Unknown,Transcriptomics,Genomics,Proteomics

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Identification of metastamirs as metastasis-associated microRNAs in clear cell renal cell carcinomas

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

SUBMITTER: Hellmuth-A Meyer

PROVIDER: E-GEOD-37989 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Identification of metastamirs as metastasis-associated microRNAs in clear cell renal cell carcinomas.

Wotschofsky Zofia Z Liep Julia J Meyer Hellmuth-Alexander HA Jung Monika M Wagner Ina I Disch Alexander C AC Schaser Klaus D KD Melcher Ingo I Kilic Ergin E Busch Jonas J Weikert Steffen S Miller Kurt K Erbersdobler Andreas A Mollenkopf Hans-Joachim HJ Jung Klaus K

International journal of biological sciences 20121028 10

MicroRNAs (miRNAs) play a pivotal role in cancerogenesis and cancer progression, but their specific role in the metastasis of clear cell renal cell carcinomas (ccRCC) is still limited. Based on microRNA microarray analyses from normal and cancerous samples of ccRCC specimens and from bone metastases of ccRCC patients, we identified a set of 57 differentially expressed microRNAs between these three sample groups of ccRCC. A selected panel of 33 miRNAs was subsequently validated by RT-qPCR on tota ...[more]

PMID: 23139634

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Project description:Patients with loss-of-function mutations of the von Hippel Lindau gene (“VHL-patients”) often develop clear cell renal cell carcinoma (ccRCC). Using archived, formalin-fixed, paraffin-embedded (FFPE) samples and a cohort of eight cases, we sought to determine global proteome alterations that distinguish ccRCC tissue from adjacent, non-malignant kidney tissue in VHL-patients. Our quantitative proteomic analysis clearly discriminated tumor and non-malignant tissue, yielding comparable proteome profiles for the eight ccRCC cases. Limma statistics was used to identify significantly dysregulated proteins in ccRCC. Functional classification of these proteins highlighted a decrease in proteins involved in the tricarboxylic acid cycle and an increase in proteins involved in glycolysis. This profile possibly represents a proteomic fingerprint of the “Warburg effect”, which is a molecular hallmark of ccRCC. Furthermore, we observed an increase in proteins involved in extracellular matrix organization. Of particular note were opposing alterations of Xaa-Pro Aminopeptidases-1 and -2 (XPNPEP-1 and -2): a strong decrease of XPNPEP-2 in ccRCC was accompanied by a strong increase of the related protease XPNPEP-1. In both cases, we corroborated the proteomic results by immunohistochemical analysis of ccRCC and adjacent, non-malignant kidney tissue of VHL patients. To functionally investigate the role of XPNPEP-1 in ccRCC, we performed small-hairpin RNA mediated XPNPEP-1 expression silencing in 786-O ccRCC cells harboring a mutated VHL gene. We found that XPNPEP-1 expression suppresses cellular proliferation and migration. These results suggest that XPNPEP-1 is rather an anti-target in VHL-driven ccRCC. Generally, we present one of the first proteomic profiling studies of ccRCC in VHL patients, comparing normal and tumor tissue, which are both deficient for the VHL tumor suppressor. Methodologically, our work further validates the robustness of using FFPE material for quantitative proteomics.

Dataset Information

Identification of metastamirs as metastasis-associated microRNAs in clear cell renal cell carcinomas

Publications

Identification of metastamirs as metastasis-associated microRNAs in clear cell renal cell carcinomas.

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