title: Glucagon-induced angiogenesis and tumor growth through the HIF-1-VEGF-dependent pathway in hyperglycemic nude mice.
abstract: In this study, we examined the effect glucagon-induced hyperglycemia on tumor growth as well as the role of the hypoxia-inducible factor 1 (HIF-1)-vascular endothelial growth factor (VEGF) pathway in this condition. A high concentration of glucose (HG) was utilized to treat HeLa cells under hypoxic or normoxic conditions, and transcriptional levels of HIF-1, VEGF, and basic fibroblast growth factor (bFGF) were evaluated. Moreover, the ability of an HIF-1 inhibitor to block the effect induced by HG was examined. By contrast, hyperglycemia was induced in nude mice by glucagon released from an osmotic pump, and microvessel density was determined with CD31 staining. Thus, the relationship among hyperglycemia, microvessel density, tumor growth, and the HIF-1 inhibitor were analyzed. We found that HG increased transcription of the VEGF gene, which is downstream of HIF-1. Moreover, HG impaired the function of HIF-1 inhibitors [HIF-1 small interfering RNA (siRNA) and berberine] to affect the VEGF transcription level in tumor cells. By contrast, hyperglycemia increased tumor microvessel density and promoted tumor growth, which was inhibited by the HIF-1 inhibitor. However, hyperglycemia attenuated the effect of the HIF-1 inhibitor. Glucagon-induced hyperglycemia influenced tumor microenvironments through the HIF-1-VEGF-dependent pathway and promoted tumor growth and resistance to HIF-1 inhibition treatments.
authors.affiliation: Pediatric Department, Southwest Hospital of The Third Military Medical University, Chongqing, China wangy_0517@163.com.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pharmacy, Children's Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Y D
authors.initials: YD
authors.lastname: Zhu
authors.affiliation: Pediatric Department, Southwest Hospital of The Third Military Medical University, Chongqing, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Gui
authors.affiliation: Department of Clinical Laboratory, The Fifth People's Hospital of Wuxi, The Affiliated Hospital of Nanjing Medical University, Wuxi, Jiangsu, China.
authors.forename: X D
authors.initials: XD
authors.lastname: Wang
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Y X
authors.initials: YX
authors.lastname: Zhu
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005934:Glucagon / Q000378:metabolism* / Q000494:pharmacology; D064593:Heterografts; D006801:Humans; D006943:Hyperglycemia / Q000139:chemically induced; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D008820:Mice, Obese; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D047368:Tumor Burden / Q000187:drug effects; D059016:Tumor Microenvironment / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
chemical_list: D051793:Hypoxia-Inducible Factor 1; D042461:Vascular Endothelial Growth Factor A; D005934:Glucagon