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VRK1 promotes cisplatin resistance by up-regulating c-MYC via c-Jun activation and serves as a therapeutic target in esophageal squamous cell carcinoma.

ABSTRACT: Esophageal squamous cell carcinoma (ESCC) is a common malignant disease characterized by poor prognosis. Chemoresistance remains a major cause of ESCC relapse. Vaccinia-related kinase 1 (VRK1) has previously been identified as a cancer-related gene. However, there is little research demonstrating an association between VRK1 and ESCC. In this study, we show that VRK1 is overexpressed in ESCC primary tumor samples and cell lines. VRK1 expression was significantly correlated with clinical characteristics and predicted poor outcomes in ESCC patients. Functionally, knockdown of VRK1 inhibited ESCC cell proliferation, survival, migration and invasion; conversely, VRK1 overexpression produced the opposite effects. Furthermore, we found that up-regulation of VRK1 promoted cisplatin (CDDP) resistance in ESCC both in vitro and in vivo, whereas knockdown of VRK1 reduced this resistance. Further studies verified that VRK1 phosphorylated c-Jun and that the VRK1/c-Jun pathway contributed to CDDP resistance in ESCC. Mechanistically, a dual luciferase reporter assay revealed that c-Jun transcriptionally activated the expression of c-MYC. Silencing c-MYC abolished the c-Jun-mediated CDDP resistance of ESCC cells. A Kaplan-Meier analysis indicated that c-MYC is a potential prognostic factor in ESCC. Finally, luteolin, a VRK1 inhibitor, attenuated the malignant biological behaviors and CDDP resistance in ESCC cells. Collectively, we conclude that VRK1 promotes CDDP resistance through c-MYC by activating c-Jun and potentiating a malignant phenotype in ESCC. Our studies provide novel insight into the role of VRK1 in carcinogenesis and indicate that VRK1 can serve as a potential therapeutic target in ESCC.

SUBMITTER: Liu ZC

PROVIDER: S-EPMC5630360 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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VRK1 promotes cisplatin resistance by up-regulating c-MYC via c-Jun activation and serves as a therapeutic target in esophageal squamous cell carcinoma.

Liu Zhen-Chuan ZC Cao Kuo K Xiao Zhao-Hua ZH Qiao Liang L Wang Xue-Qing XQ Shang Bin B Jia Yang Y Wang Zhou Z

Oncotarget 20170807 39

Esophageal squamous cell carcinoma (ESCC) is a common malignant disease characterized by poor prognosis. Chemoresistance remains a major cause of ESCC relapse. Vaccinia-related kinase 1 (VRK1) has previously been identified as a cancer-related gene. However, there is little research demonstrating an association between VRK1 and ESCC. In this study, we show that VRK1 is overexpressed in ESCC primary tumor samples and cell lines. VRK1 expression was significantly correlated with clinical character ...[more]

