Expression of RAP1B is associated with poor prognosis and promotes an aggressive phenotype in gastric cancer.
Metastasis is the major cause of death among gastric cancer (GC) patients, and altered expression of Ras-related protein RAP1B is associated with cancer development. The present study assessed RAP1B expression ex vivo and the effect of hypoxia‑induced RAP1B overexpression on the promotion of the metastatic potential of GC cells in vitro. Immunohistochemistry was used to detect the expression of RAP1B and hypoxia‑inducible factor-1α (HIF-1α) in 178 GC tissue specimens. GC cell lines were used to assess the effects of hypoxia and RAP1B knockdown with RAP1B small interfering RNA (siRNA). Tumor cell viability was detected by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, invasion capacity was evaluated by a Transwell assay, and gene expression was determined by qRT-PCR and western blotting. The data showed that expression levels of RAP1B and HIF-1α proteins were high in the GC tissue specimens, and RAP1B expression was significantly associated with tumor-node-metastasis (TNM) stage and tumor size, while HIF-1α expression was significantly associated with TNM stage, Borrmann type and tumor differentiation. Moreover, RAP1B expression was associated with HIF-1α expression (r=0.547, P<0.001). The expression of RAP1B and HIF-1α proteins was associated with a shorter overall survival of patients according to the univariate analysis (log-rank test, P<0.01), and RAP1B expression and TNM stage were independent prognostic predictors in patients using a multivariate analysis (P<0.001). In vitro, hypoxia induced the invasion of GC cells and the expression of RAP1B and HIF-1α (P<0.05); whereas knockdown of RAP1B expression using siRNA inhibited the tumor cell invasion capacity even under hypoxic culture conditions (P<0.05). In conclusion, the protein expression of RAP1B and HIF-1α contributed to GC malignant behavior and poor prognosis. Future studies will evaluate whether targeting RAP1B expression can be used as a novel strategy to control GC or as a biomarker for prognosis prediction.
The Second Department of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
Ya
Y
Yang
The Second Department of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
Min
M
Li
The Second Department of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
Yan
Y
Yan
The Second Department of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
Jia
J
Zhang
The Second Department of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
Kai
K
Sun
The Second Department of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
Jing-Kun
JK
Qu
The Second Department of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
Jian-Sheng
JS
Wang
Department of Radiology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
Xiao-Yi
XY
Duan
D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009361:Neoplasm Invasiveness; D010641:Phenotype; D011379:Prognosis; D016016:Proportional Hazards Models; D013270:Stomach / Q000473:pathology; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D020668:rap GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C116753:RAP1B protein, human; D020668:rap GTP-Binding Proteins