Dual regulatory role of CCNA2 in modulating CDK6 and MET‐mediated cell‐cycle pathway and EMT progression is blocked by miR‐381‐3p in bladder cancer

Li, Jiangfeng; Ying, Yufan; Xie, Haiyun; Jin, Ke; Yan, Huaqing; Wang, Song; Xu, Mingjie; Xu, Xin; Wang, Xiao; Yang, Kai; Zheng, Xiangyi; Xie, Liping

doi:10.1096/fj.201800667r

Cited by 64 publications

(50 citation statements)

References 36 publications

(55 reference statements)

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“…et al, miR-433 in the DLK1-DIO3 domain was also confirmed to be downregulated by upstream DNA methylation [16]. Recently, our team revealed that miR-381-3p, which is neighboring miR-300 in DLK-DIO3 imprinted domain, was also downregulated in BCa because of the hypermethylated status [37]. To clarify why miR-300 is downregulated in bladder cancer, we treated UM-UC3 cells with the demethylation agent 5-aza-CdR, and an obvious upregulation of the miR-300 expression level was detected.…”

Section: Discussionmentioning

confidence: 77%

MIR-300 in the imprinted DLK1-DIO3 domain suppresses the migration of bladder cancer by regulating the SP1/MMP9 pathway

Yan

Ying

et al. 2018

Cell Cycle

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Emerging research has suggested that miRNAs play a significant role in oncogenesis and tumor progression by regulating multiple molecular pathways. Here, we investigated miR-300, which inhibited bladder cancer (BCa) migration by regulating the SP1/MMP9 pathway. miR-300, belonging to the DLK1-DIO3 miRNA cluster, is frequently expressed at lower levels in BCa tissue than in adjacent normal tissue due to DNA methylation. Reinforced expression of miR-300 significantly suppressed the migration of BCa cells. We carried out a search of online databases to predict potential targets of miR-300. Further studies determined that miR-300 directly targeted SP1 and suppressed its expression by specifically binding to its 3ʹ-untranslated region. Meanwhile, downregulated MMP9 may be the final effector of BCa cell mobility. Small interference RNAs silencing SP1 phenocopied the effects of miR-300 overexpression, while restoration of SP1 expression partially rescued the inhibition of metastasis induced by miR-300 overexpression in BCa cells. In conclusion, we unveiled a miR-300/SP1/MMP9 pathway in BCa. These findings demonstrate that miR-300 is a promising tumor suppressor in BCa. ARTICLE HISTORY

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Section: Discussionmentioning

confidence: 77%

MIR-300 in the imprinted DLK1-DIO3 domain suppresses the migration of bladder cancer by regulating the SP1/MMP9 pathway

Yan

Ying

et al. 2018

Cell Cycle

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“…The results of miRNA analysis showed that CCNA2 , AURKA and UBE2C were potential target genes shared by mir-300 and mir-381-3p . Prior studies have shown that the expression of mir-300 and mir-381-3p in gastric cancer, thyroid cancer, osteosarcoma and other tumors is disordered[52–55]. Although the mechanisms of mir-300 and mir-381-3p in HCC are not clear, we hypothesize that mir-300 and mir-381-3p may alter the cell cycle by regulating CCNA2 , AURKA and UBE2C , thereby promoting the proliferation of liver cancer cells.…”

Section: Disscusionmentioning

confidence: 78%

Identification of differentially expressed genes in hepatocellular carcinoma by integrated bioinformatic analysis

