (5.8 fold) (Table 2)
Summary
Extensive research has increased our understanding of the molecular alterations needed for non-small cell lung cancer (NSCLC) development. Deregulation of a pathway including MYCN, HMGA2 and CDKN2A, with the participation of DICER1, is of importance in several solid tumours, and may be of significance in the pathogenesis of NSCLC. Non-small cell lung cancer (NSCLC) constitutes over 80 % of all lung cancers and can be divided into histological subtypes. Epidermal growth factor receptor (EGFR) mutational testing has been performed routinely in Norway since 2010. Targeted therapies such as EGFR inhibitors and anaplastic lymphoma kinase (ALK) inhibitors are currently in clinical use. Increased understanding of different levels of tumour development, of genetic, epigenetic, protein alterations and their functional influence are of clinical importance. For a disease where a majority of patients are diagnosed in late stages, there is a need to discover biomarkers as well as new targets for therapeutic interventions
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