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BUB1B promotes hepatocellular carcinoma progression via activation of the mTORC1 signaling pathway.

ABSTRACT: BACKGROUND AND AIMS:Accumulating studies identified that BUB1 mitotic checkpoint serine/threonine kinase B (BUB1B) is integrally involved in the initiation and development of tumors. Nevertheless, the precise biological role and underlying mechanisms of BUB1B in hepatocellular carcinoma (HCC) remain indistinct. METHOD:To figure out the role of BUB1B in HCC, we first assessed its expression using The Cancer Genome Atlas (TCGA) and Gene Expression Profiling Interactive Analysis (GEPIA) databases. We then verified BUB1B expression in HCC tissues, nontumor tissues, and HCC cell lines through western blotting, quantitative reverse transcription-polymerase chain reaction, and immunohistochemistry. To explore the specific function of BUB1B in HCC in vivo and in vitro, we performed the flow cytometry, Cell Counting Kit-8, 5-ethynyl-2'-deoxyuridine incorporation, colony formation, Transwell, wound-healing, subcutaneous tumor growth, and metastasis assays. Additionally, we identified the BUB1B-regulated pathways involved in HCC by using gene set enrichment analysis. RESULTS:Our data displayed that higher BUB1B expression was detected in HCC tissues and HCC cell lines. The overexpression of BUB1B was positively correlated with adverse clinicopathological characteristics. Survival analyses showed that lower recurrence-free and overall survival rates were correlated with the overexpression of BUB1B in patients with HCC. Moreover, the malignancy of HCC was facilitated by BUB1B both in vivo and in vitro. Lastly, the results were confirmed by western blots, which showed that BUB1B upregulated mTORC1 signaling pathway in HCC. Meanwhile, the oncogenic effect of BUB1B will be impaired when the mTORC1 signaling pathway was inhibited by rapamycin. CONCLUSION:We highlighted that BUB1B played an oncogenic role in HCC and was identified as a possible clinical prognostic factor and a potential novel therapeutic target for HCC.

SUBMITTER: Qiu J

PROVIDER: S-EPMC7643650 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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BUB1B promotes hepatocellular carcinoma progression via activation of the mTORC1 signaling pathway.

Qiu Jiannan J Zhang Shaopeng S Wang Peng P Wang Hao H Sha Bowen B Peng Hao H Ju Zheng Z Rao Jianhua J Lu Ling L

Cancer medicine 20200925 21

<h4>Background and aims</h4>Accumulating studies identified that BUB1 mitotic checkpoint serine/threonine kinase B (BUB1B) is integrally involved in the initiation and development of tumors. Nevertheless, the precise biological role and underlying mechanisms of BUB1B in hepatocellular carcinoma (HCC) remain indistinct.<h4>Method</h4>To figure out the role of BUB1B in HCC, we first assessed its expression using The Cancer Genome Atlas (TCGA) and Gene Expression Profiling Interactive Analysis (GEP ...[more]

PMID: 32977361

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Project description:BackgroundHepatocellular carcinoma (HCC) is the second lethal malignancy among all cancers. Many molecular alterations have been found in HCC. However, the interactions and modulatory mechanisms among these molecules in HCC are still unclear.MethodsCTB-193M12.5 expression in tissues and cells were detected by quantitative polymerase chain reaction (qPCR). In vitro experiments were conducted to evaluate the function of CTB-193M12.5 in cell proliferation, apoptosis, migration and invasion. The interaction between CTB-193M12.5 and nuclear receptor binding SET domain-containing protein 1 (NSD1) was assessed by RNA-protein pull-down and RNA immunoprecipitation assays. The roles of CTB-193M12.5 on WNT10B and Wnt/β-catenin signaling was detected by chromatin immunoprecipitation assay, qPCR, Western blot, and dual luciferase reporter assay.ResultsWe identified a novel prognosis-related long noncoding RNA (lncRNA) CTB-193M12.5 in HCC. CTB-193M12.5 was upregulated in HCC and its high expression was correlated with alpha fetoprotein, large tumor size, aggressive clinical characteristics, and poor survival. Functional experiments showed that CTB-193M12.5 enhanced HCC cellular proliferation, suppressed HCC cellular apoptosis, and promoted HCC cellular migration and invasion. CTB-193M12.5 knockdown exerted opposite effects in HCC. Mechanistic investigation demonstrated that CTB-193M12.5 was mainly distributed in nucleus. Histone methyltransferase NSD1 was identified as a CTB-193M12.5 interactor. CTB-193M12.5 bound and recruited NSD1 to the promoter of WNT10B, leading to an increase in di-methylation of histone H3 at lysine 36 (H3K36me2) and the reduction of tri-methylation of histone H3 at lysine 27 (H3K27me3) at WNT10B promoter. Therefore, CTB-193M12.5 epigenetically activated WNT10B transcription. Through upregulating WNT10B, CTB-193M12.5 further activated Wnt/β-catenin signaling. Functional rescue experiments demonstrated that overexpression of WNT10B reversed the tumor suppressive roles of CTB-193M12.5 knockdown, while Wnt/β-catenin signaling inhibitor ICG-001 abolished the oncogenic roles of CTB-193M12.5 overexpression.ConclusionCTB-193M12.5 was a highly expressed and poor prognosis-related lncRNA in HCC. CTB-193M12.5 functioned as an oncogenic lncRNA through promoting NSD1-mediated WNT10B/Wnt/β-catenin signaling activation.

Dataset Information

BUB1B promotes hepatocellular carcinoma progression via activation of the mTORC1 signaling pathway.

Publications

BUB1B promotes hepatocellular carcinoma progression via activation of the mTORC1 signaling pathway.

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