High-Resolution Analysis of Dna Copy Number Alterations and the Gene Expression in Renal Clear Cell Carcinoma

Yoshimoto, Taichiro; Matsuura, Keiko; Seto, Masao; Narimatsu, Takahiro; Sato, Fuminori; Mimata, Hiromitsu; Moriyama, Masatsugu

doi:10.1016/s0022-5347(08)60398-5

Cited by 11 publications

(27 citation statements)

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“…In this study we demonstrated that kidney‐specific knockout of Sav1 enhances the proliferation of epithelial cells in renal tubules, supporting our hypothesis that down‐regulation of SAV1 due to genomic loss of 14q contributes to the malignant transformation of ccRCC . Enhanced epithelial cell proliferation could be explained by suppressed Hippo signalling activity, since nuclear localization of Yap1 was accompanied by loss of Sav1, reflecting the results of in vitro assays in our previous study showing that knockdown of SAV1 enhanced the nuclear localization and transcriptional activity of YAP1 through suppression of Hippo signalling .…”

Section: Discussionsupporting

confidence: 88%

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Kidney-specific knockout ofSav1in the mouse promotes hyperproliferation of renal tubular epithelium through suppression of the Hippo pathway

et al. 2016

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We have previously reported that Salvador homologue 1 (SAV1), a component of the Hippo pathway, is significantly down-regulated in high-grade clear cell renal cell carcinoma (ccRCC) due to 14q copy number loss, and that this down-regulation contributes to the proliferation and survival of renal tubular epithelial cells through activation of Yes-associated protein 1 (YAP1), a downstream target of the Hippo pathway. However, the impact of SAV1 loss on the proliferation and survival of kidney cells in vivo remained to be determined. To address this issue, we generated kidney-specific Sav1-knockout (Cdh16-Cre;Sav1(fl/fl) ) mice. Sav1 deficiency enhanced the proliferation of renal tubular epithelial cells in Cdh16-Cre;Sav1(fl/fl) mice, accompanied by nuclear localization of Yap1, suggesting suppression of the Hippo pathway. Sav1 deficiency in renal tubules also caused structural and cellular abnormalities of the epithelial cells, including significant enlargement of their nuclei. Furthermore, Cdh16-Cre;Sav1(fl/fl) mice developed both glomerular and tubular cysts. Although lining cells of the glomerular cysts showed no atypia, those of the tubular cysts showed variations in cell size and nuclear shape, which became more severe as the mice aged. In aged Cdh16-Cre;Sav1(fl/fl) mice, we observed focal disruption of proximal tubules and perivascular lymphocytic infiltration. In conclusion, Sav1 is required for the maintenance of growth, nuclear size and structure of renal tubules under physiological conditions, and its deficiency leads to the acquisition of enhanced proliferation of renal epithelial cells through suppression of Hippo signalling.

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Section: Discussionsupporting

confidence: 88%

“…Previously, we found that genomic copy number loss at 14q was more frequent in high‐grade than in low‐grade ccRCC, and that many of the genes located on 14q were down‐regulated due to this copy number loss . Furthermore, we identified Salvador homologue 1 ( SAV1 ) as a candidate gene responsible for 14q loss .…”

Section: Introductionmentioning

confidence: 99%

Kidney-specific knockout ofSav1in the mouse promotes hyperproliferation of renal tubular epithelium through suppression of the Hippo pathway

et al. 2016

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“…For gene expression microarray, 300 ng of total RNA extracted from cells transfected with pre375 or preNeg in quadruplicate were subjected to microarray analysis in a similar way to that described in our previous study (25,26). Details of the procedures are provided in Supplementary Data 1.…”

Section: Methodsmentioning

confidence: 99%

MicroRNA-375 Is Downregulated in Gastric Carcinomas and Regulates Cell Survival by Targeting PDK1 and 14-3-3ζ

