Abstract

Esophageal cancer is a worldwide health problem with a very poor prognosis. Therefore, new diagnostic biomarkers or therapeutic strategies for identifying and managing esophageal squamous cell carcinoma (ESCC) are urgently needed. Glucoseregulated protein 94 (GRP94) is one of major endoplasmic reticulum-stress response proteins that plays a key role in cancer progression and therapeutic responses. However, the role of GRP94 in ESCC progression and metastasis remains unclear. The tissue array results indicated that higher GRP94 expression levels were associated with lower overall survival and higher lympho-node metastasis. Silencing GRP94 (GRP94-KD) reduced cell proliferation, migration and invasion in ESCC cells. In a xenotransplantation assay, silencing GRP94 reduced cell proliferation in the zebrafish embryo. Transmission electron microscopy revealed impaired mitochondria in GRP94- KD cells, which exhibited reduced basal respiration, spare respiratory capacity and ATP production and increased oxidative damage compared with scrambled control cells. Regarding the molecular mechanism underlying the effects of GRP94 knockdown, we found that silencing GRP94 may reduce the level of NF-kB, c-Jun, p38, IL-6, vascular endothelial growth factor (VEGF), and cyclooxygenase-2 (COX-2) as well as activation of AKT and ERK. In conclusion, our results indicate that silencing GRP94 in ESCC cells suppressed cancer growth and the metastatic potential via mitochondrial functions and NF-kB/COX-2/VEGF in ESCC cells.

Original languageEnglish
Pages (from-to)9425-9441
Number of pages17
JournalOncotarget
Volume9
Issue number10
DOIs
Publication statusPublished - Jan 1 2018

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NF-kappa B
Cyclooxygenase 2
Vascular Endothelial Growth Factor A
Neoplasm Metastasis
Proteins
Cell Proliferation
glucose-regulated proteins
Esophageal Squamous Cell Carcinoma
Heterologous Transplantation
Endoplasmic Reticulum Stress
Zebrafish
Esophageal Neoplasms
Heat-Shock Proteins
Transmission Electron Microscopy
Cell Movement
Interleukin-6
Neoplasms
Mitochondria
Respiration
Embryonic Structures

Keywords

  • COX-2
  • ESCC
  • GRP94
  • VEGF

ASJC Scopus subject areas

  • Oncology

Cite this

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title = "Glucose-regulated protein 94 mediates progression and metastasis of esophageal squamous cell carcinoma via mitochondrial function and the NF-kB/COX-2/VEGF axis",
abstract = "Esophageal cancer is a worldwide health problem with a very poor prognosis. Therefore, new diagnostic biomarkers or therapeutic strategies for identifying and managing esophageal squamous cell carcinoma (ESCC) are urgently needed. Glucoseregulated protein 94 (GRP94) is one of major endoplasmic reticulum-stress response proteins that plays a key role in cancer progression and therapeutic responses. However, the role of GRP94 in ESCC progression and metastasis remains unclear. The tissue array results indicated that higher GRP94 expression levels were associated with lower overall survival and higher lympho-node metastasis. Silencing GRP94 (GRP94-KD) reduced cell proliferation, migration and invasion in ESCC cells. In a xenotransplantation assay, silencing GRP94 reduced cell proliferation in the zebrafish embryo. Transmission electron microscopy revealed impaired mitochondria in GRP94- KD cells, which exhibited reduced basal respiration, spare respiratory capacity and ATP production and increased oxidative damage compared with scrambled control cells. Regarding the molecular mechanism underlying the effects of GRP94 knockdown, we found that silencing GRP94 may reduce the level of NF-kB, c-Jun, p38, IL-6, vascular endothelial growth factor (VEGF), and cyclooxygenase-2 (COX-2) as well as activation of AKT and ERK. In conclusion, our results indicate that silencing GRP94 in ESCC cells suppressed cancer growth and the metastatic potential via mitochondrial functions and NF-kB/COX-2/VEGF in ESCC cells.",
keywords = "COX-2, ESCC, GRP94, VEGF",
author = "Huang, {Chien Yu} and Lee, {Chia Hwa} and Tu, {Chao Chiang} and Wu, {Chih Hsiung} and Huang, {Ming Te} and Wei, {Po Li} and Chang, {Yu Jia}",
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T1 - Glucose-regulated protein 94 mediates progression and metastasis of esophageal squamous cell carcinoma via mitochondrial function and the NF-kB/COX-2/VEGF axis

AU - Huang, Chien Yu

AU - Lee, Chia Hwa

AU - Tu, Chao Chiang

AU - Wu, Chih Hsiung

AU - Huang, Ming Te

AU - Wei, Po Li

AU - Chang, Yu Jia

PY - 2018/1/1

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N2 - Esophageal cancer is a worldwide health problem with a very poor prognosis. Therefore, new diagnostic biomarkers or therapeutic strategies for identifying and managing esophageal squamous cell carcinoma (ESCC) are urgently needed. Glucoseregulated protein 94 (GRP94) is one of major endoplasmic reticulum-stress response proteins that plays a key role in cancer progression and therapeutic responses. However, the role of GRP94 in ESCC progression and metastasis remains unclear. The tissue array results indicated that higher GRP94 expression levels were associated with lower overall survival and higher lympho-node metastasis. Silencing GRP94 (GRP94-KD) reduced cell proliferation, migration and invasion in ESCC cells. In a xenotransplantation assay, silencing GRP94 reduced cell proliferation in the zebrafish embryo. Transmission electron microscopy revealed impaired mitochondria in GRP94- KD cells, which exhibited reduced basal respiration, spare respiratory capacity and ATP production and increased oxidative damage compared with scrambled control cells. Regarding the molecular mechanism underlying the effects of GRP94 knockdown, we found that silencing GRP94 may reduce the level of NF-kB, c-Jun, p38, IL-6, vascular endothelial growth factor (VEGF), and cyclooxygenase-2 (COX-2) as well as activation of AKT and ERK. In conclusion, our results indicate that silencing GRP94 in ESCC cells suppressed cancer growth and the metastatic potential via mitochondrial functions and NF-kB/COX-2/VEGF in ESCC cells.

AB - Esophageal cancer is a worldwide health problem with a very poor prognosis. Therefore, new diagnostic biomarkers or therapeutic strategies for identifying and managing esophageal squamous cell carcinoma (ESCC) are urgently needed. Glucoseregulated protein 94 (GRP94) is one of major endoplasmic reticulum-stress response proteins that plays a key role in cancer progression and therapeutic responses. However, the role of GRP94 in ESCC progression and metastasis remains unclear. The tissue array results indicated that higher GRP94 expression levels were associated with lower overall survival and higher lympho-node metastasis. Silencing GRP94 (GRP94-KD) reduced cell proliferation, migration and invasion in ESCC cells. In a xenotransplantation assay, silencing GRP94 reduced cell proliferation in the zebrafish embryo. Transmission electron microscopy revealed impaired mitochondria in GRP94- KD cells, which exhibited reduced basal respiration, spare respiratory capacity and ATP production and increased oxidative damage compared with scrambled control cells. Regarding the molecular mechanism underlying the effects of GRP94 knockdown, we found that silencing GRP94 may reduce the level of NF-kB, c-Jun, p38, IL-6, vascular endothelial growth factor (VEGF), and cyclooxygenase-2 (COX-2) as well as activation of AKT and ERK. In conclusion, our results indicate that silencing GRP94 in ESCC cells suppressed cancer growth and the metastatic potential via mitochondrial functions and NF-kB/COX-2/VEGF in ESCC cells.

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