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HIF-1α Expression Correlates with Cellular Apoptosis, Angiogenesis and Clinical Prognosis in Rectal Carcinoma

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Pathology & Oncology Research

Abstract

Regional hypoxia caused by accelerated cell proliferation and overgrowth is an important characteristic of neoplasm. Hypoxia can cause a series of changes in gene transcription and protein expression, thereby not only inducing tumor cell resistance to radiotherapy and chemotherapy but also promoting tumor invasion and metastasis. This study aimed to investigate the relationship between HIF-1α expression and cellular apoptosis, angiogenesis and clinical prognosis in rectal carcinoma. In 113 rectal carcinoma cases, cellular apoptosis was analyzed by the in situ terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay, whereas the levels of HIF-1α expression, VEGF expression, microvessel density (MVD) and lymphatic vessel density(LVD) were examined by immunohistochemical staining. HIF-1 expression was detected in 67 of 113 rectal carcinoma cases (59.3 %). A positive correlation was found among HIF-1α expression, cellular apoptosis and angiogenesis. The 5-year survival rate in the HIF-1α-negative group was significantly higher than that in the HIF-1α-positive group (81.34 % versus 50 %, P < 0.05). According to the Cox regression analysis, HIF-1α expression, VEGF expression and cellular apoptosis index were independent risk factors for clinical prognosis in rectal carcinoma. Aberrant HIF-1α expression correlates with apoptosis inhibition, angiogenesis and poor prognosis in rectal carcinoma.

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References

  1. Gupta SC, Kim JH, Prasad S et al (2010) Regulation of survival, proliferation, invasion, angiogenesis, and metastasis of tumor cells through modulation of inflammatory pathways by nutraceuticals. Cancer Metastasis Rev 29(3):405–434

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. de Krijger I, Mekenkamp LJ, Punt CJ et al (2011) MicroRNAs in colorectal cancer metastasis. J Pathol 224(4):438–447

    Article  PubMed  Google Scholar 

  3. Arvelo F, Cotte C (2009) Hypoxia in cancer malignity. Invest Clin 50(4):529–546

    PubMed  Google Scholar 

  4. Greijer AE, van der Groep P, Kemming D et al (2005) Up-regulation of gene expression by hypoxia is medi-ated predominantly by hypoxia-inducible factor 1 (HIF-1). J Pathol 206:291–304

    Article  CAS  PubMed  Google Scholar 

  5. Belozerov VE, Van Meir EG (2005) Hypoxia inducible factor-1: a novel target for cancer therapy. Anticancer Drugs 16(9):901–909

    Article  CAS  PubMed  Google Scholar 

  6. Mucaj V, Shay JE, Simon MC (2012) Effects of hypoxia and HIFs on cancer metabolism. Int J Hematol 95(5):464–670

    Article  CAS  PubMed  Google Scholar 

  7. Semenza GL (2000) HIF-1: mediator of physiological and pathophysiological responses to hypoxia. J Appl Physiol 88(4):1474–1480

    CAS  PubMed  Google Scholar 

  8. Yeung SJ, Pan J, Lee MH (2008) Roles of p53, MYC and HIF-1 in regulating glycolysis - the seventh hallmark of cancer. Cell Mol Life Sci 65(24):3981–3999

    Article  CAS  PubMed  Google Scholar 

  9. Rapisarda A, Melillo G (2012) Role of the VEGF/VEGFR axis in cancer biology and therapy. Adv Cancer Res 114:237–267

    Article  CAS  PubMed  Google Scholar 

  10. Kerbel RS (2008) Tumor angiogenesis. N Engl J Med 358(19):2039–2049

    Article  CAS  PubMed  Google Scholar 

  11. Merritt WM, Sood AK (2007) Markers of angiogenesis in ovarian cancer. Dis Markers 23(5–6):419–431

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Menrad H, Werno C, Schmid T et al (2010) Roles of hypoxia-inducible factor-1alpha (HIF-1alpha) versus HIF-2alpha in the survival of hepatocellular tumor spheroids. Hepatology 51(6):2183–2192

    Article  CAS  PubMed  Google Scholar 

  13. Ardyanto TD, Osaki M, Nagahama Y et al (2008) Down-regulation of cobalt-induced HIF-1alpha expression correlates with cell proliferation and apoptosis in human gastric carcinoma cells. Oncol Rep 19(2):339–343

    CAS  PubMed  Google Scholar 

  14. Hao X, Du M, Bishop AE et al (1998) Imbalance between proliferation and apoptosis in development of colorectal carcinoma. Virchows Arch 433:523–527

    Article  CAS  PubMed  Google Scholar 

  15. Benchabane H, Ahmed Y (2009) The adenomatous polyposis coli tumor suppressor and Wnt signaling in the regulation of apoptosis. Adv Exp Med Biol 656:75–84

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Lampropoulos P, Zizi-Sermpetzoglou A, Rizos S et al (2012) TGF-beta signalling in colon carcinogenesis. Cancer Lett 314(1):1–7

