HIF-1α: Its Role in Metastasis of Oesophageal Malignancy

  • A. M. V. N. Prathyusha
  • Godi Raghu
  • Pallaval Veera BramhachariEmail author


Hypoxia is a significant factor of the tumor microenvironment. Transcriptional factor HIF-1α serves as a drive for tumor hypoxic microenvironment and triggers gene transcription that intricate in important aspects of cancer biology. Hypoxic effects can be either positive or negative, depending on the context, severity and duration on a tissue. In oesophagus cancer, hypoxia stabilizes the transcription factor HIF-1α and regulates diverse functions such as metastasis, angiogenesis, cell cycle regulation and apoptosis chemo-resistance. miRNAs also play essential roles in the adaptive response of tumors to hypoxia. Therefore, HIF-1α acts as a promising target in advancement of new therapeutics for oesophagus cancer therapy. Recent developments in regulation of HIF-1α and functional involvement in tumor growth, migration, stemness and drugs affecting HIF-1α expression will be discussed in this review.


Hypoxia HIF-1α Cell proliferation Metastasis Angiogenesis Apoptosis Growth factors Cytokines Stemness Tumor resistance 


  1. 1.
    Ahluwalia A, S Tarnawski A (2012) Critical role of hypoxia sensor-HIF-1α in VEGF gene activation. Implications for angiogenesis and tissue injury healing. Curr Med Chem 19(1):90–97CrossRefPubMedGoogle Scholar
  2. 2.
    Arnal MJD, Arenas ÁF, Arbeloa ÁL (2015) Esophageal cancer: risk factors, screening and endoscopic treatment in Western and Eastern countries. World J Gastroenterol: WJG 21(26):7933CrossRefGoogle Scholar
  3. 3.
    Chau NM, Rogers P, Aherne W, Carroll V, Collins I, McDonald E, … Ashcroft M (2005) Identification of novel small molecule inhibitors of hypoxia-inducible factor-1 that differentially block hypoxia-inducible factor-1 activity and hypoxia-inducible factor-1α induction in response to hypoxic stress and growth factors. Cancer Res, 65(11):4918–4928CrossRefPubMedGoogle Scholar
  4. 4.
    Chen J, Bai M, Ning C, Xie B, Zhang J, Liao H, … Chen X (2016) Gankyrin facilitates follicle-stimulating hormone-driven ovarian cancer cell proliferation through the PI3K/AKT/HIF-1α/cyclin D1 pathway. Oncogene 35(19):2506–2517CrossRefPubMedGoogle Scholar
  5. 5.
    Chen J, Ding Z, Peng Y, Pan F, Li J, Zou L, … Liang H (2014) HIF-1α inhibition reverses multidrug resistance in colon cancer cells via downregulation of MDR1/P-glycoprotein. PLoS One 9(6):e98882CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Clark AS, West KA, Blumberg PM, Dennis PA (2003) Altered protein kinase C (PKC) isoforms in non-small cell lung cancer cells PKCδ promotes cellular survival and chemotherapeutic resistance. Cancer Res 63(4):780–786PubMedGoogle Scholar
  7. 7.
    Cui Y, Li YY, Li J, Zhang HY, Wang F, Bai X, Li SS (2016) STAT3 regulates hypoxia-induced epithelial mesenchymal transition in esophageal squamous cell cancer. Oncol Rep 36(1):108–116CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Daenen LG, Roodhart JM, van Amersfoort M, Dehnad M, Roessingh W, Ulfman LH, … Voest EE (2011) Chemotherapy enhances metastasis formation via VEGFR-1–expressing endothelial cells. Cancer Res 71(22):6976–6985CrossRefPubMedGoogle Scholar
  9. 9.
    Ding Y, Shimada Y, Maeda M, Kawabe A, Kaganoi J, Komoto I, … Imamura M (2003) Association of CC chemokine receptor 7 with lymph node metastasis of esophageal squamous cell carcinoma. Clin Cancer Res 9(9):3406–3412Google Scholar
  10. 10.
