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

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 prognosic 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 establihsed. Effects of HIF-1α siRNA silencing as well as PI3K activator sc3036 on proliferation, migration and invasion of gastric cancer cells were detected by 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 downregulated 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 diagnosic 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. Downregulation of HIF-1α can inhibit the proliferation and migration and invasion of gastric cancer possibly by inhibiting PI3K/AKT pathway and VEGF expression.

<p>The Regulatory Mechanism and Biological Significance of Mitochondrial Calcium Uniporter in the Migration, Invasion, Angiogenesis and Growth of Gastric Cancer</p>

“…8 HIF-1α can induce the proliferation, migration and invasion of gastric cancer cells by promoting the expression of VEGF. 18 Our results showed that silencing MCU could inhibit the expression of VEGF in subcutaneous xenograft tumors induced by gastric cancer cells in nude mice, indicating that MCU might regulate the expression of VEGF via HIF-1α.…”

CircHIPK3 Promotes Metastasis of Gastric Cancer via miR-653-5p/miR-338-3p-NRP1 Axis Under a Long-Term Hypoxic Microenvironment

“…In a hypoxic microenvironment, hypoxia-inducible factors (HIFs) are upregulated due to the stabilization of HIF-α subunits and play a vital role in tumor progression including angiogenesis, metabolic reprogramming, invasion, and resistance to radiation therapy or chemotherapy ( 5 ). Hundreds of genes including VEGFA, Glut1, KLF8, ITGβ1 and etc., transcribed by HIFs are reported to promote metastasis and result in poor prognosis of GC ( 6 – 9 ). However, most of these studies are based on acute hypoxia treatment, while the actual condition inside solid tumors is chronic or cycling hypoxia, which deserves greater concern ( 10 , 11 ).…”

<p>CREB1 Suppresses Transcription of microRNA-186 to Promote Growth, Invasion and Epithelial–Mesenchymal Transition of Gastric Cancer Cells Through the KRT8/HIF-1α Axis</p>

“…HIF-1α is frequently overexpressed in cancers as a consequence of the response to hypoxic niches. 28 The promoting roles of HIF-1α in tumors including triggering metabolism, proliferation, inflammation, metastasis vascular homeostasis and tumorigenesis is also true for GC, 29 leaving it a potential target for GC treatment. 30 Clinically, high expression of HIF-1α has been documented to be correlated with unfavorable prognosis in GC patients.…”