Targeting PPM1D by lentivirus-mediated RNA interference inhibits the tumorigenicity of bladder cancer cells

Wang, W.; Zhu, Hongguang; Zhang, H.; Zhang, L.; Ding, Qiang; Jiang, H.

doi:10.1590/1414-431x20143645

Cited by 13 publications

(8 citation statements)

References 29 publications

(34 reference statements)

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“…The top 30 up-regulated and down-regulated candidate genes were listed in Table 1 and 2, respectively. Among these candidates, there are several notable features: 1) some nuclear small RNA transcripts such as RN7SK, RNU1G2, RNU1–5, RNU1–3 and RNU1A3 are highly up-regulated, which has also been observed in c-MET inhibitor treated KSHV+ PEL tumor cells in spite of unknown mechanisms or functions (20); 2) multiple Metallothionein genes such as MTE, MT1F/E/G and MT2A are significantly up-regulated, and they have been shown to be increased during oxidative stress (21, 22) to protect the cells against cytotoxicity (23, 24), radiation and DNA damage (25, 26), and be increased in a variety of human tumors (27); 3) some genes have been reported related to tumor cell proliferation, such as PPM1D , silencing of which by RNAi inhibits lung cancer cells proliferation and the tumorigenicity of bladder cancer cells, respectively (28, 29). However, we found that the functional role of most genes listed here remains unclear for KSHV pathogenesis or tumorigenicity, which requires further investigation.…”

Section: Resultsmentioning

confidence: 99%

ABC294640, A Novel Sphingosine Kinase 2 Inhibitor, Induces Oncogenic Virus–Infected Cell Autophagic Death and Represses Tumor Growth

Dai

Bai

Smith

et al. 2017

Molecular Cancer Therapeutics

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Kaposi’s Sarcoma-associated herpesvirus (KSHV) is the etiologic agent of several malignancies, including Kaposi’s Sarcoma (KS) and primary effusion lymphoma (PEL), which preferentially arise in HIV+ patients and lack effective treatment. Sphingosine kinase 2 (SphK2) is a key factor within sphingolipid metabolism, responsible for the conversion of pro-apoptotic ceramides to anti-apoptotic sphingosine-1-phosphate (S1P). We have previously demonstrated that targeting SphK2 using a novel selective inhibitor, ABC294640, leads to the accumulation of intracellular ceramides and induces apoptosis in KSHV-infected primary endothelial cells and PEL tumor cells but not in uninfected cells. In the current study, we found that ABC294640 induces autophagic death instead of apoptosis in a KSHV long-term-infected immortalized endothelial cell-line, TIVE-LTC, but not in uninfected TIVE cells, through the up-regulation of LC3B protein. Transcriptomic analysis indicates that many genes related to cellular stress responses, cell cycle/proliferation, and cellular metabolic process are altered in TIVE-LTC exposed to ABC294640. One of the candidates, Egr-1, was found to directly regulate LC3B expression and required for the ABC294640-induced autophagic death. By using a KS-like nude mice model with TIVE-LTC, we found that ABC294640 treatment significantly suppressed KSHV-induced tumor growth in vivo, which indicates that targeting sphingolipid metabolism especially SphK2 may represent a promising therapeutic strategy against KSHV-related malignancies.

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Section: Resultsmentioning

confidence: 99%

ABC294640, A Novel Sphingosine Kinase 2 Inhibitor, Induces Oncogenic Virus–Infected Cell Autophagic Death and Represses Tumor Growth

Dai

Bai

Smith

et al. 2017

Molecular Cancer Therapeutics

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“…PPM1D is a stress-responsive PP2C phosphatase that plays a key role in stress signaling (35). In addition, it was suggested that PPM1D is associated with carcinogenesis (36,37). It negatively regulates the DNA damage response through the dephosphorylation and inactivation of p53, ataxia telangiectasia mutated, p38 and checkpoint kinase 1/2 (38).…”

