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DGK? Plays Crucial Roles in the Proliferation and Tumorigenicity of Human glioblastoma.

ABSTRACT: Glioblastoma is one of the most malignant brain cancers in adults, and it is a fatal disease because of its untimely pathogenetic location detection, infiltrative growth, and unfavorable prognosis. Unfortunately, multimodal treatment with maximal safe resection, chemotherapy and radiation has not increased the survival rate of patients with glioblastoma. Gene- and molecular-targeted therapy is considered to be a promising anticancer strategy for glioblastoma. The identification of novel potential targets in glioblastoma is of high importance. In this study, we found that both the mRNA and protein levels of diacylglycerol kinase ? (DGK?) were significantly higher in glioblastoma tissues than in precancerous lesions. The silencing of DGK? by lentivirus-delivered shRNA reduced glioblastoma cell proliferation and induced G0/G1 phase arrest. Moreover, knockdown of DGK? expression in U251 cells markedly reduced in vitro colony formation and in vivo tumorigenic capability. Further study showed that DGK? inhibition resulted in decreases in cyclin D1, p-AKT and p-mTOR. Moreover, the rescue or overexpression of DGK? in glioblastoma cells demonstrated the oncogenic function of DGK?. In conclusion, these studies suggest that the suppression of DGK? may inhibit the tumor growth of glioblastoma cells with high DGK? expression. Thus, DGK? might be a potential therapeutic target in malignant glioblastoma.

SUBMITTER: Gu X

PROVIDER: S-EPMC6743304 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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DGKζ Plays Crucial Roles in the Proliferation and Tumorigenicity of Human glioblastoma.

Gu Xuefeng X Wan Guoqing G Chen Nianhong N Li Jinhong J Chen Bing B Tang Yeling Y Gu Wangxian W Jin Cuiting C Meng Jihong J Zhang Peng P Liu Li L Yang Zhifang Z Lu Changlian C

International journal of biological sciences 20190720 9

Glioblastoma is one of the most malignant brain cancers in adults, and it is a fatal disease because of its untimely pathogenetic location detection, infiltrative growth, and unfavorable prognosis. Unfortunately, multimodal treatment with maximal safe resection, chemotherapy and radiation has not increased the survival rate of patients with glioblastoma. Gene- and molecular-targeted therapy is considered to be a promising anticancer strategy for glioblastoma. The identification of novel potentia ...[more]

PMID: 31523189

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Project description:BackgroundGlioblastoma is devastating cancer with a high frequency of occurrence and poor survival rate and it is urgent to discover novel glioblastoma-specific antigens for the therapy. Cancer-germline genes are known to be related to the formation and progression of several cancer types by promoting tumor transformation. Dazl is one such germline gene and is up-regulated in a few germ cell cancers. In this study, we analyzed the expression of Dazl in human glioblastoma tissues and cells, and investigated its significance in proliferation, migration, invasion and chemoresistance of the glioblastoma cell lines.MethodsWe evaluated the expression of Dazl in different pathologic grades of glioblastoma tissues by immunohistochemistry. We assessed the expression of Dazl in glioblastoma cells and normal human astrocytes (NHA) cells by western blotting and RT-qPCR. Then we generated Dazl knockout glioblastoma cell lines using the CRISPR/Cas9 gene-editing technology to explore the cellular function of Dazl. We detected the proliferation and germline traits via CCK-8 assays and alkaline phosphatase staining, respectively. Boyden chamber assays were performed to measure glioblastoma cell migration and invasion. Crystal violet staining was used to determine the number of viable cells after the treatment of Doxorubicin and Temozolomide. Finally, we used subcutaneous xenograft studies to measure the growth of tumors in vivo.ResultsWe found that Dazl was upregulated in glioblastoma tissues and glioblastoma cell lines. Dazl knockdown glioblastoma cells showed decreased cellular proliferation, migration, invasion, and resistance in vitro, and inhibited the initiation of glioblastoma in vivo. The glioblastoma cell lines A172, U251, and LN229 were found to express stem cell markers CD133, Oct4, Nanog, and Sox2. The expression of these markers was downregulated in Dazl-deficient cells.ConclusionsOur results indicated that Dazl contributes to the tumorigenicity of glioblastoma via reducing cell stemness. Therefore, cancer-germline genes might represent a new paradigm of glioblastoma-initiating cells in the treatment of malignant tumors.

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DGK? Plays Crucial Roles in the Proliferation and Tumorigenicity of Human glioblastoma.

Publications

DGKζ Plays Crucial Roles in the Proliferation and Tumorigenicity of Human glioblastoma.

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