miR-200c Targets CDK2 and Suppresses Tumorigenesis in Renal Cell Carcinoma

Wang, Xuegang; Chen, Xuanyu; Wang, Han; Ruan, Anming; Chen, Li; Wang, Rong; Xu, Zhenghong; Xiao, Pei; Lu, Xing; Zhao, Yan; Zhou, Jia; Chen, Shaoyong; Du, Quansheng; Yang, Hongmei; Zhang, Xiaoping

doi:10.1158/1541-7786.mcr-15-0128

Cited by 35 publications

(24 citation statements)

References 46 publications

(49 reference statements)

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“…The microarray datasets of GSE96574, GSE71302 ( 11 ) and GSE61441 ( 12 ) were downloaded from the Gene Expression Omnibus (GEO) database ( ). GSE96574, which was an mRNA expression profile with 5 ccRCC tissues and 5 normal kidney tissues, was detected with the platform of Agilent-067406 CBC lncRNA + mRNA microarray V4.0; GSE71302, an miRNA expression profile with 5 ccRCC tissues and 5 normal kidney tissues, was detected with the platform of Agilent-021827 Human miRNA Microarray V3; GSE61441, a methylation profile with 46 ccRCC tissues and 46 normal kidney tissues, was detected with the platform of Illumina HumanMethylation450 BeadChip.…”

Section: Methodsmentioning

confidence: 99%

Identification of potential pathogenic biomarkers in clear cell renal cell carcinoma

Wang

Zhang

2018

Oncol Lett

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The purpose of the present study was to screen potential pathogenic biomarkers of clear cell renal cell carcinoma (ccRCC) via microarray analysis. The mRNA and microRNA (miRNA) expression profiles of GSE96574 and GSE71302 were downloaded from the Gene Expression Omnibus (GEO) database, as well as the methylation profile of GSE61441. A total of 5 ccRCC tissue samples and 5 normal kidney tissue samples were contained in each profile of GSE96574 and GSE71302, and 46 ccRCC tissue samples and 46 normal kidney tissue samples were involved in GSE61441. The differentially expressed genes (DEGs) and the differentially expressed miRNAs (DEMs) were obtained via limma package in ccRCC tissues compared with normal kidney tissues. The Two Sample t-test and the Beta distribution test were used to identify the differentially methylated sites (DMSs). The Database for Annotation, Visualization and Integrated Discovery (DAVID) was used to perform the Gene Ontology (GO) term and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of the DEGs. The targets of the DEMs were screened with the miRWalk database, and the further combination analyses of DEGs, DEMs and DMSs were conducted. Additionally, reverse transcription PCR (RT-PCR) and methylation-specific PCR (MS-PCR) were performed to detect the mRNA level and methylation status of HAPLN1. The mRNA levels of hsa-miR-204 and hsa-miR-218 were tested by RT-PCR. A total of 2,172 DEGs, 202 DEMs and 2,172 DMSs were identified in RCC samples compared with normal samples. The DEGs were enriched in 1,015 GO terms and 69 KEGG pathways. A total of 10,601 miRNA-gene pairs were identified in at least 5 algorithms of the miRWalk database. A total of 143 overlaps were identified between the DEGs and the differentially methylated genes. Furthermore, the DEGs were involved in 851 miRNA-gene pairs, including 127 pairs in which the target genes were negatively associated with their corresponding DEMs and DMSs. HAPLN1 was lowly expressed and highly methylated in ccRCC tissues, while hsa-miR-204 and hsa-miR-218 were highly expressed. The results of the present study indicated that HAPLN1, hsa-miR-204 and hsa-miR-218 may be involved in the pathogenesis of ccRCC.

