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CircMAT2B facilitates the progression of head and neck squamous cell carcinoma via sponging miR-491-5p to trigger ASCT2-mediated glutaminolysis

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Abstract

Circular RNAs (circRNAs) are well-known to exert significant roles in regulating the pathological processes, including human carcinogenesis. Currently, less is known about their exact roles in head and neck squamous cell carcinoma (HNSCC). Herein, we aimed to investigate and validate the role of a novel circRNA, circMAT2B, as well as its potential molecular mechanism in HNSCC progression. A cohort of 41 paired of HNSCC tumor tissues and adjacent normal tissues from HNSCC patients were collected. Further, we characterized circMAT2B expression patterns in HNSCC tissues and cell lines, as well as exploring its association with the prognosis of HNSCC patients. Biological functions on cell proliferation, apoptosis, migration, and invasion were assessed using Cell Counting Kit-8, EdU incorporation, TUNEL, wound healing, and transwell assays. Glutaminolysis was evaluated by measuring glutamine, glutamate, and α-ketoglutarate (α-KG) levels. The regulatory network of circMAT2B/miR-491-5p/ASCT2 axis was verified by RNA immunoprecipitation and luciferase reporter assays. Western blot was conducted to detect the level of ASCT2 and GLS1. Remarkably overexpressed circMAT2B was observed in HNSCC tissues and cell lines, of which high abundance was positively correlated with patients’ poor prognosis. Silencing of circMAT2B inhibited cell proliferation, migration, and invasion, as well as glutaminolysis. miR-491-5p, interacted with ASCT2, was identified to be a downstream target of circMAT2B, thereby involving in circMAT2B-mediated biological effects. In summary, we draw a conclusion that circMAT2B could modulate the processes of cell proliferation, migration, invasion, and glutaminolysis of HNSCC cells partly via the miR-491-5p/ASCT2 axis by a molecular mechanism of competing endogenous RNA (ceRNA), implying an underlying circRNA-targeted therapy for HNSCC treatment.

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Funding

This study was supported by Natural Science Foundation of China (No. 82073006, No. 81902757, No. 82002757).

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Authors and Affiliations

  1. Department of Maxillofacial and Otorhinolaryngology Oncology and Department of Head and Neck Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer & Key Laboratory of Cancer Prevention and Therapy & Tianjin’s Clinical Research Center for Cancer, Tianjin, 300060, People’s Republic of China

    Jing-Tao Luo, Ya-fei Wang, Yun Wang, Chun-Li Wang, Ruo-Yan Liu & Ze Zhang

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  1. Jing-Tao Luo
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  2. Ya-fei Wang
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  3. Yun Wang
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  4. Chun-Li Wang
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  6. Ze Zhang
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Contributions

J-TL: Conceptualization; Writing-original draft; Methodology; Formal analysis; Y-fW: Supervision; Validation; YW, R-YL: Data curation; Resources; C-LW: Investigation; ZZ: Funding acquisition; Project administration; Writing-review & editing. All authors have read and approved the final version of this manuscript to be published.

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Correspondence to Jing-Tao Luo or Ze Zhang.

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Patients enrolled in this study signed their informed consent for participation and our work was approved by the Ethics Committee of Tianjin Cancer Hospital in accordance to the Declaration of Helsinki.

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11010_2022_4565_MOESM1_ESM.tif

Supplementary file1 (TIF 558 kb)— Identification of circMAT2B originated from MAT2B. (A) Schematic diagram illustrated the formation of circMAT2B originated from MAT2B pre-mRNA (exon 3, 4, 5, 6). (B) RNA stability assay was performed to detect the expression level of circMAT2B or linear mRNA transcripts in CAL27 cells under the exposure of transcription inhibitor (actinomycin D). (C) qRT-PCR analysis was performed to determine the expression of circMAT2B and MAT2B mRNA in CAL27 cells administered with RNase R or Mock control. Data were representative images or were expressed as the mean ± SD of n = 3 experiments. *, P < 0.05, **, P < 0.01, ***, P < 0.001

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Luo, JT., Wang, Yf., Wang, Y. et al. CircMAT2B facilitates the progression of head and neck squamous cell carcinoma via sponging miR-491-5p to trigger ASCT2-mediated glutaminolysis. Mol Cell Biochem 478, 1067–1081 (2023). https://doi.org/10.1007/s11010-022-04565-3

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