International Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
Division of Colorectal Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei Medical University, Taipei 110, Taiwan.
Int J Med Sci. 2021 Mar 27;18(11):2251-2261. doi: 10.7150/ijms.56024. eCollection 2021.
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.
结直肠癌（CRC）是一个全球性的健康问题。葡萄糖调节蛋白 94（GRP94）是一种重要的内质网应激反应蛋白，与侵袭性癌症行为相关。然而，GRP94 在 CRC 中的作用仍不清楚。我们的结果表明，沉默 GRP94（GRP94-KD）可降低 CRC 细胞的增殖、侵袭和迁移，并抑制异种移植小鼠模型中的肿瘤发生。挽救实验表明，ETV1 的过表达逆转了 GRP94 对细胞增殖和迁移的影响。在分子机制方面，我们发现敲低 GRP94 抑制了 MAPK 通路的水平，包括 ERK/p-ERK、JNK/p-JNK 和 p38/p-p38 信号。GRP94 敲低细胞中环氧合酶-2 和上皮间质转化生物标志物，如 N-钙粘蛋白、波形蛋白和β-连环蛋白的水平降低。MAPK 通路的特异性抑制剂处理表明，与 JNK/p-JNK 抑制剂相比，ERK/p-ERK 和 p38/p-p38 抑制剂显著影响 ETV1 的表达。我们的结果表明，沉默 GRP94 抑制了 EMT 过程、癌细胞增殖、转移和 CRC 肿瘤发生的能力。因此，GRP94 可能通过调节 ETV1 和 MAPK 通路在 CRC 中发挥重要作用。
