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Novel miRNA profiles as biomarkers for renal cell carcinoma and upper tract urothelial carcinoma

ABSTRACT: We investigated the expression profiles of microRNAs (miRNA) in 26 renal cell carcinoma (RCC) FFPE tissues (3 chRCC, 5 papRCC and 18 ccRCC), 4 urothelial cell carcinomas of the upper urinary tract (UT-UCs) and 20 normal kidneys by using the miRCURY LNA™ microRNA Array, 6th gen (Exiqon, Woburn MA), containing capture probes that target all miRNAs for all species registered in the miRBASE version 16.0. Real-time PCR (qRT-PCR) using appropriate endogenous controls was performed in order to validate the microarray results of the 27 most differentially expressed (DE) miRNAs. We identified 434 miRNAs that were significantly deregulated in all tumours compared to the normal kidney tissues. Overall, 126 miRNAs (29%) showed increased expression and 303 miRNAs (69.8%) had decreased expression in RCCs and UT-UCs vs. the normal kidneys. Specifically, 374, 420, 421 and 409 miRNAs were 90% consistently down-regulated in ccRCC, papRCC, chRCC and UT-UC, respectively. Unsupervised two-way hierarchical clustering (HCL) with Euclidian distance accurately discriminated between RCC and UT-UC. Apart from one chRCC sample that was clustered with ccRCCs, HCL also managed to successfully classify the 3 RCC subtypes among them. Furthermore, it showed that ccRCC is more closely related to papRCC and that both are distinct from chRCC or UT-UC. Ninety-four miRNAs were co-upregulated among ccRCC, papRCC and chRCC; and 11, 44 and 24 miRNAs were specifically up-regulated in each one of the three RCC subtypes (ccRCC, chRCC and papRCC), respectively. On the other hand, 222 miRNAs were co-down-regulated in the three RCC subtypes, whereas 16, 18 and 5 miRNAs were specifically down-regulated in ccRCC, chRCC and papRCC, respectively. When the DE miRNAs in each RCC subtype were combined with those in UT-UC, we identified 89 and 206 miRNAs, respectively, that were up- and down-regulated in all tumor types. miRNA profiling can distinguish between RCC and UT-UC as well as among distinct RCC subtypes. Our data validicate that miRNA expression tends to be down-regulated in RCC versus the normal kidney tissue.

ORGANISM(S): Merkel cell polyomavirus Rattus norvegicus Human gammaherpesvirus 8 Mus musculus JC polyomavirus Betapolyomavirus macacae Homo sapiens Human immunodeficiency virus 1 Human betaherpesvirus 5 Human alphaherpesvirus 2 Betapolyomavirus hominis Human alphaherpesvirus 1 Murid gammaherpesvirus 4 human gammaherpesvirus 4 Mus musculus cytomegalovirus 2 Murid betaherpesvirus 1

