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Epstein-Barr virus miR-BART3-3p promotes tumorigenesis by regulating the senescence pathway in gastric cancer.

ABSTRACT: Epstein-Barr virus-associated gastric cancer (EBVaGC) accounts for about 10% of all gastric cancer cases and has unique pathological and molecular characteristics. EBV encodes a large number of microRNAs, which actively participate in the development of EBV-related tumors. Here, we report that EBV-miR-BART3-3p (BART3-3p) promotes gastric cancer cell growth in vitro and in vivo Moreover, BART3-3p inhibits the senescence of gastric cancer cells induced by an oncogene (RAS^G12V) or chemotherapy (irinotecan). LMP1 and EBNA3C encoded by EBV have also been reported to have antisenescence effects; however, in EBVaGC specimens, LMP1 expression is very low, and EBNA3C is not expressed. BART3-3p inhibits senescence of gastric cancer cells in a nude mouse model and inhibits the infiltration of natural killer cells and macrophages in tumor by altering the senescence-associated secretory phenotype (SASP). Mechanistically, BART3-3p directly targeted the tumor suppressor gene TP53 and caused down-regulation of p53's downstream target, p21. Analysis from clinical EBVaGC samples also showed a negative correlation between BART3-3p and TP53 expression. It is well known that mutant oncogene RAS^G12V or chemotherapeutic drugs can induce senescence, and here we show that both RAS^G12V and a chemotherapy drug also can induce BART3-3p expression in EBV-positive gastric cancer cells, forming a feedback loop that keeps the EBVaGC senescence at a low level. Our results suggest that, although TP53 is seldom mutated in EBVaGC, its expression is finely regulated such that EBV-encoded BART3-3p may play an important role by inhibiting the senescence of gastric cancer cells.

SUBMITTER: Wang J

PROVIDER: S-EPMC6442059 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Epstein-Barr virus miR-BART3-3p promotes tumorigenesis by regulating the senescence pathway in gastric cancer.

Wang Jia J Zheng Xiang X Qin Zailong Z Wei Lingyu L Lu Yuanjun Y Peng Qiu Q Gao Yingxue Y Zhang Xuemei X Zhang Xiaoyue X Li Zhengshuo Z Fu Yuxin Y Liu Peishan P Liu Can C Yan Qun Q Xiong Wei W Li Guiyuan G Lu Jianhong J Ma Jian J

The Journal of biological chemistry 20190123 13

Epstein-Barr virus-associated gastric cancer (EBVaGC) accounts for about 10% of all gastric cancer cases and has unique pathological and molecular characteristics. EBV encodes a large number of microRNAs, which actively participate in the development of EBV-related tumors. Here, we report that EBV-miR-BART3-3p (BART3-3p) promotes gastric cancer cell growth in vitro and in vivo Moreover, BART3-3p inhibits the senescence of gastric cancer cells induced by an oncogene (RAS ...[more]

