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Endoplasmic reticulum ribosome-binding protein 1 (RRBP1) overexpression is frequently found in lung cancer patients and alleviates intracellular stress-induced apoptosis through the enhancement of GRP78

Oncogene volume 32, pages 4921–4931 (2013)Cite this article

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Abstract

Lung cancer is the leading cause of cancer deaths and is the most occurring malignancy worldwide. Unraveling the molecular mechanisms involved in lung tumorigenesis will greatly improve therapy. During early tumorigenesis, rapid proliferating tumor cells require increased activity of endoplasmic reticulum (ER) for protein synthesis, folding and secretion, thereby are subjected to ER stress. Ribosome-binding protein 1 (RRBP1) was originally identified as a ribosome-binding protein located on the rough ER and associated with unfolding protein response (UPR). In this report, we investigated the role of RRBP1 in lung cancer. RRBP1 was highly expressed in lung cancer tissue, as compared with adjacent normal tissues as assessed by immunohistochemistry (IHC) using lung cancer tissue array (n=87). Knockdown of RRBP1 by short-hairpin RNAs caused ER stress and significantly reduced cell viability and tumorigenicity. This effect was associated with a significant reduction in the expression of glucose-regulated protein 78 (GRP78). UPR regulator GRP78, an anti-apoptotic protein that is widely upregulated in cancer, has a critical role in chemotherapy resistance in some cancers. According to our results, cells with a higher level of RRBP1 were more resistant to ER stress. Ectopic expression of RRBP1 alleviated apoptosis that was induced by the ER-stress agent tunicamycin, 2-deoxy-D-glucose (2DG) or doxorubicin via enhancing GRP78 protein expression. A strong correlation was observed between the expression of RRBP1 and GRP78 in tumor biopsies using the database GSE10072. Our results also indicated that RRBP1 may involve in the regulation of mRNA stability of UPR components including ATF6 and GRP78. Taken together, RRBP1 could alleviate ER stress and help cancer cell survive. RRBP1 is critical for tumor cell survival, which may make it a useful target in lung cancer treatment and a candidate for the development of new targeted therapeutics.

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Acknowledgements

We thank Miss Tracy Tsai for assisting in the pathological staining analysis. RRBP1 plasmids were kindly provided by Dr Kiyoko, Japan Institute of Leather Research. The study was supported by grants from the National Science Council and Academia Sinica.

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  1. H-Y Tsai and Y-F Yang: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan

    H-Y Tsai & Y-F Yang

  2. Genomics Research Center, Academia Sinica, Taipei, Taiwan

    H-Y Tsai, Y-F Yang, Y-H Jan, Y-W Hsiao, C-N Shen & M Hsiao

  3. The PhD Program for Translational Medicine, College of Science and Technology, Taipei Medical University, Taipei, Taiwan

    A T Wu

  4. Department of Internal Medicine, Kaohsiung Medical University Hospital, School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

    C-J Yang & M-S Huang

  5. Institute of Clinical Medicine, National Cheng-Kung University, Tainan, Taiwan

    Y-P Liu & P-J Lu

  6. Translational Research Laboratory, Cancer Center, Taipei Medical University Hospital, Taipei, Taiwan

    A T Wu

  7. Department of Pharmacy, Taipei Tzu Chi General Hospital, Taipei, Taiwan

    C-H Lee

  8. Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan

    C-T Yeh & C-N Shen

  9. Cancer Center, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan

    C-T Yeh

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Tsai, HY., Yang, YF., Wu, A. et al. Endoplasmic reticulum ribosome-binding protein 1 (RRBP1) overexpression is frequently found in lung cancer patients and alleviates intracellular stress-induced apoptosis through the enhancement of GRP78. Oncogene 32, 4921–4931 (2013). https://doi.org/10.1038/onc.2012.514

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