Dataset Information

CTB-193M12.5 Promotes Hepatocellular Carcinoma Progression via Enhancing NSD1-Mediated WNT10B/Wnt/β-Catenin Signaling Activation.

ABSTRACT:

Background

Hepatocellular 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.

Methods

CTB-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.

Results

We 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.

Conclusion

CTB-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.

SUBMITTER: Zhang S

PROVIDER: S-EPMC9188405 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Publications

CTB-193M12.5 Promotes Hepatocellular Carcinoma Progression via Enhancing NSD1-Mediated WNT10B/Wnt/β-Catenin Signaling Activation.

Zhang Shuhua S Jiang Mi M Cao Huan H Xiong Jun J Xu Jianqun J

Journal of hepatocellular carcinoma 20220607

<h4>Background</h4>Hepatocellular 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.<h4>Methods</h4>CTB-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 ...[more]

PMID: 35698644

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Project description:BackgroundHepatocellular carcinoma is a widespread cancer worldwide, ranking as the fifth most frequent cancer and the fourth leading cause of cancer-related deaths. According to comprehensive research, TLK2, a phosphorylated kinase, has been discovered to play a crucial role in promoting tumor development. However, the prognostic significance and influence of TLK2 on hepatocellular carcinoma tumor cells and the immune microenvironment remain unexplored, warranting further investigation. The aim of this study was to investigate the role of TLK2 in promoting the development of hepatocellular carcinoma.MethodsThe present study utilized The Cancer Genome Atlas (TCGA) database and other databases as training sets to examine the expression of TLK2 and its prognostic significance. The findings were subsequently validated through cell proliferation assays and cell colony assays. Gene set enrichment analysis (GSEA) was employed to investigate the tumor-related biological processes associated with TLK2 in hepatocellular carcinoma, while the relationship between TLK2 expression and Wnt/β-catenin signaling pathway was analyzed via TCGA dataset analysis. Western blotting and immunofluorescence assays were used to confirm the experimental results.ResultsTLK2 showed higher expression levels in tumor tissues than in normal tissues. Alpha fetoprotein (AFP), T stage, pathological stage, and histological grade were significantly associated with TLK2 expression. High TLK2 expression correlated with worse overall survival (OS) [hazard ratio (HR) =1.62, 95% confidence interval (CI): 1.14-2.29, P=0.007], progression-free survival (PFS) (HR =1.88, 95% CI: 1.40-2.52, P<0.001) and disease specific survival (DSS) (HR =1.86, 95% CI: 1.18-2.93, P=0.007) in the training and validation sets. Both univariate and multivariate analyses showed that TLK2 was an independent prognostic factor. GSEA showed that TLK2 was significantly enriched in tumor-related biological processes. TLK2 induced the activation of β-catenin signaling, resulting in sustained tumor growth. Methyl thiazolyl tetrazolium (MTT) and colony formation assays demonstrated that TLK2 could promote hepatocellular carcinoma progression. Furthermore, TLK2 showed a significant association with β-catenin in the Wnt pathway.ConclusionsTLK2 represents an independent prognostic factor in hepatocellular carcinoma and can promote cancer progression via the β-catenin signaling pathway.

Project description:Hepatocellular carcinoma (HCC) is one of the most lethal malignancies with extremely poor prognosis. Therefore, revealing the critical molecules involved in HCC progression and prognosis is urgently needed. In this study, through combining public dataset and our cohort, we found a novel prognosis-related long non-coding RNA KB-68A7.1 in HCC. KB-68A7.1 was lowly expressed in HCC, whose low expression was associated with large tumour size, aggressive clinical characteristic, and poor survival. Gain- and loss-of-function assays demonstrated that KB-68A7.1 restricted HCC cellular proliferation, induced HCC cellular apoptosis, and suppressed HCC cellular migration and invasion in vitro. Xenograft assays demonstrated that KB-68A7.1 suppressed HCC tumour growth and metastasis in vivo. These functional assays suggested KB-68A7.1 as a tumour suppressor in HCC. Histone methyltransferase nuclear receptor binding SET domain-containing protein 1 (NSD1) was found to bind to KB-68A7.1. KB-68A7.1 was mainly distributed in the cytoplasm. The binding of KB-68A7.1 to NSD1 sequestrated NSD1 in the cytoplasm, leading to the reduction in nuclear NSD1 level. Through decreasing nuclear NSD1 level, KB-68A7.1 reduced di-methylation of histone H3 at lysine 36 (H3K36me2) and increased tri-methylation of histone H3 at lysine 27 (H3K27me3) at the promoter of WNT10B, a target of NSD1. Thus, KB-68A7.1 repressed WNT10B transcription. The expression of WNT10B was negatively correlated with that of KB-68A7.1 in HCC tissues. Through repressing WNT10B, KB-68A7.1 further repressed Wnt/β-catenin signalling. Functional rescue assays showed that overexpression of WNT10B reversed the tumour-suppressive roles of KB-68A7.1, whereas the oncogenic roles of KB-68A7.1 depletion were abolished by Wnt/β-catenin signalling inhibitor. Overall, this study identified KB-68A7.1 as a lowly expressed and prognosis-related lncRNA in HCC, which suppressed HCC progression through binding to NSD1 and repressing Wnt/β-catenin signalling.

Dataset Information

CTB-193M12.5 Promotes Hepatocellular Carcinoma Progression via Enhancing NSD1-Mediated WNT10B/Wnt/β-Catenin Signaling Activation.

Background

Methods

Results

Conclusion

Publications

CTB-193M12.5 Promotes Hepatocellular Carcinoma Progression via Enhancing NSD1-Mediated WNT10B/Wnt/β-Catenin Signaling Activation.

Similar Datasets

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