Glucose-regulated protein 94 mediates progression and metastasis of esophageal
squamous cell carcinoma via mitochondrial function and the NF-kB/COX-2/VEGF axis
#MMPMID29507700
Huang CY
; Lee CH
; Tu CC
; Wu CH
; Huang MT
; Wei PL
; Chang YJ
Oncotarget
2018[Feb]; 9
(10
): 9425-9441
PMID29507700
show ga
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.
Glucose-regulated 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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