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Cell death/proliferation roles for nc886, a non-coding RNA, in the protein kinase R pathway in cholangiocarcinoma

Oncogene volume 32, pages 3722–3731 (2013)Cite this article

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Abstract

We have recently identified nc886 (pre-miR-886 or vtRNA2-1) as a novel type of non-coding RNA that inhibits activation of protein kinase R (PKR). PKR’s pro-apoptotic role through eukaryotic initiation factor 2 α (eIF2α) phosphorylation is well established in the host defense against viral infection. Paradoxically, some cancer patients have elevated PKR activity; however, its cause and consequence are not understood. Initially, we evaluated the expression of nc886, PKR and eIF2α in non-malignant cholangiocyte and cholangiocarcinoma (CCA) cells. nc886 is repressed in CCA cells and this repression is the cause of PKR’s activation therein. nc886 alone is necessary and sufficient for suppression of PKR via direct physical interaction. Consistently, artificial suppression of nc886 in cholangiocyte cells activates the canonical PKR/eIF2α cell death pathway, suggesting a potential significance of the nc886 suppression and the consequent PKR activation in eliminating pre-malignant cells during tumorigenesis. In comparison, active PKR in CCA cells does not induce phospho-eIF2α nor apoptosis, but promotes the pro-survival nuclear factor-κB pathway. Thus, PKR has a dual life or death role during tumorigenesis. Similarly to the CCA cell lines, nc886 tends to be decreased but PKR tends to be activated in our clinical samples from CCA patients. Collectively from our data, we propose a tumor surveillance model for nc886’s role in the PKR pathway during tumorigenesis.

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Acknowledgements

We thank Dr Sopit Wongkham, Dr Kanlayanee Sawanyawisuth and Ms Sirinapa Sribenja (Khon Kaen University) for CCA cells and helpful discussion; Dr Inhan Lee (miRcore, MI) for helpful advice; Research Histology Core Laboratory Facility, University of Texas, MD Anderson Cancer Center (funded by the National Cancer Institute Grant # CA16672) for tissue preparation and IHC. This work was supported by a Research Scholar Grant, RSG-12-187-01—RMC from the American Cancer Society to YSL, by start-up funding from the Sealy Center for Cancer Biology at the University of Texas Medical Branch to YSL, by the Royal Golden Jubilee (RGJ) scholarship (PHD/0105/2550) of Thailand Research Fund (TRF) to NK and the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2011-0022022) to SHJ.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, TX, USA

    N Kunkeaw, S H Jeon, K Lee, B H Johnson & Y S Lee

  2. The Centre for Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand

    N Kunkeaw, W Wongfieng & C Leelayuwat

  3. Department of Life Science, Hallym University, Chuncheon, Korea

    S H Jeon

  4. Department of Medicine, King Chulalongkorn Memorial Hospital, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand

    S Tanasanvimon

  5. Department of Gastroenterology, Hepatology and Nutrition, MD Anderson Cancer Center, Houston, TX, USA

    S Tanasanvimon

  6. Gastrointestinal Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA

    M Javle

  7. Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand

    C Pairojkul, Y Chamgramol & C Leelayuwat

  8. Department of Pathology, The University of Texas Medical Branch, Galveston, TX, USA

    B Gong

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Kunkeaw, N., Jeon, S., Lee, K. et al. Cell death/proliferation roles for nc886, a non-coding RNA, in the protein kinase R pathway in cholangiocarcinoma. Oncogene 32, 3722–3731 (2013). https://doi.org/10.1038/onc.2012.382

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