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Long noncoding RNA HAR1A regulates oral cancer progression through the alpha-kinase 1, bromodomain 7, and myosin IIA axis

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Abstract

Studies suggested that long noncoding HAR1A RNA may be a tumor suppressor, but its association with oral cancer remains unclear. Here, we show the functional role and mechanisms of HAR1A in oral cancer progression. Microarray analysis was performed to screen the related candidates of long noncoding RNA (lncRNA) in human monocytes. Following lncRNA HAR1A, the regulation of HAR1A, ALPK1, myosin IIA, and BRD7 was tested using reverse-transcription quantitative polymerase chain reaction (RT-qPCR) in oral cancer cells. The inflammatory and epithelial-to-mesenchymal transition marker expressions were analyzed using enzyme-linked immunosorbent assay and western blot. Phenotypic experiments were verified by colony formation assay, transwell migration assay, and Annexin V-apoptotic assay. In the nuclei of cancer cells, HAR1A functions upstream of signaling pathways and knockdown of HAR1A promoted ALPK1 expression and downregulated BRD7 resulting in inflammation and oral cancer progression. In monocytes, the expressions of TNF-α and CCL2 were increased following HAR1A knockdown and reduced following ALPK1 knockdown. HAR1A knockdown upregulated the expression of ALPK1, slug, vimentin, fibronectin, and N-cadherin but reduced the expression of E-cadherin in oral cancer cells. Myosin IIA was primarily located in the cytoplasm and that its decrease in the nuclei of oral cancer cells was likely to demonstrate suppressive ability in late-stage cancer. Our findings suggest that the HAR1A, BRD7, and myosin IIA are tumor suppressors while ALPK1 has oncogene-like property in the nucleus and is involved in inflammation and oral cancer progression. More research for HAR1A activators or ALPK1 inhibitors is required to develop potential therapeutic agents for advanced oral cancer.

Key messages

  • lncRNA HAR1A, BRD7, and myosin IIA are tumor suppressors whereas ALPK1 has an oncogenic-like property in the nucleus.

  • lncRNA HAR1A/ALPK1/BRD7/myosin IIA axis plays a critical role in the progression of oral cancer.

  • lncRNA HAR1A localizes upstream of signaling pathways to inhibit ALPK1 expression and then upregulated BRD7.

  • lncRNA HAR1A and ALPK1 are involved in cancer progression via epithelial-to-mesenchymal transition regulations.

  • ALPK1 inhibitors are potential kinase-targeted therapeutic agents for patients with advanced oral cancer.

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Data availability

All data generated or analyzed during this study are included in this published article (and its Supplementary Materials).

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Funding

This work was supported by the Ministry of Science and Technology (grant number MOST 106-2314-B-039-017-MY3) and the China Medical University & Hospital (grant number DMR-108-042, DMR-109-156).

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Authors and Affiliations

  1. Environment-Omics-Disease Research Center, China Medical University Hospital, China Medical University, No. 2 Yude Road, Taichung, 40447, Taiwan

    Chi-Pin Lee, Srinivasan Nithiyanantham & Ying-Chin Ko

  2. Graduate Institute of Biomedical Sciences, China Medical University, Taichung, 40402, Taiwan

    Chi-Pin Lee

  3. Key Laboratory of Vertebrate Evolution and Human Origins of Chinese Academy of Sciences, Institute of Vertebrate Paleontology and Paleoanthropology, CAS, Beijing, 100044, China

    Albert Min-Shan Ko

  4. Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung, 41354, Taiwan

    Chu-Hu Lai

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  1. Chi-Pin Lee
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  2. Albert Min-Shan Ko
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  4. Chu-Hu Lai
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  5. Ying-Chin Ko
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Contributions

Study conception and design: YC Ko. Acquisition, analysis, or interpretation of data: CP Lee, AMS Ko, S Nithiyanantham, CH Lai, and YC Ko. Drafting the manuscript: CP Lee, AMS Ko, and YC Ko. All authors approved the final manuscript for submission and final approval of the version to be published. We thank Dr. Po-Ku Chen for his technical assistance.

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Correspondence to Ying-Chin Ko.

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Lee, CP., Ko, A.MS., Nithiyanantham, S. et al. Long noncoding RNA HAR1A regulates oral cancer progression through the alpha-kinase 1, bromodomain 7, and myosin IIA axis. J Mol Med 99, 1323–1334 (2021). https://doi.org/10.1007/s00109-021-02095-x

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