PMID: 30674552

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Project description:BackgroundLong noncoding RNA small nucleolar RNA host gene 16 (lncRNA SNHG16) has been revealed to be involved in the tumorigenesis of neuroblastoma. However, the role of SNHG16 in regulating cisplatin sensitivity in neuroblastoma remains largely unknown.MethodsThe expression of SNHG16, microRNA (miR)-338-3p and polo-like kinase 4 (PLK4) mRNA was measured using quantitative real-time polymerase chain reaction. The protein levels of PLK4, multidrug resistance protein 1 (MRP1), multidrug-resistance gene 1-type p-glycoprotein (P-gp) and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway-related proteins were detected by Western blot. The half maximal inhibitory concentration (IC50) value, cell proliferation, migration and invasion were analyzed using Cell Counting Kit-8 assays or Transwell assay. Apoptotic cells were measured by Flow cytometry. The interaction between miR-338-3p and SNHG16 or PLK4 was confirmed by dual-luciferase reporter and RNA immunoprecipitation assay. In vivo experiments were conducted through the murine xenograft model.ResultsSNHG16 was up-regulated, while miR-338-3p was down-regulated in cisplatin-resistant neuroblastoma tissues and cells. SNHG16 silencing weakened cisplatin resistance, reflected by the reduction of IC50 value, down-regulation of MRP-1 and P-gp protein expression, suppression of proliferation, migration and invasion, as well as enhancement of apoptosis in SNHG16 deletion cisplatin-resistant neuroblastoma cells. Besides that, SNHG16 could regulate PLK4 expression by sponging miR-338-3p and SNHG16/miR-338-3p/PLK4 axis could affect the activation of PI3K/AKT pathway in cisplatin-resistant neuroblastoma cells. MiR-338-3p inhibition attenuated SNHG16 deletion-mediated impairment on cisplatin resistance and PLK4 overexpression reversed the decrease of cisplatin-resistance induced by miR-338-3p re-expression. Furthermore, SNHG16 knockdown contributed to the anti-tumor effect of cisplatin in neuroblastoma in vivo.ConclusionSNHG16 contributed to the tumorigenesis and cisplatin resistance in neuroblastoma possibly through miR-338-3p/PLK4 pathway, indicating a novel insight for overcoming chemoresistance in neuroblastoma patients.

Project description:Epstein-Barr virus (EBV)-encoded miRNAs within the BamHI-A rightward transcript (BART) region are abundantly expressed in EBV-associated gastric cancer (EBVaGC), suggesting that they play roles in tumorigenesis. However, how these viral miRNAs contribute to the development of EBVaGC remains largely obscure. In this study, we found that EBV-encoded miR-BART11-3p targets 3' -UTR of dual-specificity phosphatase 6 (DUSP6) mRNA to upregulate ERK phosphorylation and downregulate JNK and p38 phosphorylation. By doing so, miR-BART11-3p promotes gastric cancer (GC) cell proliferation, migration, and invasion in vitro, and facilitates tumor growth in vivo. Restoration of DUSP6 expression reverses the tumor-promoting activity of miR-BART11-3p in AGS GC cells. Consistently, knockdown of DUSP6 ablates the antitumor effects of miR-BART11-3p inhibitors in EBV-positive GC cells. Furthermore, blocking ERK phosphorylation with trametinib inhibited the proliferation, migration, and invasion of miR-BART11-3p-expressing AGS cells. Administration of a miR-BART11-3p antagomir reduced the growth of EBV-positive xenograft tumors. Together, these findings reveal a novel mechanism by which EBV dysregulates MAPK pathways through an EBV-encoded microRNA to promote the development and progression of EBVaGC, which may be harnessed to develop new therapeutics to treat EBVaGC. IMPORTANCE The Epstein-Barr virus (EBV) is the first human tumor virus found to encode miRNAs, which within the BART region have been detected abundantly in EBV-associated gastric cancer (EBVaGC) and play various roles in promoting tumorigenesis. In our study, we observed that EBV-miR-BART11-3p promotes cell proliferation and induces migration and invasion in GC. Interestingly, we showed that miR-BART11-3p upregulates p-ERK and downregulates p-JNK and p-p38 by directly targeting 3'-UTR of dual-specificity phosphatase 6 (DUSP6). Restoration of DUSP6 rescues the effects generated by miR-BART11-3p in GC cells, and blocking ERK phosphorylation with Trametinib augments JNK and p38 phosphorylation and inhibits the effects of miR-BART11-3p-expressing AGS cells, suggesting that miR-BART11-3p promotes cell proliferation, migration, and invasion by modulating DUSP6-MAPK axis in EBVaGC. The findings presented in this study provide new mechanisms into the tumorigenesis in EBVaGC and new avenues for the development of therapeutic strategies to combat EBVaGC targeting miR-BART11-3p or phospho-ERK.

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Dataset Information

Epstein-Barr virus miR-BART3-3p promotes tumorigenesis by regulating the senescence pathway in gastric cancer.

Publications

Epstein-Barr virus miR-BART3-3p promotes tumorigenesis by regulating the senescence pathway in gastric cancer.

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