Role of HIF-2α-VEGF-Notch in angiogenesis of residual hepatocellular carcinoma after high intensity focused ultrasound

Hang Liu; Weimin Wang; Jianbo Zhang; Haitao Gu; Jijian Wang; Shiji Zhou

doi:10.16016/j.1000-5404.201610123

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Role of HIF-2α-VEGF-Notch in angiogenesis of residual hepatocellular carcinoma after high intensity focused ultrasound

更新时间：2026-01-09

- Role of HIF-2α-VEGF-Notch in angiogenesis of residual hepatocellular carcinoma after high intensity focused ultrasound
- Journal of Third Military Medical University Vol. 39, Issue 7, Pages: 608-615(2017)
- 作者机构：
- 作者简介：
- 基金信息：
  
  the National Natural Science Foundation for Young Scholars of China(81301975);the General Program of Natural Science Foundation of Chongqing(CSTC2016jcyjA016)
- DOI：10.16016/j.1000-5404.201610123
  CLC：
- Received：18 October 2016，
  
  Published：2017-07
- 稿件说明：
移动端阅览
Hang Liu, Weimin Wang, Jianbo Zhang, et al. Role of HIF-2α-VEGF-Notch in angiogenesis of residual hepatocellular carcinoma after high intensity focused ultrasound[J]. Journal of Third Military Medical University, 2017, 39(7): 608-615.
DOI：

Hang Liu, Weimin Wang, Jianbo Zhang, et al. Role of HIF-2α-VEGF-Notch in angiogenesis of residual hepatocellular carcinoma after high intensity focused ultrasound[J]. Journal of Third Military Medical University, 2017, 39(7): 608-615. DOI： 10.16016/j.1000-5404.201610123.

摘要

Abstract

Objective

To determine the expression of hypoxia-inducible factor-1α (HIF-1α) and HIF-2α

vascular endothelium growth factor (VEGF) and Notch in the residual hepatocellular carcinoma (HCC) after high intensity focused ultrasound (HIFU).

Methods

The cell subline was established based on HCC SMMC7721 cells survived from HIFU treatment. Immunofluorescence staining was used to measure the expression of VEGF in normal control cells and HIFU treated cells. Real-time PCR and Western blotting were used to

measure the expression of HIF-1α

HIF-2α and VEGF at mRNA and protein levels at 0

12 and 24 h under hypoxic condition (1% O

) in both treated and control cells. Then

the treated cells was infected with lentiviral vectors LV-shRNA-VEGF

LV-shRNA-HIF-2α and LV-shRNA-NC respectively

and the mRNA and protein expression of VEGF

HIF-2α

Notch

and DLL4 was quantified by real-time PCR and Western blotting.

Results

The VEGF protein was mainly expressed in the cytoplasm in the treated and control cells. The expression of HIF-1α in the treated and control cells reached peak in 12 h after hypoxic treatment and then decreased

while the expression of HIF-2α and VEGF was increased with the time elapse (

0.05). The mRNA and protein expression of HIF-2α and VEGF was significantly lower in HIF-2α modulated cells than the treated cells (

0.05)

and that of VEGF

Notch and DLL4 was also decreased in the VEGF modulated cells than that in the treated cells (

0.05). The levels of HIF-2α

VEGF

Notch and DLL4 were significantly higher in the treated cells than control cells (

0.05).

Conclusion

Conclusion HIF-2α-VEGF-Notch signaling pathway is involved in the regulation of angiogenesis in residual hepatocellular carcinoma after HIFU treatment.

关键词

Keywords

references

张映林陈蛟吴涯昆高强度聚焦超声不完全消融对体外培养肝癌细胞的影响第三军医大学学报 2015 37 3 261 266 10.16016/j.1000-5404.201408161 http://aammt.tmmu.edu.cn/oa/DArticle.aspx?type=view&id=201408161 张映林, 陈蛟, 吴涯昆, 等.高强度聚焦超声不完全消融对体外培养肝癌细胞的影响[J].第三军医大学学报, 2015, 37(3):261-266. DOI:10.16016/j.1000-5404.201408161

Zhang Y L Chen J Wu Y K Effect of insufficient ablation of high intensity focused ultrasound on hepatoma cells in vitro J Third Mil Med Univ 2015 37 3 261 266 10.16016/j.1000-5404.201408161 http://aammt.tmmu.edu.cn/oa/DArticle.aspx?type=view&id=201408161 Zhang Y L, Chen J, Wu Y K, et al.Effect of insufficient ablation of high intensity focused ultrasound on hepatoma cells in vitro [J ] .J Third Mil Med Univ, 2015, 37(3):261-266. DOI:10.16016/j.1000-5404.201408161