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Section: Methodsmentioning

confidence: 99%

Identification of potential pathogenic biomarkers in clear cell renal cell carcinoma

Wang

Zhang

2018

Oncol Lett

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“…Among them, miR-200c has been demonstrated to function as a tumor suppressor, and loss of miR-200c expression has been reported in many cancer types, restoration of miR-200c expression has been shown to abrogate tumorigenesis 10 – 14 . To date, some genes have been identified as miR-200c target genes, including K-RAS, CDK2, ZEB2, Snail1, USP25, HMGB1 15 – 20 , which are involved in pathogenesis of cancers. A number of reports have investigated the role of miRNAs in osteosarcoma.…”

Section: Introductionmentioning

confidence: 99%

MiR-200c regulates tumor growth and chemosensitivity to cisplatin in osteosarcoma by targeting AKT2

Liu

Zhu

Wang

et al. 2017

Sci Rep

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MicroRNAs (miRNAs) expression aberration has been discovered in almost all human cancers, thus offering a group of potential diagnostic markers, prognostic factors and therapeutic targets in tumorigenesis. Now our data showed that miR-200c, which is downregulated in osteosarcoma tissues, drives chemosensitivity to cisplatin in osteosarcoma. We demonstrated that AKT2 is a direct target of miR-200c, Spearman’s rank correlation analysis showed that the expression levels of AKT2 and miR-200c in 35 pairs of osteosarcoma specimens were inversely correlated. Moreover, miR-200c inhibited cell proliferation and cell migration. Taken together, for the first time, our results demonstrate that miR-200c plays a significant role in osteosarcoma tumor growth and chemosensitivity by regulating AKT2, which may provide a novel therapeutic strategy for treatment of osteosarcoma.

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“…In addition, there has been significant interest in targeting cell cycle through inhibition of CDK2 activity as a strategy to treat cancer [34-36]. Since aspirin is known to inhibit cell proliferation, we hypothesized that its anti-cancer effects may involve down-regulation of cyclin A2 / CDK2 proteins or their mRNA levels or both.…”

Section: Introductionmentioning

confidence: 99%

Cyclin A2 and CDK2 as Novel Targets of Aspirin and Salicylic Acid: A Potential Role in Cancer Prevention

Dachineni

Kumar

et al. 2016

Molecular Cancer Research

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Data emerging from the past 10 years have consolidated the rationale for investigating the use of aspirin as a chemopreventive agent; however, the mechanisms leading to its anti-cancer effects are still being elucidated. We hypothesized that aspirin’s chemopreventive actions may involve cell cycle regulation through modulation of the levels or activity of cyclin A2/cyclin dependent kinase-2 (CDK2). In this study, HT-29 and other diverse panel of cancer cells were used to demonstrate that both aspirin and its primary metabolite, salicylic acid, decreased cyclin A2 (CCNA2) and CDK2 protein and mRNA levels. The down regulatory effect of either drugs on cyclin A2 levels was prevented by pretreatment with lactacystin, an inhibitor of proteasomes, suggesting the involvement of 26S proteasomes. In-vitro kinase assays showed that lysates from cells treated with salicylic acid had lower levels of CDK2 activity. Importantly, three independent experiments revealed that salicylic acid directly binds to CDK2. Firstly, inclusion of salicylic acid in naïve cell lysates, or in recombinant CDK2 preparations, increased the ability of the anti-CDK2 antibody to immunoprecipitate CDK2, suggesting that salicylic acid may directly bind and alter its conformation. Secondly, in 8-anilino-1-naphthalene-sulfonate (ANS)-CDK2 fluorescence assays, pre-incubation of CDK2 with salicylic acid, dose-dependently quenched the fluorescence due to ANS. Thirdly, computational analysis using molecular docking studies identified Asp145 and Lys33 as the potential sites of salicylic acid interactions with CDK2. These results demonstrate that aspirin and salicylic acid down-regulate cyclin A2/CDK2 proteins in multiple cancer cell lines, suggesting a novel target and mechanism of action in chemoprevention. Implications Biochemical and structural studies indicate that the anti-proliferative actions of aspirin are mediated through cyclin A2/CDK2.

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miR-200c Targets CDK2 and Suppresses Tumorigenesis in Renal Cell Carcinoma

Cited by 35 publications

References 46 publications

Identification of potential pathogenic biomarkers in clear cell renal cell carcinoma

Identification of potential pathogenic biomarkers in clear cell renal cell carcinoma

MiR-200c regulates tumor growth and chemosensitivity to cisplatin in osteosarcoma by targeting AKT2

Cyclin A2 and CDK2 as Novel Targets of Aspirin and Salicylic Acid: A Potential Role in Cancer Prevention

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