et al. 2010

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We investigated expression profiles of microRNA (miRNA) in gastric carcinomas by use of a miRNA microarray platform covering a total of 470 human miRNAs. We identified 39 differentially expressed miRNAs in gastric carcinoma, of which six were significantly downregulated and the other 33 were upregulated. We found that miRNA-375 (miR-375) was the most downregulated and that its ectopic expression in gastric carcinoma cells markedly reduced cell viability via the caspase-mediated apoptosis pathway. Interestingly, we found that expression of miR-375 inhibited expression of PDK1, which is a direct target of miR-375, followed by suppression of Akt phosphorylation. Further analysis by gene expression microarray revealed that 14-3-3zeta, a potent antiapoptotic gene, was significantly downregulated at both the mRNA and protein levels in cells transfected with miR-375. The activity of a luciferase reporter containing the miR-375 binding sequence at the 3' untranslated region (UTR) of 14-3-3zeta mRNA was repressed by the ectopic expression of miR-375, suggesting that miR-375 targets the 3' UTR of 14-3-3zeta. In addition, knockdown of either PDK1 or 14-3-3zeta in gastric carcinoma cells induced caspase activation, which was also observed in miR-375-transfected cells, suggesting that miR-375 may exert its proapoptotic function, at least in part, through the downregulation of PDK1 and 14-3-3zeta. Taken together, we propose that miR-375 is a candidate tumor suppressor miRNA in gastric carcinoma.

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“…Recently, high throughput methods for genome-wide screening of DNA copy number alterations and loss of heterozygosity have been developed and tested in small series of renal cell cancers 204–206. If proven reliable and feasible, these powerful methods hold promise for novel discoveries in large scale investigations of gene-environment and gene-gene interactions.…”

Section: Genetic Susceptibility and Environmentmentioning

confidence: 99%

Contemporary Epidemiology of Renal Cell Cancer

2008

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We analyzed renal cell cancer incidence patterns in the United States and reviewed recent epidemiologic evidence with regard to environmental and host genetic determinants of renal cell cancer risk. Renal cell cancer incidence rates continued to rise among all racial/ethnic groups in the United States, across all age groups, and for all tumor sizes, with the most rapid increases for localized stage disease and small tumors. Recent cohort studies confirmed the association of smoking, excess body weight, and hypertension with an elevated risk of renal cell cancer, and suggested that these factors can be modified to reduce the risk. There is increasing evidence for an inverse association between renal cell cancer risk and physical activity and moderate intake of alcohol. Occupational exposure to TCE has been positively associated with renal cell cancer risk in several recent studies, but its link with somatic mutations of the VHL gene has not been confirmed. Studies of genetic polymorphisms in relation to renal cell cancer risk have produced mixed results, but genome-wide association studies with larger sample size and a more comprehensive approach are underway. Few epidemiologic studies have evaluated risk factors by subtypes of renal cell cancer defined by somatic mutations and other tumor markers. Keywords renal cell cancer; incidence trends; cohort studies; smoking; obesity; hypertension; diet; occupation; genetic polymorphism; somatic mutation Malignant tumors of the kidney account for about 4% of cancer incidence and 2% of cancer mortality in the United States, with over 54,000 new cases and 13,000 deaths having been estimated for 2008. 1 More than 85% of kidney cancers arise in the renal parenchyma, with the remainder arising in the renal pelvis. 2 Renal pelvis cancer is mostly of the transitional cell type and is not the focus of this review. Nearly all cancers originating in the renal parenchyma are adenocarcinomas (renal cell carcinoma), in which clear cell is the predominant subtype. 3 The remainder is made up of the papillary type and other rare histologic types, such as collecting duct and chromophobe carcinomas. 3,4 Distinct morphologic and genetic characteristics have also been described for renal cell carcinoma in familial cancer syndromes. [5][6][7] Descriptive and analytic epidemiologic studies in general have not distinguished the subtypes of renal cell carcinoma, except for studies involving the von Hippel-Lindau (VHL) gene mutation that is seen primarily in the clear cell type. 8 Since the clear cell type comprises 85% to 90% of renal cell carcinoma, 3 the epidemiology of renal cell carcinoma is strongly influenced by that of the clear cell type.* Correspondence: Wong-Ho Chow, National Cancer Institute, 6120 Executive Blvd, EPS 8100, Bethesda, Maryland 20892-7240, USA. choww@mail.nih.gov. NIH Public Access Author ManuscriptCancer J. Author manuscript; available in PMC 2011 April 15. DESCRIPTIVE EPIDEMIOLOGY Incidence patterns and temporal trendsIncidence rates of renal cell carcinoma h...

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High-Resolution Analysis of Dna Copy Number Alterations and the Gene Expression in Renal Clear Cell Carcinoma

Cited by 11 publications

References 0 publications

Kidney-specific knockout ofSav1in the mouse promotes hyperproliferation of renal tubular epithelium through suppression of the Hippo pathway

Kidney-specific knockout ofSav1in the mouse promotes hyperproliferation of renal tubular epithelium through suppression of the Hippo pathway

MicroRNA-375 Is Downregulated in Gastric Carcinomas and Regulates Cell Survival by Targeting PDK1 and 14-3-3ζ

Contemporary Epidemiology of Renal Cell Cancer

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