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Tumor necrosis factor ? knockout impaired tumorigenesis in chronic myeloid leukemia cells partly by metabolism modification and miRNA regulation.

ABSTRACT: Purpose:Half of the chronic myeloid leukemia (CML) patients with sustained deep molecular response suffer from relapse after discontinuation mainly because tyrosine kinase inhibitors (TKIs) cannot eradicate leukemia stem cells (LSCs). In addition, tumor necrosis factor ? (TNF-?) is highly detected in CML patients. Our aim was to explore whether TNF-? is a potential target for LSC elimination. Materials and methods:We applied a CRISPR/Cas9 gene editing technique, colony-forming cell assay, subcutaneous tumor models, miRNA-seq and liquid chromatography-mass spectroscopy (LC-MS) on metabonomics to explore the feasibility and mechanism of TNF-? as a new therapeutic target for CML. Results:We demonstrated that TNF-? knockout remarkably decreased the proliferative, colony-forming and in vivo tumorigenesis capacities of the CML K562 cell line. The apoptosis was increased when TNF-? knockout cells were cultured with imatinib. The mechanisms involved in the abovementioned phenomena were that TNF-? knockout inhibited the citrate cycle and increased starch, sucrose, amino sugar and nucleotide sugar metabolism. In addition, differentially expressed miRNAs between TNF-? knockout and control cells were involved in the cell cycle, CML, P13K-Akt and pathways in cancer. Conclusion:We identified that TNF-? may serve as a new target therapy for CML and described the metabolic pathways associated with TNF-? in CML cells for the first time.

SUBMITTER: Shen N

PROVIDER: S-EPMC6446984 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Tumor necrosis factor α knockout impaired tumorigenesis in chronic myeloid leukemia cells partly by metabolism modification and miRNA regulation.

Shen Na N Liu Songya S Cui Jieke J Li Qing Q You Yong Y Zhong Zhaodong Z Cheng Fanjun F Guo An-Yuan AY Zou Ping P Yuan Guolin G Zhu Xiaojian X

OncoTargets and therapy 20190329

<h4>Purpose</h4>Half of the chronic myeloid leukemia (CML) patients with sustained deep molecular response suffer from relapse after discontinuation mainly because tyrosine kinase inhibitors (TKIs) cannot eradicate leukemia stem cells (LSCs). In addition, tumor necrosis factor α (TNF-α) is highly detected in CML patients. Our aim was to explore whether TNF-α is a potential target for LSC elimination.<h4>Materials and methods</h4>We applied a CRISPR/Cas9 gene editing technique, colony-forming cel ...[more]

PMID: 31015764

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Project description:BackgroundMicroRNAs (miRNAs) are important regulators involved in diverse physiological and pathological processes including cancer. SUMO (small ubiquitin-like modifier) is a reversible protein modifier. We recently found that SUMOylation of TARBP2 and DGCR8 is involved in the regulation of the miRNA pathway. KHSRP is a single stranded nucleic acid binding protein with roles in transcription and mRNA decay, and it is also a component of the Drosha-DGCR8 complex promoting the miRNA biogenesis.MethodsThe in vivo SUMOylation assay using the Ni2+-NTA affinity pulldown or immunoprecipitation (IP) and the in vitro E.coli-based SUMOylation assay were used to analyze SUMOylation of KHSRP. Nuclear/Cytosol fractionation assay and immunofluorescent staining were used to observe the localization of KHSRP. High-throughput miRNA sequencing, quantantive RT-PCR and RNA immunoprecipitation assay (RIP) were employed to determine the effects of KHSRP SUMO1 modification on the miRNA biogenesis. The soft-agar colony formation, migration, vasculogenic mimicry (VM) and three-dimensional (3D) cell culture assays were performed to detect the phenotypes of tumor cells in vitro, and the xenograft tumor model in mice was conducted to verify that SUMO1 modification of KHSRP regulated tumorigenesis in vivo.ResultsKHSRP is modified by SUMO1 at the major site K87, and this modification can be increased upon the microenvironmental hypoxia while reduced by the treatment with growth factors. SUMO1 modification of KHSRP inhibits its interaction with the pri-miRNA/Drosha-DGCR8 complex and probably increases its translocation from the nucleus to the cytoplasm. Consequently, SUMO1 modification of KHSRP impairs the processing step of pre-miRNAs from pri-miRNAs which especially harbor short G-rich stretches in their terminal loops (TL), resulting in the downregulation of a subset of TL-G-Rich miRNAs such as let-7 family and consequential tumorigenesis.ConclusionsOur data demonstrate how the miRNA biogenesis pathway is connected to tumorigenesis and cancer progression through the reversible SUMO1 modification of KHSRP.

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Tumor necrosis factor ? knockout impaired tumorigenesis in chronic myeloid leukemia cells partly by metabolism modification and miRNA regulation.

Publications

Tumor necrosis factor α knockout impaired tumorigenesis in chronic myeloid leukemia cells partly by metabolism modification and miRNA regulation.

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