    Domanska UM, Kruizinga RC, Nagengast WB, Timmer-Bosscha H, Huls G, de Vries EG, Walenkamp AM (2013) A review on CXCR4/CXCL12 axis in oncology: no place to hide. Eur J Cancer 49(1):219–230CrossRefPubMedGoogle Scholar
  11. 11.
    Elsir T, Eriksson A, Orrego A, Lindstrom MS, Nister M (2010) Expression of PROX1 is a common feature of high-grade malignant astrocyticgliomas. J Neuropathol Exp Neurol 69(2):129–138CrossRefPubMedGoogle Scholar
  12. 12.
    Feldser D, Agani F, Iyer NV, Pak B, Ferreira G, Semenza GL (1999) Reciprocal positive regulation of hypoxia-inducible factor 1α and insulin-like growth factor 2. Cancer Res 59(16):3915–3918PubMedGoogle Scholar
  13. 13.
    Foskolou IP, Stellas D, Rozani I, Lavigne MD, Politis PK (2013) Prox1 suppresses the proliferation of neuroblastoma cells via a dual action in. p27-Kip1 and Cdc25A. Oncogene 32(8):947–960CrossRefPubMedGoogle Scholar
  14. 14.
    Fu J, Chen Y, Cao J, Luo T, Qian YW, Yang W et al (2011) p28GANK overexpression accelerates hepatocellular carcinoma invasiveness and metastasis via phosphoinositol 3-kinase/AKT/hypoxia-inducible factor-1α pathways. Hepatology 53(1):181–192CrossRefPubMedGoogle Scholar
  15. 15.
    Gao H, Teng C, Huang W, Peng J, Wang C (2015) SOX2 promotes the epithelial to mesenchymal transition of esophageal squamous cells by modulating Slug expression through the activation of STAT3/HIF-α signaling. Int J Mol Sci 16(9):21643–21657CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Gao L, Xie H, Dong L, Zou J, Fu J, Gao X et al (2014) Gankyrin is essential for hypoxia enhanced metastatic potential in breast cancer cells. Mol Med Rep 9(3):1032–1036CrossRefPubMedGoogle Scholar
  17. 17.
    Ge, X., Zhen, F., Yang, B., Yang, X., Cai, J., Zhang, C., … & Sun, X. (2014). Ginsenoside Rg3 enhances radiosensitization of hypoxic esophageal cancer cell lines through vascular endothelial growth factor and hypoxia inducible factor 1α. J Int Med Res, 0300060513505491Google Scholar
  18. 18.
    Goda N, Ryan HE, Khadivi B, McNulty W, Rickert RC, Johnson RS (2003) Hypoxia-inducible factor 1α is essential for cell cycle arrest during hypoxia. Mol Cell Biol 23(1):359–369CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Gort EH, Groot AJ, Van De Ven TD, Van Der Groep P, Verlaan I, Van Laar T et al (2006) Hypoxia-inducible factor-1α expression requires PI 3-kinase activity and correlates with Akt1 phosphorylation in invasive breast carcinomas. Oncogene 25(45):6123–6127CrossRefPubMedGoogle Scholar
  20. 20.
    Graves EE, Maity A, Le QT (2010) The tumor microenvironment in non–small-cell lung cancer. Semin Radiat Oncol 20(3):156–163. WB SaundersCrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Greijer AE, Van der Wall E (2004) The role of hypoxia inducible factor 1 (HIF-1) in hypoxia induced apoptosis. J Clin Pathol 57(10):1009–1014CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Griffiths EA, Pritchard SA, Valentine HR, Whitchelo N, Bishop PW, Ebert MP, … West CM (2007) Hypoxia-inducible factor-1α expression in the gastric carcinogenesis sequence and its prognostic role in gastric and gastro-esophageal adenocarcinomas. Br J Cancer 96(1):95–103CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Gros SJ, Graeff H, Drenckhan A, Kurschat N, Blessmann M, Rawnaq T, Izbicki JR (2012) CXCR4/SDF-1α-mediated chemotaxis in an in vivo model of metastatic esophageal carcinoma. In Vivo 26(4):711–718PubMedGoogle Scholar
  24. 24.
