Accurate Molecular Classification of Renal Tumors Using MicroRNA Expression

Fridman, Eduard; Dotan, Zohar; Barshack, Iris; David, M; Dov, Avital; Tabak, Sarit; Zion, Orit; Schwessinger, Benjamin; Benjamin, H.; Kuker, Hagit; Avivi, Camila; Rosenblatt, Kinneret; Polak‐Charcon, Sylvie; Ramon, Jacob; Rosenfeld, Nitzan; Spector, Yael

doi:10.2353/jmoldx.2010.090187

Cited by 103 publications

(84 citation statements)

References 54 publications

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“…In consistence with previous studies (15,39), no significant correlation was identified between miR-141 expression and RCC tumor stage, grade, or size. Recent reports have also showed the ability of miRNAs to distinguish between RCC subtypes with an accuracy of about 90%, including ccRCC, papillary RCC (pRCC), chRCC, and the closely related benign tumor oncocytoma (40,41). Here, miR-141 expression was equally decreased in malignant (ccRCC, chRCC, and sarcoma RCC) and benign renal tumors (AML).…”

Section: Discussionmentioning

confidence: 70%

miR-141 Is a Key Regulator of Renal Cell Carcinoma Proliferation and Metastasis by Controlling EphA2 Expression

Chen

Wang

Ruan

et al. 2014

Clinical Cancer Research

124

117

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Purpose: Although microRNAs (miRNA) have been revealed as crucial modulators of tumorigenesis, our understanding of their roles in renal cell carcinoma (RCC) is limited. Here we sought to identify human miRNAs that act as key regulators of renal carcinogenesis.Experimental Design: We performed microarray-based miRNA profiling of clear cell RCC (ccRCC) and adjacent normal tissues and then explored the roles of miR-141 both in vitro and in vivo, which was the most significantly downregulated in ccRCC tissues.Results: A total of 74 miRNAs were dysregulated in ccRCC compared with normal tissues. miR-141 was remarkably downregulated in 92.6% (63/68) ccRCC tissues and would serve as a promising biomarker for discriminating ccRCC from normal tissues with an area under the receiver operating characteristics curve of 0.93. Overexpression of miR-141 robustly impaired ccRCC cell migratory and invasive properties and suppressed cell proliferation by arresting cells at G 0 -G 1 phase in vitro and in human RCC orthotopic xenografts. Significantly, the antitumor activities of miR-141 were mediated by its reversal regulation of erythropoietin-producing hepatocellular (Eph) A2 (EphA2), which then relayed a signaling transduction cascade to attenuate the functions of focal adhesion kinase (FAK), AKT, and MMP2/9.

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Section: Discussionmentioning

confidence: 70%

miR-141 Is a Key Regulator of Renal Cell Carcinoma Proliferation and Metastasis by Controlling EphA2 Expression

Chen

Wang

Ruan

et al. 2014

Clinical Cancer Research

124

117

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“…The cluster of similar miRNAs in benign and malignant follicular tumors displaying Hürthle cell features supports also the assumption that such features represent a phenotype that is superimposed on different oncogenic genotypes. This assumption is further reinforced by the upregulation of miR-221 in renal oncocytomas (Fridman et al 2010; Table 3). …”