Wu L Fu Z Zhou S HIF-1α and HIF-2α: Siblings in promoting angiogenesis of residual hepatocellular carcinoma after high-intensity focused ultrasound ablation PLoS ONE 2014 9 2 e88913 10.1371/journal.pone.0088913 Wu L, Fu Z, Zhou S, et al. HIF-1α and HIF-2α: Siblings in promoting angiogenesis of residual hepatocellular carcinoma after high-intensity focused ultrasound ablation[J]. PLoS ONE, 2014, 9(2): e88913. DOI:10.1371/journal.pone.0088913

Bao S Wu Q Sathornsumetee S Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor Cancer Res 2006 66 16 7843 7848 10.1158/0008-5472.CAN-06-1010 Bao S, Wu Q, Sathornsumetee S, et al. Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor[J]. Cancer Res, 2006, 66(16): 7843-7848. DOI:10.1158/0008-5472.CAN-06-1010

Carmeliet P Dor Y Herbert J M Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis Nature 1998 394 6692 485 490 10.1038/28867 Carmeliet P, Dor Y, Herbert J M, et al. Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis[J]. Nature, 1998, 394(6692): 485-490. DOI:10.1038/28867

Kaseb A O Hanbali A Cotant M Vascular endothelial growth factor in the management of hepatocellular carcinoma: a review of literature Cancer 2009 115 21 4895 4906 10.1002/cncr.24537 Kaseb A O, Hanbali A, Cotant M, et al. Vascular endothelial growth factor in the management of hepatocellular carcinoma: a review of literature[J]. Cancer, 2009, 115(21): 4895-4906. DOI:10.1002/cncr.24537

Kaseb A O Morris J S Hassan M M Clinical and prognostic implications of plasma insulin-like growth factor-1 and vascular endothelial growth factor in patients with hepatocellular carcinoma J Clin Oncol 2011 29 29 3892 3899 10.1200/JCO.2011.36.0636 Kaseb A O, Morris J S, Hassan M M, et al. Clinical and prognostic implications of plasma insulin-like growth factor-1 and vascular endothelial growth factor in patients with hepatocellular carcinoma[J]. J Clin Oncol, 2011, 29(29): 3892-3899. DOI:10.1200/JCO.2011.36.0636

Zhao J Du F Shen G The role of hypoxia-inducible factor-2 in digestive system cancers Cell Death Dis 2015 6 e1600 10.1038/cddis.2014.565 Zhao J, Du F, Shen G, et al. The role of hypoxia-inducible factor-2 in digestive system cancers[J]. Cell Death Dis, 2015, 6: e1600. DOI:10.1038/cddis.2014.565

Boreddy S R Sahu R P Srivastava S K Benzyl isothiocyanate suppresses pancreatic tumor angiogenesis and invasion by inhibiting HIF-α/VEGF/Rho-GTPases: pivotal role of STAT-3 PLoS ONE 2011 6 10 e25799 10.1371/journal.pone.0025799 Boreddy S R, Sahu R P, Srivastava S K. Benzyl isothiocyanate suppresses pancreatic tumor angiogenesis and invasion by inhibiting HIF-α/VEGF/Rho-GTPases: pivotal role of STAT-3[J]. PLoS ONE, 2011, 6(10): e25799. DOI:10.1371/journal.pone.0025799

Holmquist-Mengelbier L Fredlund E Löfstedt T Recruitment of HIF-1alpha and HIF-2alpha to common target genes is differentially regulated in neuroblastoma: HIF-2alpha promotes an aggressive phenotype Cancer Cell 2006 10 5 413 423 10.1016/j.ccr.2006.08.026 Holmquist-Mengelbier L, Fredlund E, Löfstedt T, et al. Recruitment of HIF-1alpha and HIF-2alpha to common target genes is differentially regulated in neuroblastoma: HIF-2alpha promotes an aggressive phenotype[J]. Cancer Cell, 2006, 10(5): 413-423. DOI:10.1016/j.ccr.2006.08.026

Benedito R Rocha S F Woeste M Notch-dependent VEGFR3 upregulation allows angiogenesis without VEGF-VEGFR2 signalling Nature 2012 484 7392 110 114 10.1038/nature10908 Benedito R, Rocha S F, Woeste M, et al. Notch-dependent VEGFR3 upregulation allows angiogenesis without VEGF-VEGFR2 signalling[J]. Nature, 2012, 484(7392): 110-114. DOI:10.1038/nature10908

Torre L A Bray F Siegel R L Global cancer statistics, 2012 CA Cancer J Clin 2015 65 2 87 108 10.3322/caac.21262 Torre L A, Bray F, Siegel R L, et al. Global cancer statistics, 2012[J]. CA Cancer J Clin, 2015, 65(2): 87-108. DOI:10.3322/caac.21262