    Hammond EM, Giaccia AJ (2005) The role of p53 in hypoxia-induced apoptosis. Biochem Biophys Res Commun 331(3):718–725CrossRefPubMedGoogle Scholar
  25. 25.
    Han B, Li W, Sun Y, Zhou L, Xu Y, Zhao X (2014) A prolyl-hydroxylase inhibitor, ethyl-3, 4-dihydroxybenzoate, induces cell autophagy and apoptosis in esophageal squamous cell carcinoma cells via up-regulation of BNIP3 and N-myc downstream-regulated gene-1. PLoS One 9(9):e107204CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    He B, Yin B, Wang B, Xia Z, Chen C, Tang J (2012) microRNAs in esophageal cancer (review). Mol Med Rep 6(3):459–465CrossRefPubMedGoogle Scholar
  27. 27.
    Hu YY, Zheng MH, Zhang R, Liang, Y. M., & Han, H. (2012).Notch signaling pathway and cancer metastasis. In: Notch signaling in embryology and cancer, Springer US, p 186–198.Google Scholar
  28. 28.
    Ishikawa T, Nakashiro KI, Klosek SK, Goda H, Hara S, Uchida D, Hamakawa H (2009) Hypoxia enhances CXCR4 expression by activating HIF-1 in oral squamous cell carcinoma. Oncol Rep 21(3):707–712PubMedGoogle Scholar
  29. 29.
    Jing SW, Wang YD, Kuroda M, Su JW, Sun GG, Liu Q et al (2012) HIF-1α contributes to hypoxia-induced invasion and metastasis of esophageal carcinoma via inhibiting E-cadherin and promoting MMP-2 expression. Acta Med Okayama 66(5):399–407PubMedGoogle Scholar
  30. 30.
    Kaifi JT, Yekebas EF, Schurr P, Obonyo D, Wachowiak R, Busch P, … Izbicki JR (2005) Tumor-cell homing to lymph nodes and bone marrow and CXCR4 expression in esophageal cancer. J Natl Cancer Inst 97(24):1840–1847CrossRefPubMedGoogle Scholar
  31. 31.
    Kamei D, Murakami M, Nakatani Y, Ishikawa Y, Ishii T, Kudo I (2003) Potential role of microsomal prostaglandin E synthase-1 in tumorigenesis. J Biol Chem 278(21):19396–19405CrossRefPubMedGoogle Scholar
  32. 32.
    Kamura T, Conrad MN, Yan Q, Conaway RC, Conaway JW (1999) The Rbx1 subunit of SCF and VHL E3 ubiquitin ligase activates Rub1 modification of cullins Cdc53 and Cul2. Genes Dev 13(22):2928–2933CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Kang HJ, Kim HJ, Rih JK, Mattson TL, Kim KW, Cho CH, … Bae I (2006) BRCA1 plays a role in the hypoxic response by regulating HIF-1α stability and by modulating vascular endothelial growth factor expression. J Biol Chem 281(19):13047–13056CrossRefPubMedGoogle Scholar
  34. 34.
    Kase S, Osaki M, Honjo S, Adachi H, Tsujitani S, Kaibara N, Ito H (2003) Expression of cyclo-oxygenase-2 is correlated with high intratumoral microvessel density and low apoptotic index in human esophageal squamous cell carcinomas. Virchows Arch 442(2):129–135PubMedGoogle Scholar
  35. 35.
    Kato Y, Yashiro M, Fuyuhiro Y, Kashiwagi S, Matsuoka J, Hirakawa T, … Sawada T (2011) Effects of acute and chronic hypoxia on the radiosensitivity of gastric and esophageal cancer cells. Anticancer Res 31(10):3369–3375Google Scholar
  36. 36.
