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01.12.2016 | Research article | Ausgabe 1/2016 Open Access

BMC Cancer 1/2016

The MYCN-HMGA2-CDKN2A pathway in non-small cell lung carcinoma—differences in histological subtypes

Zeitschrift:
BMC Cancer > Ausgabe 1/2016
Autoren:
Hanne A. Eide, Ann Rita Halvorsen, Maria Moksnes Bjaanæs, Hossein Piri, Ruth Holm, Steinar Solberg, Lars Jørgensen, Odd Terje Brustugun, Cecilie Essholt Kiserud, Åslaug Helland
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​s12885-016-2104-9) contains supplementary material, which is available to authorized users.

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

HAE performed the data analysis and wrote the manuscript. ARH and HP performed the RT-qPCR. ARH and MMB performed the microRNA microarrays and provided the adenocarcinoma validation set. RH evaluated the immunostained sections. SS, LJ and OTB provided patient material and patient data. CEK participated in the data analysis and in writing the manuscript. ÅH conceived the study, provided patient material and data, and participated in writing the manuscript. All authors read and approved the final manuscript.

Abstract

Background

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 also be of significance in the pathogenesis of NSCLC.

Methods

Gene 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.

Results

Compared 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).

Conclusions

A 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.
Zusatzmaterial
Additional file 1: Table S1. Characteristics of the microRNA sample set. Table S2: Characteristics of the adenocarcinoma validation sample set. Table S3: Characteristics of the squamous cell carcinoma (TCGA) validation sample set. Table S4: Independent samples t-test. Mean let-7 microRNA expression in tumour and normal tissue samples. Table S5: Independent samples t-test. Mean let-7 microRNA expression and association with MYCN mRNA expression in tumour samples. Table S6: Independent samples t-test. Mean let-7 microRNA expression and association with HMGA2 mRNA expression in tumour samples. Table S7: Independent samples t-test. Mean let-7 microRNA expression and association with CDKN2A mRNA expression in tumour samples. Table S8: Independent samples t-test. Mean let-7 microRNA expression and association with DICER1 mRNA expression in tumour samples and additional figures (Figure S1: REMARK diagram detailing sample availability and use of different analytical techniques in the present study. Figure S2: Boxplots illustrating the distribution of gene expression (fold change) from the RT-qPCR . Figure S3: Scatterplots illustrating significant correlations. Figure S4: Associations between HMGA2 protein expression and patient outcome). Figure S1. REMARK diagram detailing sample availability and use of different analytical techniques in the present study. Figure S2. Boxplots illustrating the distribution of gene expression from the RT-qPCR. Figure S3. Scatterplots illustrating significant correlations. Figure S4. Associations between NSCLC stage, HMGA2 protein expression and patient outcome. HMGA2 protein expression values dichotomized to low expression (blue) and overexpression (green) based on immunohistochemistry. Low expression of HMGA2 protein had a significantly better prognosis compared to overexpression in stage I non-small cell lung cancer tumour samples (A, p = 0.034). No significant association in stage II (B, p = 0.492) or stage III (C, p = 0.862) patients was seen. (DOCX 401 kb)
Literatur
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