PROVIDER: GSE48008 | GEO | 2013/06/18

SECONDARY ACCESSION(S): PRJNA208630

REPOSITORIES: GEO

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Project description:We investigated the expression profiles of microRNAs (miRNA) in 27 renal cell carcinoma (RCC) FFPE tissues (3 chRCC, 5 papRCC and 18 ccRCC), 4 upper urinary tract-urothelial cell carcinomas of the renal pelvis-ureter (UUT-UCCs) and 20 normal kidneys by using the miRCURY LNAM-bM-^DM-" microRNA Array, 6th gen (Exiqon, Woburn MA), containing capture probes that target all miRNAs for all species registered in the miRBASE version 16.0. Real-time PCR (qRT-PCR) using appropriate endogenous controls was performed in order to validate the microarray results of the 27 most differentially expressed (DE) miRNAs. We identified 434 miRNAs that were significantly deregulated in all kidney tumours compared to the normal tissues. A total of 126 miRNAs (29%) had increased expression while 303 (69.8%) had decreased expression in RCC. Out of the 434 DE miRNAs, we detected 94 co-up-regulated and 218 co-down-regulated microRNAs among chRCC, papRCC and ccRCC. Of these, 89 and 203 were co-up- and co-down-regulated between RCCs and UUT-UCCs, respectively. We detected 11, 44 and 24 up-regulated miRNAs, which were specific for ccRCC, chRCC and papRCC, respectively. Moreover, 19, 18 and 8 miRNAs were uniquelly down-regulated in ccRCC, chRCC and papRCC, respectively. We also detected 89 and 203 co-up- and co-down-regulated miRNAs between kidney cancer and UUT-UCCs. Five miRNAs were up-regulated specifically in renal tumours and 49 in UUT-UCCs, whereas 15 miRNAs were down-regulated specifically in renal tumours and 89 in UUT-UCCs, respectively. Our data validicate that expression of miRNAs tends to be down-regulated renal cell carcinomas compared with normal kidney. We used 18 ccRCC, 3 chRCC, 5 papRCC, 4 UUT-UCC, 1 undifferentiated carcinoma and 19 normal tissue samples for miRNA profiling. Total RNA (0.5 M-BM-5g) from each sample and reference was labeled with Hy3M-bM-^DM-" fluorescent label, using the miRCURY LNAM-bM-^DM-" microRNA Hi-Power Labeling Kit (Exiqon, Woburn MA). The Hy3M-bM-^DM-\"-labeled samples were hybridized to the miRCURY LNAM-bM-^DM-" microRNA Array, 6th gen (Exiqon, Woburn MA), using an Agilent hybridization SureHyb chamber and gasket slide kits. After hybridization, the microarray slides were scanned at 10 M-NM-<m using the High-Resolution Microarray Scanner (Agilent Technologies) and stored in an ozone free environment. The image analysis was carried out using the ImaGene 8.0 software (BioDiscovery, Inc., USA). Raw microarray data were filtered, background corrected and quantile normalizated. Normalized data were further extracted, pre-processed and sorted with Microsoft ExcelM-BM-.. MicroRNAs were considered to be significantly differentially expressed if they obtained a p-value<0.05 and a FDRM-bM-^IM-$0.05.

Project description:Background/Objective: MicroRNAs (miRNAs) play a pivotal role in cancerogenesis and cancer progression, but their specific role in metastasis of clear cell renal cell carcinomas (ccRCCs) as so-called metastamirs is still limited. Based on microRNA microarray analyses from normal (n=12) and cancerous (n=12) samples of ccRCC specimens and from bone metastases (n=9) of ccRCC patients, we identified a set of 57 differentially expressed microRNAs between those three sample groups of ccRCC. A selected panel of 33 miRNAs, including miRNAs reported in the literature as differentially expressed in non-metastatic RCC, was validated by RT-qPCR on 57 clinical samples. 30 of the 33 examined miRNAs were confirmed to be deregulated. A stepwise down-regulated miRNA expression from normal over primary tumor to metastatic tissue samples was found to be typical. 23 miRNAs (miR-10b/-19a/-19b/-20a/-29a/-29b/-29c/-100/-101/-126/-127/-130/-141/-143/-145/-148a/-192/-194/-200c/-210/-215/-370/-514) were down-regulated in metastatic tissue samples in comparison to normal tissue. This down-regulated expression in metastatic tissue was also present in 21 miRNAs except for miR-127 and miR-370. The altered miRNA profiles including the newly identified metastasis-associated miRNAs, the compiled predicted miRNA-target interactions, and the significant correlations of miRNAs which were either lost or newly appeared in the studied sample groups afford a solid basis for further functional analyses of individual miRNAs. In this study, microarray-based profiling was performed from 9 bone metastatic tissue samples from 9 patients with clear cell renal cell carcinoma (ccRCC). For controls, 2 bone metastatic samples from two patients with prostate carcinoma and 5 total RNA pools (2 different pools of total RNAs isolated from malignant renal tissue samples derived from different ccRCC patients; 1 pool from non-malignant renal tissue of ccRCC patients; 2 pools of total RNA both from malignant and non-malignant prostate cancer tissue) were used. In addition, matched malignant (e.g., malignant NC2) and non-malignant (e.g., non-malignant NN1) samples from two independent 12 ccRCC sets were profiled (these samples were previously analyzed on a different Platform in GSE12105). The 2002 TNM System and the 2004 WHO classification was used for staging and grading.

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Novel miRNA profiles as biomarkers for renal cell carcinoma and upper tract urothelial carcinoma

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