    Kimura, S., Kitadai, Y., Kuwai, T., Tanaka, S., Hihara, J., Yoshida, K., …& Chayama, K. (2005). Expression of p53 protein in esophageal squamous cell carcinoma: Relation to hypoxia-inducible factor-1α, angiogenesis and apoptosis. Pathobiology, 72(4), 179–185CrossRefPubMedGoogle Scholar
  37. 37.
    Kimura S, Kitadai Y, Tanaka S, Kuwai T, Hihara J, Yoshida K, … Chayama K (2004) Expression of hypoxia-inducible factor (HIF)-1α is associated with vascular endothelial growth factor expression and tumor angiogenesis in human esophageal squamous cell carcinoma. Eur J Cancer 40(12):1904–1912CrossRefPubMedGoogle Scholar
  38. 38.
    Kitajima Y, Miyazaki K (2013) The critical impact of HIF-1a on gastric cancer biology. Cancer 5(1):15–26CrossRefGoogle Scholar
  39. 39.
    Koshikawa N, Hayashi JI, Nakagawara A, Takenaga K (2009) Reactive oxygen species-generating mitochondrial DNA mutation up-regulates hypoxia-inducible factor-1α gene transcription via phosphatidylinositol 3-kinase-Akt/protein kinase C/histone deacetylase pathway. J Biol Chem 284(48):33185–33194CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Koukourakis MI, Giatromanolaki A, Skarlatos J, Corti L, Blandamura S, Piazza M, … Harris AL (2001) Hypoxia inducible factor (HIF-1a and HIF-2a) expression in early esophageal cancer and response to photodynamic therapy and radiotherapy. Cancer Res 61(5):1830–1832Google Scholar
  41. 41.
    Krishnamachary B, Berg-Dixon S, Kelly B, Agani F, Feldser D, Ferreira G, … Semenza GL (2003) Regulation of colon carcinoma cell invasion by hypoxia-inducible factor 1. Cancer Res 63(5):1138–1143Google Scholar
  42. 42.
    Kumar V, Gabrilovich DI (2014) Hypoxia-inducible factors in regulation of immune responses in tumor microenvironment. Immunology 143(4):512–519CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Laughner E, Taghavi P, Chiles K, Mahon PC, Semenza GL (2001) HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1α (HIF-1α) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. Mol Cell Biol 21(12):3995–4004CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Lee JJ, Natsuizaka M, Ohashi S, Wong GS, Takaoka M, Michaylira CZ, … Naomoto Y (2010) Hypoxia activates the cyclooxygenase-2–prostaglandin E synthase axis. Carcinogenesis 31(3):427–434CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Lee KB, Ye S, Park MH, Park BH, Lee JS, Kim SM (2014) p63-Mediated activation of the b-catenin/c-Myc signaling pathway stimulates esophageal squamous carcinoma cell invasion and metastasisGoogle Scholar
  46. 46.
    Leszczynska KB, Foskolou IP, Abraham AG, Anbalagan S, Tellier C, Haider S, … Hammond E M (2015) Hypoxia-induced p53 modulates both apoptosis and radiosensitivity via AKT. J Clin Invest 125(6):2385–239CrossRefPubMedGoogle Scholar
  47. 47.
    Li C, Zhou X, Wang Y, Jing S, Yang C, Sun G, … Wang L (2014) miR-210 regulates esophageal cancer cell proliferation by inducing G2/M phase cell cycle arrest through targeting PLK1. Mol Med Rep 10(4):2099–2104CrossRefPubMedGoogle Scholar
  48. 48.
    Liao D, Johnson RS (2007) Hypoxia: a key regulator of angiogenesis in cancer. Cancer Metastasis Rev 26(2):281–290CrossRefPubMedGoogle Scholar
  49. 49.
    Lin Y, Totsuka Y, He Y, Kikuchi S, Qiao Y, Ueda J, … Tanaka H (2013) Epidemiology of esophageal cancer in Japan and China. J Epidemiol 23(4):233–242CrossRefPubMedGoogle Scholar
  50. 50.
