Gerashchenko G V, Mevs L V, Chashchina L I, Pikul M V, Gryzodub O P, Stakhovsky E O, Kashuba V I
Institute of Molecular Biology and Genetics NAS of Ukraine, Kyiv 03680, Ukraine.
National Cancer Institute, Ministry of Health of Ukraine, Kyiv 03022, Ukraine.
Exp Oncol. 2018 Jun;40(2):101-108.
To analyze an expression pattern of the steroid and peptide hormone receptors, metabolic enzymes and EMT-related genes in prostate tumors in relation to the presence of the TMPRSS2/ERG fusion; and to examine a putative correlation between gene expression and clinical characteristics, to define the molecular subtypes of prostate cancer.
The relative gene expression (RE) of 33 transcripts (27 genes) and the presence/absence of the TMPRSS2/ERG fusion were analyzed by a quantitative PCR. 37 prostate cancer tissues (T) paired with conventionally normal prostate tissue (CNT) and 21 samples of prostate adenomas were investigated. RE changes were calculated, using different protocols of statistics.
We demonstrated differences in RE of seven genes between tumors and CNT, as was calculated, using the 2-ΔCT model and the Wilcoxon matched paired test. Five genes (ESR1, KRT18, MKI67, MMP9, PCA3) showed altered expression in adenocarcinomas, in which the TMPRSS2/ERG fusion was detected. Two genes (INSR, isoform B and HOTAIR) expressed differently in tumors without fusion. Comparison of the gene expression pattern in adenomas, CNT and adenocarcinomas demonstrated that in adenocarcinomas, bearing the TMPRSS2/ERG fusion, genes KRT18, PCA3, and SCHLAP1 expressed differently. At the same time, we detected differences in RE of AR (isoform 2), MMP9, PRLR and HOTAIR in adenocarcinomas without the TMPRSS2/ERG fusion. Two genes (ESR1 and SRD5A2) showed differences in RE in both adenocarcinoma groups. Fourteen genes, namely AR (isoforms 1 and 2), CDH1, OCLN, NKX3-1, XIAP, GCR (ins AG), INSR (isoform A), IGF1R, IGF1R tr, PRLR, PRL, VDR and SRD5A2 showed correlation between RE and tumor stage. RE of four genes (CDH2, ESR2, VDR and SRD5A2) correlated with differentiation status of tumors (Gleason score). Using the K-means clustering, we could cluster adenocarcinomas in three groups, according to gene expression profiles. A specific subtype of prostate tumors is characterized by the activated ERG signaling, due to the presence of TMPRSS2/ERG fusion, and also by high levels of the androgen receptor, prolactin, IGF, INSR and PCA3.
We have found the specific differences in expression of the steroid and peptide hormone receptors, metabolic enzymes and EMT-related genes, depending on the pre-sence/absence of the TMPRSS2/ERG fusion in prostate adenocarcinomas, CNT and adenomas. We showed three different gene expression profiles of prostate adenocarcinomas. One of them is characteristic for adenocarcinomas with the TMPRSS2/ERG fusion. Further experiments are needed to confirm these data in a larger cohort of patients.
分析前列腺肿瘤中类固醇和肽类激素受体、代谢酶及上皮-间质转化（EMT）相关基因的表达模式与TMPRSS2/ERG融合的关系；研究基因表达与临床特征之间的假定相关性，以确定前列腺癌的分子亚型。
通过定量PCR分析33个转录本（27个基因）的相对基因表达（RE）以及TMPRSS2/ERG融合的有无。研究了37例与传统正常前列腺组织（CNT）配对的前列腺癌组织（T）和21例前列腺腺瘤样本。使用不同的统计方法计算RE变化。
使用2-ΔCT模型和Wilcoxon配对检验计算得出，肿瘤与CNT之间7个基因的RE存在差异。5个基因（ESR1、KRT18、MKI67、MMP9、PCA3）在检测到TMPRSS2/ERG融合的腺癌中表达改变。2个基因（INSR，异构体B和HOTAIR）在无融合的肿瘤中表达不同。腺瘤、CNT和腺癌中基因表达模式的比较表明，在携带TMPRSS2/ERG融合的腺癌中，基因KRT18、PCA3和SCHLAP1表达不同。同时，我们在无TMPRSS2/ERG融合的腺癌中检测到AR（异构体2）、MMP9、PRLR和HOTAIR的RE差异。2个基因（ESR1和SRD5A2）在两个腺癌组中的RE均有差异。14个基因，即AR（异构体1和2）、CDH1、OCLN、NKX3-1、XIAP、GCR（插入AG）、INSR（异构体A）、IGF1R、IGF1R tr、PRLR、PRL、VDR和SRD5A2的RE与肿瘤分期相关。4个基因（CDH2、ESR2、VDR和SRD5A2）的RE与肿瘤分化状态（Gleason评分）相关。使用K均值聚类，根据基因表达谱可将腺癌分为三组。一种特定的前列腺肿瘤亚型的特征是由于存在TMPRSS2/ERG融合而导致ERG信号激活，同时雄激素受体、催乳素、胰岛素样生长因子、胰岛素受体和PCA3水平较高。
我们发现，根据前列腺腺癌、CNT和腺瘤中TMPRSS2/ERG融合的有无，类固醇和肽类激素受体、代谢酶及EMT相关基因的表达存在特定差异。我们展示了前列腺腺癌的三种不同基因表达谱。其中一种是具有TMPRSS2/ERG融合的腺癌的特征。需要进一步的实验在更大的患者队列中证实这些数据。