PMID: 29029460

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Project description:BackgroundAbnormal expression of numerous long non-coding RNAs (lncRNAs) has been reported in esophageal squamous cell carcinoma (ESCC) recently, but the great majority of their roles and mechanisms remain largely unclear. We aim to identify the critical ESCC-associated lncRNAs and elucidate the functions and mechanisms in detail.MethodsMicroarrays were used to analyze the differentially expressed lncRNAs in ESCC tissues. qRT-PCR was used to verify the result of microarrays. The effects of the most up-regulated lncRNA, cancer susceptibility candidate 9(CASC9), on cell growth, proliferation and cell cycle were investigated by in vivo and in vitro assays. Microarrays and recovery tests were used to discover the regulatory targets of CASC9. RNA FISH and subcellular fractionation assays were used to detect the subcellular location of CASC9. Finally, the mechanism of CASC9 regulating PDCD4 was explored by RIP, RNA-protein pull down and ChIP assays.ResultsESCC tissue microarrays showed that CASC9 was the most up-regulated lncRNA. qRT-PCR analysis indicated that CASC9 expression was positively associated with tumor size and TNM stage, and predicted poor overall survival of ESCC patients. Knockdown of CASC9 inhibited ESCC cell growth in vitro and tumorigenesis in nude mice. Furthermore interfering CASC9 decreased cell proliferation and blocked cell cycle G1/S transition. CASC9-associated microarrays indicated that PDCD4 might be the target of CASC9. Consistent with this, PDCD4 expression was negatively associated with CASC9 expression in ESCC tissues and predicted good prognosis. Manipulating CASC9 expression in ESCC cells altered both PDCD4 mRNA and protein levels and cell cycle arrest caused by CASC9 knockdown could be rescued by suppressing PDCD4 expression. CASC9 located both in the nucleus and cytoplasm. Mechanistically, enhancer of zeste homolog2 (EZH2) could bind to both CASC9 and PDCD4 promoter region. Interfering CASC9 reduced the enrichment of EZH2 and H3K27me3 in the PDCD4 promoter region.ConclusionsOur study firstly demonstrates that lncRNA CASC9 functions as an oncogene by negatively regulating PDCD4 expression through recruiting EZH2 and subsequently altering H3K27me3 level. Our study implicates lncRNA CASC9 as a valuable biomarker for ESCC diagnosis and prognosis.

Project description:BackgroundEsophageal squamous cell carcinoma (ESCC) is one of the most prevalent gastrointestinal malignancies with high mortality. Circular RNAs (CircRNAs) have become a research hotspot in recent years for their vital roles in cancer development and progression. This study aims to clarify the roles of circNTRK2 and its underlying molecular mechanisms in ESCC.MethodsThe levels of circNTRK2, miR-140-3p, and nuclear receptor-interacting protein 1 (NRIP1) mRNA were examined by qRT-PCR. The cell proliferation ability was detected via CCK-8, EdU and colony formation assays. The invasion capacity was tested by using transwell assay. The apoptotic rate was evaluated through flow cytometry. The protein levels of cleaved PARP, cleaved caspase-3, E-cadherin, vimentin, and NRIP1 were measured by western blot assay. The validation of circular structure was performed by Sanger sequencing, divergent primer PCR, and RNase R treatments. The ceRNA regulatory mechanism of circNTRK2 was observed via dual-luciferase reporter, RIP and RNA pull-down assays. The mice xenograft models were constructed to confirm the oncogenicity of circNTRK2 in ESCC in vivo.ResultsCircNTRK2 was highly expressed in ESCC tissues and cells. High expression of circNTRK2 was correlated with advanced TNM stage, lymph node metastasis and short survival. Knockdown of circNTRK2 inhibited ESCC cell proliferation, invasion and epithelial-mesenchymal transition (EMT), and accelerated apoptosis in vitro. Mechanistic assays disclosed that circNTRK2 could act as a sponge for miR-140-3p to abate its suppression on target NRIP1 expression. Moreover, miR-140-3p-induced inhibitory effects on ESCC cell malignant phenotypes were attenuated by the overexpression of circNTRK2. In addition, depletion of NRIP1 impeded cell proliferation, invasion and EMT, while enhanced apoptosis. Furthermore, silencing of circNTRK2 suppressed cell proliferation and invasion through regulating NRIP1 expression. Also, knockdown of circNTRK2 slowed ESCC tumor growth in vivo.ConclusionCircNTRK2 promoted ESCC progression by regulating miR-140-3p/NRIP1 pathway. Our findings contribute to a better understanding of circRNAs as miRNA sponges and highlight a promising therapy target in ESCC.

Dataset Information

VRK1 promotes cisplatin resistance by up-regulating c-MYC via c-Jun activation and serves as a therapeutic target in esophageal squamous cell carcinoma.

Publications

VRK1 promotes cisplatin resistance by up-regulating c-MYC via c-Jun activation and serves as a therapeutic target in esophageal squamous cell carcinoma.

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