    Liu J, Chen L, Deng H, Xu B, Li M, Zheng X, … Jiang J (2014) Epithelial-to-mesenchymal transition in human esophageal cancer associates with tumor progression and patient’s survival. Int J Clin Exp Pathol 7(10):6943Google Scholar
  51. 51.
    Liu L, Ning X, Sun L, Zhang H, Shi Y, Guo C, … Wu K (2008) Hypoxia-inducible factor-1α contributes to hypoxia-induced chemoresistance in gastric cancer. Cancer Sci 99(1):121–128Google Scholar
  52. 52.
    Liu Y, Zhang JB, Qin Y, Wang W, Wei L, Teng Y, … Ren ZG (2013) PROX1 promotes hepatocellular carcinoma metastasis by way of up-regulating hypoxia-inducible factor 1α expression and protein stability. Hepatology 58(2):692–705CrossRefPubMedGoogle Scholar
  53. 53.
    Long A, Giroux V, Whelan KA, Tétreault MP, Tanaka K, Lee JS, … Rustgi AK (2015) WNT10A promotes an invasive and self-renewing phenotype in esophageal squamous cell carcinoma. Carcinogenesis, bgv025Google Scholar
  54. 54.
    Lu X, Kang Y (2010) Hypoxia and hypoxia-inducible factors: master regulators of metastasis. Clin Cancer Res 16(24):5928–5935CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Ma T, Wang N, Su Z, Chen L, Zhu N, Ma C, … Chen H (2011) Characterization of apoptosis and proliferation in esophageal carcinoma EC109 cells following siRNA-induced down-regulation of TRAF6. Mol Cell Biochem 352(1–2):77–85CrossRefPubMedGoogle Scholar
  56. 56.
    Masoud GN, Wang J, Chen J, Miller D, Li W (2015) Design, synthesis and biological evaluation of novel HIF-1α inhibitors. Anticancer Res 35(7):3849–3859PubMedPubMedCentralGoogle Scholar
  57. 57.
    Maxwell PJ, Gallagher R, Seaton A, Wilson C, Scullin P, Pettigrew J, … Waugh DJJ (2007) HIF-1 and NF-κB-mediated upregulation of CXCR1 and CXCR2 expression promotes cell survival in hypoxic prostate cancer cells. Oncogene 26(52):7333–7345CrossRefPubMedGoogle Scholar
  58. 58.
    Nagoya H, Futagami S, Shimpuku M, Tatsuguchi A, Wakabayashi T, Yamawaki H, … Miyashita M (2014) Apurinic/apyrimidinic endonuclease-1 is associated with angiogenesis and VEGF production via upregulation of COX-2 expression in esophageal cancer tissues. Am J Physiol-Gastrointest Liver Physiol 306(3):G183–G190CrossRefPubMedGoogle Scholar
  59. 59.
    Nakanishi M, Gokhale V, Meuillet EJ, Rosenberg DW (2010) mPGES-1 as a target for cancer suppression: A comprehensive invited review “Phospholipase A2 and lipid mediators”. Biochimie 92(6):660–664CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Natsuizaka M, Naganuma S, Kagawa S, Ohashi S, Ahmadi A, Subramanian H, … Klein-Szanto AJ (2012) Hypoxia induces IGFBP3 in esophageal squamous cancer cells through HIF-1α-mediated mRNA transcription and continuous protein synthesis. FASEB J 26(6):2620–2630CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Noronha V, Patil VM, Joshi A, Chougule A, Banavali S, Prabhash K (2017) Potential role of metronomic chemotherapy in the treatment of esophageal and gastroesophageal cancer. Cancer LettGoogle Scholar
  62. 62.
    Ohta M, Kitadai Y, Tanaka S, Yoshihara M, Yasui W, Mukaida N, … Chayama K (2002) Monocyte chemoattractant protein-1 expression correlates with macrophage infiltration and tumor vascularity in human esophageal squamous cell carcinomas. Int J Cancer 102(3):220–224CrossRefPubMedGoogle Scholar
  63. 63.
