Int J Med Sci 2021; 18(11):2251-2261. doi:10.7150/ijms.56024

Research Paper

Glucose-Regulated Protein 94 Mediates the Proliferation and Metastasis through the Regulation of ETV1 and MAPK Pathway in Colorectal Cancer

Uyanga Batzorig1, Po-Li Wei2,3,4,5, Weu Wang3, Chien-Yu Huang3,6,7,9✉, Yu-Jia Chang1,8,9,10✉

1. International Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
2. Division of Colorectal Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei Medical University, Taipei 110, Taiwan.
3. Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
4. Cancer Research Center, Taipei Medical University Hospital, Taipei Medical University, Taipei 110, Taiwan.
5. Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei 110, Taiwan.
6. Division of General Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan.
7. Division of Colorectal Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University.
8. Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
9. Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
10. Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.

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Citation:
Batzorig U, Wei PL, Wang W, Huang CY, Chang YJ. Glucose-Regulated Protein 94 Mediates the Proliferation and Metastasis through the Regulation of ETV1 and MAPK Pathway in Colorectal Cancer. Int J Med Sci 2021; 18(11):2251-2261. doi:10.7150/ijms.56024. Available from https://www.medsci.org/v18p2251.htm

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Abstract

Colorectal cancer (CRC) is a worldwide health problem. Glucose-regulated protein 94 (GRP94) is known as an important endoplasmic reticulum-stress response protein that shows correlation with aggressive cancer behavior. However, the role of GRP94 in CRC is still unclear. Our results showed that silencing GRP94 (GRP94-KD) reduced cell proliferation, invasion and migration of CRC cells and suppressed tumorigenesis in the xenograft mouse model. Rescue assay showed that ETV1 overexpression reversed the effect of GRP94 on cell proliferation and migration. In the molecular mechanism, we found that knockdown of GRP94 inhibited the level of MAPK pathway, including ERK/p-ERK, JNK/p-JNK, and p38/p-p38 signals. Cyclooxygenase-2 and epithelial-mesenchymal transformation biomarkers, such as N-cadherin, vimentin, and β-catenin were suppressed in GRP94 knockdown cells. Treatment of specific inhibitors of MAPK pathway showed that ERK/p-ERK, and p38/p-p38 inhibitors significantly influenced ETV1 expression as compared to JNK/p-JNK inhibitor. Our results indicated that silencing GRP94 repressed the ability of EMT process, cancer cell proliferation, metastasis, and CRC tumorigenesis. Therefore, GRP94 may play an important role in CRC by regulating ETV1 and MAPK pathway.

Keywords: GRP94, colorectal cancer, ETV1, proliferation, metastasis.