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Glucose-regulated protein 78 (GRP78) regulates colon cancer metastasis through EMT biomarkers and the NRF-2/HO-1 pathway

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Tumor Biology

Abstract

Glucose-regulated protein 78 (GRP78) is a key chaperone and stress response protein. Previous studies have demonstrated that high GRP78 expression may be correlated with cancer progression and therapeutic response. However, the role of GRP78 in the metastasis of colon cancer is unclear. In this study, we used small interfering RNA (siRNA) to knock down GRP78 expression in colon cancer cells (HT-29 and DLD-1 cells). In wound-healing migration assays, we found that GRP78-knockdown (GRP78KD) cells showed better wound-healing ability than control cells. We also found that GRP78KD cells displayed a better migratory ability than control cells in migration and invasion assays. As we further dissected the underlying molecular mechanism, we found that silencing GRP78 may cause an increase in vimentin expression and a decrease in the E-cadherin level, which was correlated with the increase in migratory ability. In addition, we found that GRP78KD may activate the NRF-2/HO-1 pathway, and this activation was also correlated with the increase in cell invasiveness. Furthermore, we examined GRP78 expression in a tissue array and found that the GRP78 expression in metastatic adenocarcinoma in lymph nodes tended to be weaker than that in primary colonic adenocarcinoma. In conclusion, a low level of GRP78 may cause an increase in metastasis ability in colon cancer cells by altering E-cadherin and vimentin expression and activating the NRF-2/HO-1 signaling pathway. Our study demonstrates that low expression of GRP78 may correlate with a high risk of metastasis in colon cancer.

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Acknowledgments

This study was supported by grants from the National Science Council (NSC101-2314-B-038-029-MY3 and NSC101-2314-B-038-016-MY3) and MOHW103-TDU-B-212-113001.

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Authors and Affiliations

  1. Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

    Yu-Jia Chang

  2. Department of Surgery, College of Medicine, Taipei Medical University, No. 250, Wuxing St., Taipei, 11031, Taiwan

    Yu-Jia Chang & Po-Li Wei

  3. Division of General Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei, Taiwan

    Yu-Jia Chang & Po-Li Wei

  4. Cancer Research Center, Taipei Medical University Hospital, Taipei, Taiwan

    Yu-Jia Chang & Po-Li Wei

  5. Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan

    Wei-Yu Chen

  6. Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

    Wei-Yu Chen

  7. Division of General Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan

    Chien-Yu Huang

  8. Department of Neurosurgery, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan

    Chien-Yu Huang

  9. School of Public Health, College of Public Health and Nutrition, Taipei Medical University, Taipei, Taiwan

    Hui-Hsiung Liu

  10. Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan

    Po-Li Wei

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  1. Yu-Jia Chang
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Correspondence to Po-Li Wei.

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Chang, YJ., Chen, WY., Huang, CY. et al. Glucose-regulated protein 78 (GRP78) regulates colon cancer metastasis through EMT biomarkers and the NRF-2/HO-1 pathway. Tumor Biol. 36, 1859–1869 (2015). https://doi.org/10.1007/s13277-014-2788-x

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  • DOI: https://doi.org/10.1007/s13277-014-2788-x

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