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. 2018 Dec 21;38(6):BSR20180741.
doi: 10.1042/BSR20180741. Print 2018 Dec 21.

Down-regulation of HIF-1α inhibits the proliferation, migration, and invasion of gastric cancer by inhibiting PI3K/AKT pathway and VEGF expression

Jingjing Zhang  1 , Jun Xu  2 , Yonghong Dong  3 , Bo Huang  1
Affiliations

Down-regulation of HIF-1α inhibits the proliferation, migration, and invasion of gastric cancer by inhibiting PI3K/AKT pathway and VEGF expression

Jingjing Zhang et al. Biosci Rep. .

Abstract

In view of the high incidence of gastric cancer and the functions of hypoxia-inducible factor 1α (HIF-1α), our study aimed to investigate the functionality of HIF-1α in gastric cancer, and to explore the diagnostic and prognostic values of HIF-1α for this disease. Expression of HIF-1α in tumor tissues and adjacent healthy tissues as well as serum collected from both gastric cancer patients and normal healthy controls was detected by qRT-PCR. Survival analysis was performed using Kaplan-Meier method. HIF-1α siRNA silencing cell lines were established. Effects of HIF-1α siRNA silencing as well as PI3K activator sc3036 on proliferation, migration, and invasion of gastric cancer cells were detected by Cell counting kit (CCK-8) assay, and Transwell migration and invasion assay. Effects of HIF-1α siRNA silencing on AKT and VEGF were detected by Western blot. Expression of HIF-1α was significantly down-regulated in tumor tissues than in adjacent healthy tissues in most gastric cancer patients. Serum levels of HIF-1α were also higher in gastric cancer patients than in normal healthy people. Serum HIF-1α showed promising diagnostic and prognostic values for gastric cancer. HIF-1α siRNA silencing inhibited the proliferation, migration, and invasion of gastric cancer cells, while PI3K activator sc3036 treatment reduced those inhibitory effects. Down-regulation of HIF-1α can inhibit the proliferation, migration, and invasion of gastric cancer possibly by inhibiting PI3K/AKT pathway and VEGF expression.

Keywords: HIF-1α; PI3K/AKT pathway; gastric cancer.

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Conflict of interest statement

The authors declare that there are no competing interests associated with the manuscript.

Figures

Figure 1
Figure 1. Expression of HIF-1α mRNA in tumor tissues and adjacent healthy tissues
Expression level of HIF-1α mRNA was significantly higher in tumor tissues than in adjacent healthy tissues in most patients. *Compared with tumor tissues, P<0.05.
Figure 2
Figure 2. Serum levels of HIF-1α protein in gastric cancer patients and normal healthy people with the diagnostic value
(A) Comparison of serum levels of HIF-1α protein between gastric cancer patients and normal healthy people. (B) ROC curve analysis of the diagnostic value of serum levels of HIF-1α protein for gastric cancer. Up-regulated serum levels of HIF-1α effectively distinguished gastric cancer patients from healthy controls. *, P<0.05.
Figure 3
Figure 3. Comparison of survival curves of patients with high and low serum HIF-1α level
Overall survival of gastric cancer patient with high expression level of HIF-1α was significantly shorter than that of patients with low expression level of HIF-1α.
Figure 4
Figure 4. Down-regulation of HIF-1α inhibited proliferation, migration, and invasion of gastric cancer cells
(A) Down-regulation of HIF-1α after siRNA transfection; (B) down-regulation of HIF-1α inhibited proliferation of gastric cancer cells; (C) down-regulation of HIF-1α inhibited migration of gastric cancer cells; and (D) down-regulation of HIF-1α inhibited invasion of gastric cancer cells. *P<0.05.
Figure 5
Figure 5. Down-regulation of HIF-1α inhibited PI3K/AKT pathway and VEGF
This figure shows the effects of HIF-1α siRNA silencing on expression of VEGF (A) and phosphorylation and expression of AKT (B). In (A,B) the upper part is Western blot results and the lower part is the normalized expression. HIF-1α siRNA silencing inhibited VEGF expression and AKT phosphorylation. *, P<0.05.
Figure 6
Figure 6. Effects of PI3K activator sc-3036 on proliferation, migration, and invasion of gastric cancer cells
(A) Effects of PI3K activator sc-3036 on proliferation of gastric cancer cells; (B) effects of PI3K activator sc-3036 on migration of gastric cancer cells; (C) effects of PI3K activator sc-3036 on invasion of gastric cancer cells. Treatment with sc-3036 significantly reduced the inhibitory effects of HIF-1α siRNA silening on cell proliferation, migration, and invaison. *, P<0.05, compared with group C; #, P<0.05, compared with group siRNA.
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