Yan

2019

Preprint

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31Hepatocellular carcinoma is one of the most common tumors in the world 32 and has a high mortality rate. This study elucidates the mechanism of hepatocellular 33 carcinoma-(HCC) related development. The HCC gene expression profile 34 (GSE54238, GSE84004) was downloaded from Gene Expression Omnibus for 35 comprehensive analysis. A total of 359 genes were identified, of which 195 were 36 upregulated and 164 were downregulated. Analysis of the condensed results showed 37 that "extracellular allotrope" is a substantially enriched term. "Cell cycle", "metabolic 38 pathway" and "DNA replication" are three significantly enriched Kyoto Encyclopedia 39 of Genes and Genomespathways. Subsequently, a protein-protein interaction network 40 was constructed. The most important module in the protein-protein interaction 41 network was selected for path enrichment analysis. The results showed that CCNA2, 42 PLK1, CDC20, UBE2C and AURKA were identified as central genes, and the 43 expression of these five hub genes in liver cancer was significantly increased in The 44 Cancer Genome Atlas. Univariate regression analysis was also performed to show that 45 the overall survival and disease-free survival of patients in the high expression group 46 were longer than in the expression group. In addition, genes in important modules are 47 mainly involved in "cell cycle", "DNA replication" and "oocyte meiosis" signaling 48 pathways. Finally, through upstream miRNA analysis, mir-300 and mir-381-3p were 49 found to coregulate CCNA2,AURKA and UBE2C. These results provide a set of 50 targets that can help researchers to further elucidate the underlying mechanism of 51 liver cancer. 3 52 53 Key Words HCC;GEO;TCGA;DEGs;bioinformatic analysis; 54 55 1. Introduction 56 Liver cancer is one of the most common cancers in the world, and mainly 57 includes three different pathological types comprising hepatocellular carcinoma 58 (HCC), intrahepatic bile duct (ICC) and HCC-ICC hybrid types, among which HCC 59accounts for 85% to 90% of all HCCs.The incidence and mortality of HCC increase 60 with age, and the incidence of HCC is about three times higher in men than in 61 women[1]. Although HCC treatment has made great progress in recent years, the 62 5-year survival rate of HCC patients is still <25%[2]. Therefore, more research are 63 needed to understand the molecular mechanisms of HCC development and 64 progression, which is important to develop more effective diagnostics and treatments. 65 66 At present, gene microarray technology has been widely used to collect 67 gene chip expression profiling data and to study gene expression profiles in many 68 human cancers. A large amount of data has been published in public database 69 platforms, and researchers have integrated these databases to find valuable 70 information about cancer pathogenesis. Lau et al. identified approximately 4,000 71 genes in 10 pairs of HCC and non-tumor tissues by microarray technology[3].Zhou et 72 al. analyzed the mRNA expression profiles of a large number of human HCC 73 spe...

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“…14 Recent studies have suggested that miR-381-3p level was decreased in several cancers and overexpression of miR-381-3p inhibited cell proliferation and metastasis, and induced cell cycle arrest and apoptosis. [15][16][17][18][19] However, the functions and mechanisms of miR-381-3p in NPC are still unclear. In our study, miR-381-3p was observed to be down-regulated in NPC.…”

Section: Discussionmentioning

confidence: 99%

<p>Long Non-Coding RNA DLEU1 Up-Regulates BIRC6 Expression by Competitively Sponging miR-381-3p to Promote Cisplatin Resistance in Nasopharyngeal Carcinoma</p>

Li¹,

Huang²,

Yu³

et al. 2020

OTT

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Background: Cisplatin (DDP) resistance has become an obstacle to chemotherapy for nasopharyngeal carcinoma (NPC) patients. Recent evidences indicate that long noncoding RNAs (lncRNAs) are involved in tumorigenesis and chemoresistance. However, the potential role of lncRNAs in NPC progression remains largely unknown. Methods: First, lncRNA expression profiling in NPC was performed via microarray analysis. To explore the involvement of DLEU1 in DDP resistance, loss-of-function experiments were employed in vitro and in vivo. Bioinformatics analysis, luciferase reporter assay, qRT-PCR, and Western blot assays were used to investigate the underlying mechanisms. Results: Here, we identified 153 differentially expressed lncRNAs. Among them, DLEU1 was remarkably up-regulated in NPC tissues and associated with worse outcome. Knockdown of DLEU1 could sensitize NPC cells to DDP in vitro and in vivo. Further investigations revealed that DLEU1 positively regulated BIRC6 expression via its competing endogenous RNA (ceRNA) activity on miR-381-3p. We also observed that BIRC6 overexpression or miR-381-3p silence could significantly reverse DLEU1-dependent DDP resistance. Conclusion: Our data suggest that DLEU1 acts as an oncogene to promote DDP resistance and BIRC6 expression in NPC through interacting with miR-381-3p, which may help to develop new strategy against NPC chemoresistance.

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Dual regulatory role of CCNA2 in modulating CDK6 and MET‐mediated cell‐cycle pathway and EMT progression is blocked by miR‐381‐3p in bladder cancer

Cited by 64 publications

References 36 publications

MIR-300 in the imprinted DLK1-DIO3 domain suppresses the migration of bladder cancer by regulating the SP1/MMP9 pathway

MIR-300 in the imprinted DLK1-DIO3 domain suppresses the migration of bladder cancer by regulating the SP1/MMP9 pathway

Identification of differentially expressed genes in hepatocellular carcinoma by integrated bioinformatic analysis

<p>Long Non-Coding RNA DLEU1 Up-Regulates BIRC6 Expression by Competitively Sponging miR-381-3p to Promote Cisplatin Resistance in Nasopharyngeal Carcinoma</p>

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