Section: Microrna Alterations In Hü Rthle Cell Tumorsmentioning

confidence: 89%

The biology and the genetics of Hürthle cell tumors of the thyroid

Máximo¹,

Lima²,

Prazeres³

et al. 2012

Endocrine-Related Cancer

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The biology and the genetics of Hü rthle cell tumors are reviewed starting from the characterization and differential diagnosis of the numerous benign and malignant, neoplastic and nonneoplastic lesions of the thyroid in which Hü rthle cell transformation is frequently observed. The clinicopathologic and molecular evidence obtained from the comparative study of the aforementioned conditions indicate that Hü rthle cell appearance represents a phenotype that is superimposed on the genotypic and conventional histopathologic features of the tumors. Hürthle cell tumors differ from their non-Hü rthle counterparts regarding the prevalence of large deletions of mitochondrial DNA (mtDNA), mutations of mtDNA genes coding for oxidative phosphorylation (OXPHOS) proteins (namely mutations of complex I subunit genes) and mutations of nuclear genes coding also for mitochondrial OXPHOS proteins. Such mitochondrial alterations lead to energy production defects in Hü rthle cell tumors; the increased proliferation of mitochondria may reflect a compensatory mechanism for such defects and is associated with the overexpression of factors involved in mitochondrial biogenesis. The mitochondrial abnormalities are also thought to play a major role in the predisposition for necrosis instead of apoptosis which seems to be blocked in most Hü rthle cell tumors. Finally, the results obtained in experimental models using cybrid cell lines and the data obtained from histopathologic and molecular studies of familial Hü rthle cell tumors are used, together with the aforementioned genetic and epigenetic alterations, to progress in the understanding of the mechanisms through which mitochondrial abnormalities may be involved in the different steps of thyroid carcinogenesis, from tumor initiation to metastization.

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“…Similarly, miR-204 loss enhanced migration and stem cell phenotype in vivo (37 ). MiR-139 expression was shown to differ between different kidney cancer subtypes (38 ) and was also linked to metastasis and prognosis in ccRCC (39 ). In our network, miR-139 targets ETS1, TCF4, ZEB1, and CCND2.…”

Section: Discussionmentioning

confidence: 93%

Integrative Bioinformatics Analysis Reveals New Prognostic Biomarkers of Clear Cell Renal Cell Carcinoma

et al. 2014

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BACKGROUND The outcome of clear cell renal cell carcinoma (ccRCC) is still unpredictable. Even with new targeted therapies, the average progression-free survival is dismal. Markers for early detection and progression could improve disease outcome. METHODS To identify efficient and hitherto unrecognized pathogenic factors of the disease, we performed a uniquely comprehensive pathway analysis and built a gene interaction network based on large publicly available data sets assembled from 28 publications, comprising a 3-prong approach with high-throughput mRNA, microRNA, and protein expression profiles of 593 ccRCC and 389 normal kidney samples. We validated our results on 2 different data sets of 882 ccRCC and 152 normal tissues. Functional analyses were done by proliferation, migration, and invasion assays following siRNA (small interfering RNA) knockdown. RESULTS After integration of multilevel data, we identified aryl-hydrocarbon receptor (AHR), grainyhead-like-2 (GRHL2), and KIAA0101 as new pathogenic factors. GRHL2 expression was associated with higher chances for disease relapse and retained prognostic utility after controlling for grade and stage [hazard ratio (HR), 3.47, P = 0.012]. Patients with KIAA0101-positive expression suffered worse disease-free survival (HR, 3.64, P < 0.001), and in multivariate analysis KIAA0101 retained its independent prognostic significance. Survival analysis showed that GRHL2- and KIAA0101-positive patients had significantly lower disease-free survival (P = 0.002 and P < 0.001). We also found that KIAA0101 silencing decreased kidney cancer cell migration and invasion in vitro. CONCLUSIONS Using an integrative system biology approach, we identified 3 novel factors as potential biomarkers (AHR, GRHL2 and KIAA0101) involved in ccRCC pathogenesis and not linked to kidney cancer before.

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Accurate Molecular Classification of Renal Tumors Using MicroRNA Expression

Cited by 103 publications

References 54 publications

miR-141 Is a Key Regulator of Renal Cell Carcinoma Proliferation and Metastasis by Controlling EphA2 Expression

miR-141 Is a Key Regulator of Renal Cell Carcinoma Proliferation and Metastasis by Controlling EphA2 Expression

The biology and the genetics of Hürthle cell tumors of the thyroid

Integrative Bioinformatics Analysis Reveals New Prognostic Biomarkers of Clear Cell Renal Cell Carcinoma

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