Section: Discussionmentioning

confidence: 99%

Cisplatin induces HepG2 cell cycle arrest through targeting specific long noncoding RNAs and the p53 signaling pathway

et al. 2016

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Cisplatin has been used effectively in the treatment of hepatocellular carcinoma (HCC). Long noncoding RNAs (lncRNAs) were recently reported to contribute to the pathogenesis and progression of HCC. Their molecular mechanism related to cisplatin treatment remains unclear. The purpose of this study is to identify specific lncRNAs and to clarify their functions in HCC after cisplatin exposure. Reannotation and identification of differentially expressed lncRNAs were performed using the microarray data set GSE38122 in the Gene Expression Omnibus database. Four significantly differentially expressed lncRNAs (RP11-134G8.8, RP11-612B6.2, RP11-363E7.4 and RP1-193H18.2) were identified in HepG2 cells exposed to cisplatin by bioinformatics methods. The upregulated RP11-134G8.8 and RP11-363E7.4 and the downregulated RP1-193H18.2 were confirmed by reverse transcription-quantitative polymerase chain reaction. Furthermore, 57 significant co-expressing genes and their corresponding pathways were annotated and identified. The p53 signaling pathway showed the most significant difference among all pathways. Based on these results, the cell cycle and three key genes, cyclin-dependent kinase inhibitor 1A (CDKN1A, also known as p21), tumor protein p53 inducible protein 3 (TP53I3) and wild-type p53-induced phosphatase 1 (Wip1, also known as PPM1D), were examined. CDKN1A, TP53I3 and PPM1D were all downregulated by RP1-193H18.2 but upregulated by RP11-134G8.8 and RP11-363E7.4. And obvious S phase arrest was induced by cisplatin treatment for 24 h in HepG2 cells. Finally, the immunofluorescence results showed upregulation of TP53I3 and Wip1 and downregulation of p21 at the protein level. The results suggested that the lncRNAs RP11-134G8.8, RP11-363E7.4 and RP1-193H18.2, and their co-expression genes, which annotated into the p53 signaling pathway, could be potential targets for cisplatin treatment.

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“…Wang et al (53) demonstrated that RNA Figure 1. Targets and functional consequences of Wip1 signaling.…”

Section: Wip1 In Bladder Cancermentioning

confidence: 99%

Role of wild-type p53-induced phosphatase 1 in cancer

2017

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Abstract. Wild-type p53-induced phosphatase (Wip1) is a member of the protein phosphatase type 2C family and is an established oncogene due to its dephosphorylation of several tumor suppressors and negative control of the DNA damage response system. It has been reported to dephosphorylate p53, ataxia telangiectasia mutated, checkpoint kinase 1 and p38 mitogen activated protein kinases, forming negative feedback loops to inhibit apoptosis and cell cycle arrest. Wip1 serves a major role in tumorigenesis, progression, invasion, distant metastasis and apoptosis in various types of human cancer. Therefore, it may be a potential biomarker and therapeutic target in the diagnosis and treatment of cancer. Furthermore, previous evidence has revealed a new role for Wip1 in the regulation of chemotherapy resistance. In the present review, the current knowledge on the role of Wip1 in cancer is discussed, as well as its potential as a novel target for cancer treatment and its function in chemotherapy resistance.

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Targeting PPM1D by lentivirus-mediated RNA interference inhibits the tumorigenicity of bladder cancer cells

Cited by 13 publications

References 29 publications

ABC294640, A Novel Sphingosine Kinase 2 Inhibitor, Induces Oncogenic Virus–Infected Cell Autophagic Death and Represses Tumor Growth

ABC294640, A Novel Sphingosine Kinase 2 Inhibitor, Induces Oncogenic Virus–Infected Cell Autophagic Death and Represses Tumor Growth

Cisplatin induces HepG2 cell cycle arrest through targeting specific long noncoding RNAs and the p53 signaling pathway

Role of wild-type p53-induced phosphatase 1 in cancer

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