    Article  CAS  PubMed  Google Scholar 

  17. Liu W, Shen SM, Zhao XY et al (2012) Targeted genes and interacting proteins of hypoxia inducible factor-1. Int J Biochem Mol Biol 3(2):165–178

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Zhong H, De Marzo AM, Laughner E et al (1999) Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. Cancer Res 59:5830–5835

    CAS  PubMed  Google Scholar 

  19. Koh MY, Spivak-Kroizman TR, Powis G (2010) HIF-1alpha and cancer therapy. Recent Results Cancer Res 180:15–34

    Article  CAS  PubMed  Google Scholar 

  20. Simiantonaki N, Taxeidis M, Jayasinghe C et al (2008) Hypoxia-inducible factor 1 alpha expression increases during colorectal carcinogenesis and tumor progression. BMC Cancer 8:320

    Article  PubMed  PubMed Central  Google Scholar 

  21. Kotch LE, Iyer NV, Laughner E et al (1999) Defective vascularization of HIF-1alpha-null embryos is not associated with VEGF deficiency but with mesenchymal cell death. Dev Biol 209:254–267

    Article  CAS  PubMed  Google Scholar 

  22. Tsuzuki Y, Fukumura D, Oosthuyse B et al (2000) Vascular endothelial growth factor (VEGF) modulation by targeting hypoxia-inducible factor-1alpha–> hypoxia re-sponse element–> VEGF cascade differentially regulates vascular response and growth rate in tumors. Cancer Res 60:6248–6252

    CAS  PubMed  Google Scholar 

  23. Rey S, Semenza GL (2010) Hypoxia-inducible factor-1-dependent mechanisms of vascularization and vascular remodelling. Cardiovasc Res 86(2):236–242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Duffy JP, Eibl G, Reber HA et al (2003) Influence of hypoxia and neoangiogenesis on the growth of pancreatic cancer. Mol Cancer 2:12

    Article  PubMed  PubMed Central  Google Scholar 

  25. Suzuki H, Tomida A, Tsuruo T (2001) Dephosphorylated hypoxia-inducible factor 1alpha as a mediator of p53-dependent apoptosis during hypoxia. Oncogene 20(41):5779–5788

    Article  CAS  PubMed  Google Scholar 

  26. Piret JP, Mottet D, Raes M et al (2002) Is HIF-1alpha a pro- or an anti-apoptotic protein? Biochem Pharmacol 64(5–6):889–892

    Article  CAS  PubMed  Google Scholar 

  27. Price DJ, Miralem T, Jiang S et al (2001) Role of vascular endothelial growth factor in the stimulation of cellular invasion and signaling of breast cancer cells. Cell Growth Differ 12(3):129–135

    CAS  PubMed  Google Scholar 

  28. Bos R, van Diest PJ, van der Groep P et al (2004) Expression of hypoxia-inducible factor-1alpha and cell cycle proteins in invasive breast cancer are estrogen receptor related. Breast Cancer Res 6(4):R450–R459

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Nagy JA, Vasile E, Feng D et al (2002) Vascular permeability factor/vascular endothelial growth factor induces lymphangiogenesis as well as angiogenesis. J Exp Med 196(11):1497–1506

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Mohammed RA, Green A, El-Shikh S et al (2007) Prognostic significance of vascular endothelial cell growth factors -A, -C and -D in breast cancer and their relationship with angio- and lymphangiogenesis. Br J Cancer 96(7):1092–1100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Gao Y, Zhong WX, Mu DB et al (2008) Distributions of angiogenesis and lymphangiogenesis in gastrointestinal intramucosal tumors. Ann Surg Oncol 15(4):1117–1123

    Article  PubMed  Google Scholar 

  32. Lee S, Choi I, Hong YK (2010) Heterogeneity and plasticity of lymphatic endothelial cells. Semin Thromb Hemost 36(3):352–361

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

The work was Supported by Chongqing Municipal Natural Science Foundation (Grant No.cstc2013jcyjA10057).

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Authors and Affiliations

  1. Department of Urinary Surgery, the Children’s Hospital, Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorder, Key Laboratory of Pediatrics in Chongqing (CSTC2009CA5002), Chongqing, 400014, China

    Liu Feng, Lin Tao, He Dawei & Li Xuliang

  2. Department of Obstetrics and Gynecology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China

    Luo Xiaodong

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  1. Liu Feng
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  2. Lin Tao
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  3. He Dawei
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  4. Li Xuliang
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Correspondence to Luo Xiaodong.

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Feng, L., Tao, L., Dawei, H. et al. HIF-1α Expression Correlates with Cellular Apoptosis, Angiogenesis and Clinical Prognosis in Rectal Carcinoma. Pathol. Oncol. Res. 20, 603–610 (2014). https://doi.org/10.1007/s12253-013-9738-6

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  • DOI: https://doi.org/10.1007/s12253-013-9738-6

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