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Yin Yang 1-induced LINC00667 up-regulates pyruvate dehydrogenase kinase 1 to promote proliferation, migration and invasion of cholangiocarcinoma cells by sponging miR-200c-3p

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Abstract

Cholangiocarcinoma (CCA) is one of the most aggressive and lethal malignancies. Long noncoding RNAs (lncRNAs) are being found to play crucial roles in CCA progression. This work aims to investigate the roles of long intergenic non-protein coding RNA 667 (LINC00667) in progression of CCA. RT-qPCR and western blot were applied to detect gene expression. Clinical correlation and survival were analyzed by statistical methods. Overexpression and RNA interference approaches were used to investigate the effects of LINC00667 on CCA cells. Tumor xenograft assay was performed to detect the function of LINC00667 in vivo. Transcriptional regulation and competing endogenous RNA (ceRNA) mechanism were predicted via bioinformatics analysis. ChIP, luciferase reporter, and Ago2 RIP assays further confirmed the predicted results. Our data indicated that LINC00667 was highly expressed in CCA tissues and cells, and transcription factor Yin Yang 1 (YY1) induced LINC00667 expression in CCA cells. Up-regulated LINC00667 was significantly associated with lymph node metastasis, advanced TNM stage, and poor prognosis. Knockdown of LINC00667 suppressed the proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) of CCA cells, while overexpression of LINC00667 acquired opposite effects. Moreover, knockdown of LINC00667 inhibited tumor growth in vivo. In addition, LINC00667 was demonstrated to function as a ceRNA for miR-200c-3p, and then LINC00667 up-regulated pyruvate dehydrogenase kinase 1 (PDK1) to promote CCA development by inhibiting miR-200c-3p. These findings identified a pivotal role of LINC00667 in tumorigenesis and development of CCA. Targeting the YY1/LINC00667/miR-200c-3p/PDK1 axis may provide a new therapeutic strategy for CCA treatment.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 81602088).

Funding

This work was supported by the National Natural Science Foundation of China (No. 81602088).

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  1. Jinglin Li, Canghai Guan, and Zengtao Hu contributed equally to this work.

Authors and Affiliations

  1. Department of General Surgery, The 2nd Affiliated Hospital of Harbin Medical University, 148 Baojian Street, Harbin, 150086, Heilongjiang, China

    Jinglin Li, Canghai Guan, Zengtao Hu, Lang Liu, Zhilei Su, Pengcheng Kang, Xingming Jiang & Yunfu Cui

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  1. Jinglin Li
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Contributions

JL: conceptualization; JL and XJ: experimental design and execution; ZH and LL: data curation and analysis; YC: experimental resources; CG and ZS: writing-original draft; PK: writing-review and editing; YC: supervision. All authors have read and approved the final manuscript.

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Correspondence to Xingming Jiang or Yunfu Cui.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the Ethics Committee of The 2nd Affiliated Hospital of Harbin Medical University (KY2018-301), and patient consent was acquired prior to the initiation of experiment. All procedures performed in studies involving animals were in accordance with the ethical standards of the Animal Care and Use Committee of The 2nd Affiliated Hospital of Harbin Medical University (SYDW2018-114).

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Li, J., Guan, C., Hu, Z. et al. Yin Yang 1-induced LINC00667 up-regulates pyruvate dehydrogenase kinase 1 to promote proliferation, migration and invasion of cholangiocarcinoma cells by sponging miR-200c-3p. Human Cell 34, 187–200 (2021). https://doi.org/10.1007/s13577-020-00448-1

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