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

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.

Impact of 9p deletion and p16, Cyclin D1, and Myc hyperexpression on the outcome of anaplastic oligodendrogliomas

“…It also confirmed the link between Myc overexpression and progression to anaplasia with a significant correlation with histological grading but not with proliferative index, MVP or necrosis as seen with Cyclin D1 and/or p16. Myc overexpression appeared only correlated to p16 overexpression which was unexpected giving the presumed inhibitory role of Myc on p16 function [ 14 , 46 ]. These data underline the complexity of molecular interactions in tumor process and may indicate an escape of p16 from Myc inhibitory control in OGs, but giving the absence of specific information on this subject in the literature, these findings need to be confirmed in future studies.…”

“…At the same time we also wished to evaluate protein p16 (CDKN2A) expression in this cohort as a possible diagnostic and /or prognostic marker since the CDKN2A gene is located on 9p21. Finally, we studied the diagnostic and prognostic value of two additional proteins which have recently been implicated as markers of anaplasia and short outcome in OG [ 11 , 12 ] and which are also linked to p16: Cyclin-D1 (CCND1) which dimerizes with CDK4, the main target of p16 [ 13 ] and Myc (c-Myc) which impacts a wide number of cellular processes and may influence p16 via overexpression of HGMA2 and downregulation of CDKN2A [ 14 ].…”

MYCN contributes to the malignant characteristics of erythroleukemia through EZH2-mediated epigenetic repression of p21

“… 9 In addition, MYCN amplification or overexpression has been shown in several other cancers, including small cell lung cancer, prostate cancer and Wilms tumor. 10 , 11 , 12 However, few studies were performed to investigate the role of MYCN in hematopoietic malignancies. Transgenic MYCN expression induced lymphoma in mouse model.…”

High mobility group protein A2 overexpression indicates poor prognosis for cancer patients: a meta-analysis

“…These studies were mainly conducted in East Asia, Europe, and the United States of America. The cancer types studied were: gastric cancer (GC) [ 16 – 18 ], breast cancer (BC) [ 10 , 19 ], hepatocellular carcinoma (HCC) [ 11 , 13 ], colorectal cancer (CRC) [ 14 , 20 , 21 ], ovarian cancer (OC) [ 22 , 23 ], nasopharyngeal carcinoma (NPC) [ 24 , 25 ], esophageal carcinoma (EC) [ 26 , 27 ], head and neck squamous cell carcinoma (HNSCC) [ 28 – 30 ], clear cell renal cell carcinoma [ 12 ], intrahepatic cholangiocarcinoma [ 31 ], glioblastoma [ 32 ], gallbladder adenocarcinoma [ 33 ], melanoma [ 34 ], non-small-cell lung cancer [ 35 ], and bladder cancer [ 36 ]. HMGA2 was detected using immunohistochemistry (IHC) (24 studies), reverse transcription-polymerase chain reaction (RT-PCR) (2 studies), or quantitative real-time polymerase chain reaction (qRT-PCR) (3 studies).…”