Corey K E Pratt D S Current status of therapy for hepatocellular carcinoma Therap Adv Gastroenterol 2009 2 1 45 57 10.1177/1756283X08100328 Corey K E, Pratt D S. Current status of therapy for hepatocellular carcinoma[J]. Therap Adv Gastroenterol, 2009, 2(1): 45-57. DOI:10.1177/1756283X08100328

Chen L P Li N Ye H The effect of high intensity focused ultrasound on vascular endothelial growth factor and microvessel density in rabbit V-X2 hepatocellular carcinoma models Hepatogastroenterology 2013 60 121 136 139 10.5754/hge12469 Chen L P, Li N, Ye H. The effect of high intensity focused ultrasound on vascular endothelial growth factor and microvessel density in rabbit V-X2 hepatocellular carcinoma models[J]. Hepatogastroenterology, 2013, 60(121): 136-139. DOI:10.5754/hge12469

Wouters B G Koritzinsky M Hypoxia signalling through mTOR and the unfolded protein response in cancer Nat Rev Cancer 2008 8 11 851 864 10.1038/nrc2501 Wouters B G, Koritzinsky M. Hypoxia signalling through mTOR and the unfolded protein response in cancer[J]. Nat Rev Cancer, 2008, 8(11): 851-864. DOI:10.1038/nrc2501

Xia G Kageyama Y Hayashi T Regulation of vascular endothelial growth factor transcription by endothelial PAS domain protein 1 (EPAS1) and possible involvement of EPAS1 in the angiogenesis of renal cell carcinoma Cancer 2001 91 8 1429 1436 http://onlinelibrary.wiley.com/doi/10.1002/1097-0142(20010415)91:8<1429::AID-CNCR1149>3.0.CO;2-V/full Xia G, Kageyama Y, Hayashi T, et al. Regulation of vascular endothelial growth factor transcription by endothelial PAS domain protein 1 (EPAS1) and possible involvement of EPAS1 in the angiogenesis of renal cell carcinoma[J]. Cancer, 2001, 91(8): 1429-1436

Akeno N Czyzyk-Krzeska M F Gross T S Hypoxia induces vascular endothelial growth factor gene transcription in human osteoblast-like cells through the hypoxia-inducible factor-2alpha Endocrinology 2001 142 2 959 962 10.1210/endo.142.2.8112 Akeno N, Czyzyk-Krzeska M F, Gross T S, et al. Hypoxia induces vascular endothelial growth factor gene transcription in human osteoblast-like cells through the hypoxia-inducible factor-2alpha[J]. Endocrinology, 2001, 142(2): 959-962. DOI:10.1210/endo.142.2.8112

Rankin E B Rha J Unger T L Hypoxia-inducible factor-2 regulates vascular tumorigenesis in mice Oncogene 2008 27 40 5354 5358 10.1038/onc.2008.160 Rankin E B, Rha J, Unger T L, et al. Hypoxia-inducible factor-2 regulates vascular tumorigenesis in mice[J]. Oncogene, 2008, 27(40): 5354-5358. DOI:10.1038/onc.2008.160

Nijjar S S Wallace L Crosby H A Altered Notch ligand expression in human liver disease: further evidence for a role of the Notch signaling pathway in hepatic neovascularization and biliary ductular defects Am J Pathol 2002 160 5 1695 1703 10.1016/S0002-9440(10)61116-9 Nijjar S S, Wallace L, Crosby H A, et al. Altered Notch ligand expression in human liver disease: further evidence for a role of the Notch signaling pathway in hepatic neovascularization and biliary ductular defects[J]. Am J Pathol, 2002, 160(5): 1695-1703. DOI:10.1016/S0002-9440(10)61116-9

Liu Z Fan F Wang A Dll4-Notch signaling in regulation of tumor angiogenesis J Cancer Res Clin Oncol 2014 140 4 525 536 10.1007/s00432-013-1534-x Liu Z, Fan F, Wang A, et al. Dll4-Notch signaling in regulation of tumor angiogenesis[J]. J Cancer Res Clin Oncol, 2014, 140(4): 525-536. DOI:10.1007/s00432-013-1534-x

Hellström M Phng L K Hofmann J J Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis Nature 2007 445 7129 776 780 10.1038/nature05571 Hellström M, Phng L K, Hofmann J J, et al. Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis[J]. Nature, 2007, 445(7129): 776-780. DOI:10.1038/nature05571

Lobov I B Renard R A Papadopoulos N Delta-like ligand 4 (Dll4) is induced by VEGF as a negative regulator of angiogenic sprouting Proc Natl Acad Sci U S A 2007 104 9 3219 3224 10.1073/pnas.0611206104 Lobov I B, Renard R A, Papadopoulos N, et al. Delta-like ligand 4 (Dll4) is induced by VEGF as a negative regulator of angiogenic sprouting[J]. Proc Natl Acad Sci U S A, 2007, 104(9): 3219-3224. DOI:10.1073/pnas.0611206104

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