Down-regulation of HIF-1α Inhibits the Proliferation, Migration, and Invasion of Gastric Cancer by Inhibiting PI3K/AKT Pathway and VEGF Expression

Overview

Journal Biosci Rep

Specialty Cell Biology

Date 2018 Jun 15

PMID 29899167

Citations 26

Authors

Jingjing Zhang

Jun Xu

Yonghong Dong

Bo Huang

Affiliations

Soon will be listed here.

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.

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References

Birner P, Schindl M, Obermair A, Plank C, Breitenecker G, Oberhuber G . Overexpression of hypoxia-inducible factor 1alpha is a marker for an unfavorable prognosis in early-stage invasive cervical cancer. Cancer Res. 2000; 60(17):4693-6. View

Semenza G . Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 2003; 3(10):721-32. DOI: 10.1038/nrc1187. View

Tang N, Wang L, Esko J, Giordano F, Huang Y, Gerber H . Loss of HIF-1alpha in endothelial cells disrupts a hypoxia-driven VEGF autocrine loop necessary for tumorigenesis. Cancer Cell. 2004; 6(5):485-95. DOI: 10.1016/j.ccr.2004.09.026. View

Generali D, Berruti A, Brizzi M, Campo L, Bonardi S, Wigfield S . Hypoxia-inducible factor-1alpha expression predicts a poor response to primary chemoendocrine therapy and disease-free survival in primary human breast cancer. Clin Cancer Res. 2006; 12(15):4562-8. DOI: 10.1158/1078-0432.CCR-05-2690. View

Mendez O, Zavadil J, Esencay M, Lukyanov Y, Santovasi D, Wang S . Knock down of HIF-1alpha in glioma cells reduces migration in vitro and invasion in vivo and impairs their ability to form tumor spheres. Mol Cancer. 2010; 9:133. PMC: 2896954. DOI: 10.1186/1476-4598-9-133. View

Saponaro C, Malfettone A, Ranieri G, Danza K, Simone G, Angelo Paradiso . VEGF, HIF-1α expression and MVD as an angiogenic network in familial breast cancer. PLoS One. 2013; 8(1):e53070. PMC: 3543407. DOI: 10.1371/journal.pone.0053070. View

Yeh Y, Chuang C, Chao K, Wang L . MicroRNA-138 suppresses ovarian cancer cell invasion and metastasis by targeting SOX4 and HIF-1α. Int J Cancer. 2013; 133(4):867-78. DOI: 10.1002/ijc.28086. View

Miyake S, Kitajima Y, Nakamura J, Kai K, Yanagihara K, Tanaka T . HIF-1α is a crucial factor in the development of peritoneal dissemination via natural metastatic routes in scirrhous gastric cancer. Int J Oncol. 2013; 43(5):1431-40. DOI: 10.3892/ijo.2013.2068. View

Gadgil M, Joshi K, Naik S, Pandit A, Otiv S, Patwardhan B . Association of homocysteine with global DNA methylation in vegetarian Indian pregnant women and neonatal birth anthropometrics. J Matern Fetal Neonatal Med. 2014; 27(17):1749-53. DOI: 10.3109/14767058.2013.879702. View

10.

Karimi P, Islami F, Anandasabapathy S, Freedman N, Kamangar F . Gastric cancer: descriptive epidemiology, risk factors, screening, and prevention. Cancer Epidemiol Biomarkers Prev. 2014; 23(5):700-13. PMC: 4019373. DOI: 10.1158/1055-9965.EPI-13-1057. View

11.

Chen W, Zheng R, Zhang S, Zhao P, Zeng H, Zou X . Annual report on status of cancer in China, 2010. Chin J Cancer Res. 2014; 26(1):48-58. PMC: 3937758. DOI: 10.3978/j.issn.1000-9604.2014.01.08. View

12.

Xue M, Li X, Li Z, Chen W . Urothelial carcinoma associated 1 is a hypoxia-inducible factor-1α-targeted long noncoding RNA that enhances hypoxic bladder cancer cell proliferation, migration, and invasion. Tumour Biol. 2014; 35(7):6901-12. DOI: 10.1007/s13277-014-1925-x. View

13.

Khalid O, Kim J, Kim H, Hoang M, Tu T, Elie O . Gene expression signatures affected by alcohol-induced DNA methylomic deregulation in human embryonic stem cells. Stem Cell Res. 2014; 12(3):791-806. PMC: 4041389. DOI: 10.1016/j.scr.2014.03.009. View

14.

Chen J, Ding Z, Peng Y, Pan F, Li J, Zou L . HIF-1α inhibition reverses multidrug resistance in colon cancer cells via downregulation of MDR1/P-glycoprotein. PLoS One. 2014; 9(6):e98882. PMC: 4047061. DOI: 10.1371/journal.pone.0098882. View

15.

Wang J, Ni Z, Duan Z, Wang G, Li F . Altered expression of hypoxia-inducible factor-1α (HIF-1α) and its regulatory genes in gastric cancer tissues. PLoS One. 2014; 9(6):e99835. PMC: 4057318. DOI: 10.1371/journal.pone.0099835. View

16.

Paul S, Amundson S . Differential Effect of Active Smoking on Gene Expression in Male and Female Smokers. J Carcinog Mutagen. 2015; 5. PMC: 4303254. DOI: 10.4172/2157-2518.1000198. View

17.

Xiang L, Gilkes D, Hu H, Luo W, Bullen J, Liang H . HIF-1α and TAZ serve as reciprocal co-activators in human breast cancer cells. Oncotarget. 2015; 6(14):11768-78. PMC: 4494903. DOI: 10.18632/oncotarget.4190. View

18.

De Donato M, Fanelli M, Mariani M, Raspaglio G, Pandya D, He S . Nek6 and Hif-1α cooperate with the cytoskeletal gateway of drug resistance to drive outcome in serous ovarian cancer. Am J Cancer Res. 2015; 5(6):1862-77. PMC: 4529609. View

19.

Zhao Q, Li Y, Tan B, Fan L, Yang P, Tian Y . HIF-1α Induces Multidrug Resistance in Gastric Cancer Cells by Inducing MiR-27a. PLoS One. 2015; 10(8):e0132746. PMC: 4546344. DOI: 10.1371/journal.pone.0132746. View

20.

Castello R, Borzone R, Daria S, Annunziata P, Piccolo P, Brunetti-Pierri N . Helper-dependent adenoviral vectors for liver-directed gene therapy of primary hyperoxaluria type 1. Gene Ther. 2015; 23(2):129-34. PMC: 4746739. DOI: 10.1038/gt.2015.107. View