Abstract
Gastric cancer (GC) ranks the third among global cancer-related mortality, especially in East Asia. Angiogenesis plays an important role in promoting tumor progression, and clinical trials have demonstrated that anti-angiogenesis therapy is effective in GC management. Natriuretic peptide receptor A (NPRA) functions significantly in promoting GC development and progression. Whether NPRA can promote angiogenesis of GC remains unclear. Tumor samples collection and immunohistochemical experiment showed that the expression of NPRA was positively correlated with the expression of CD31 and vessel density. In vivo and in vitro analysis showed that NPRA could promote GC-associated angiogenesis and tumor metastasis. Results of Co-IP/MS showed that NPRA could prevent HIF-1α from being degraded by binding to HIF-1α. Protection of HIF-1α improved VEGF levels and thus promoted angiogenesis. In summary, NPRA protected HIF-1α from proteolysis by binding to HIF-1α, increased the expression of HIF-1α, and promoted GC angiogenesis. This study has discovered a new mechanism for NPRA to promote gastric cancer development and a new regulatory mechanism for HIF-1α.
Highlights
Gastric cancer (GC) ranks third in the global cancer-related morbidity and mortality, especially in East Asia [1]
vascular endothelial growth factor (VEGF) signaling pathways were affected after the inhibition of Natriuretic peptide receptor A (NPRA) (Fig. 2C-D). These results indicated that NPRA may accelerate angiogenesis by promoting VEGF signaling in GC
We have used the transwell experiment to explore the rescue function of HIF-1α to NPRA, and we found that overexpression of HIF-1α could rescue human umbilical vein endothelial cells (HUVECs) migration and invasion ability impaired by knockdown of NPRA (Fig. S3). Quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) detection showed that NPRA had no significant influences on HIF-1α expression on mRNA level (Fig. 6E)
Summary
Gastric cancer (GC) ranks third in the global cancer-related morbidity and mortality, especially in East Asia [1]. Inhibition of the angiogenesis signaling pathway will help prevent tumor growth and prolong the survival time of cancer patients [9, 10]. Among the identified signaling pathways and molecules, vascular endothelial growth factor (VEGF), especially for VEGF-A is essential to activate the tumor angiogenesis process [5, 13]. Several studies have shown that HIF-1, especially HIF-1α promotes cancer growth and metastasis by activating angiogenesis in solid tumors containing GC [19,20,21]. Tube formation assay and HUVEC transwell assay showed that NPRA could help GC cells secret VEGF and promote angiogenesis. Live imaging of small animals and mouse xenograft models showed that NPRA promoted vessel formation and tumor cell metastasis. NPRA would be an important pro-angiogenic factor and therapeutic target of gastric cancer. The standard microplate reader (Scientific MultiskanMK3, Thermo Scientific) was used to record the absorbance at 450 nm every 24 h according to the manufacturers’ protocols
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