    Okuda H, Hirai SI, Takaki Y, Kamada M, Baba M, Sakai N, … Shuin T (1999) Direct interaction of the β-domain of VHL tumor suppressor protein with the regulatory domain of atypical PKC isotypes. Biochem Biophys Res Commun 263(2):491–497CrossRefPubMedGoogle Scholar
  64. 64.
    Ortiz CM, Ito T, Tanaka E, Tsunoda S, Nagayama S, Sakai Y, … Shimada Y (2008) Gankyrin oncoprotein overexpression as a critical factor for tumor growth in human esophageal squamous cell carcinoma and its clinical significance. Int J Cancer 122(2):325–332CrossRefGoogle Scholar
  65. 65.
    Petrova TV, Nykanen A, Norrmen C et al (2008) Transcription factor PROX1 induces colon cancer progression by promoting the transition from benign to highly dysplastic phenotype. Cancer Cell 13(5):407–419CrossRefPubMedGoogle Scholar
  66. 66.
    Powis G, Kirkpatrick L (2004) Hypoxia inducible factor-1α as a cancer drug target. Mol Cancer Ther 3(5):647–654PubMedGoogle Scholar
  67. 67.
    Prins MJ, Verhage RJ, ten Kate FJ, Van Hillegersberg R (2012) Cyclooxygenase isoenzyme-2 and vascular endothelial growth factor are associated with poor prognosis in esophageal adenocarcinoma. J Gastrointest Surg 16(5):956–966CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Qiu Y, Li P, Ji C (2015) Cell death conversion under hypoxic condition in tumor development and therapy. Int J Mol Sci 16(10):25536–25551CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Sasaki K, Natsugoe S, Ishigami S, Matsumoto M, Okumura H, Setoyama T, … Owaki T (2009) Expression of CXCL12 and its receptor CXCR4 in esophageal squamous cell carcinoma. Oncol Rep 21(1):65–71Google Scholar
  70. 70.
    Sasaki Y, Tamura M, Koyama R, Nakagaki T, Adachi Y, Tokino T (2016) Genomic characterization of esophageal squamous cell carcinoma: insights from next-generation sequencing. World J Gastroenterol 22(7):2284CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Schneider M, Buchler P, Giese N et al (2006) Role of lymphangiogenesis and lymphangiogenic factors during pancreatic cancer progression and lymphatic spread. Int J Oncol 28(4):883–890PubMedGoogle Scholar
  72. 72.
    Semenza GL (2000) HIF-1: mediator of physiological and pathophysiological responses to hypoxia. J Appl Physiol 88(4):1474–1480CrossRefPubMedGoogle Scholar
  73. 73.
    Semenza GL (2002) Involvement of hypoxia-inducible factor 1 in human cancer. Intern Med 41(2):79–83CrossRefPubMedGoogle Scholar
  74. 74.
    Semenza GL (2013) Cancer–stromal cell interactions mediated by hypoxia-inducible factors promote angiogenesis, lymphangiogenesis, and metastasis. Oncogene 32(35):4057–4063CrossRefPubMedGoogle Scholar
  75. 75.
    Seyfried TN, Huysentruyt LC (2013) On the origin of cancer metastasis. Crit Rev Oncog 18(1–2):43CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Shamma A, Yamamoto H, Doki Y, Okami J, Kondo M, Fujiwara Y, … Monden M (2000) Up-regulation of cyclooxygenase-2 in squamous carcinogenesis of the esophagus. Clin Cancer Res 6(4):1229–1238Google Scholar
  77. 77.
    Shibata-Kobayashi S, Yamashita H, Okuma K, Shiraishi K, Igaki H, Ohtomo K, Nakagawa K (2013) Correlation among 16 biological factors [p53, p21waf1, MIB-1 (Ki-67), p16INK4A, cyclin D1, E-cadherin, Bcl-2, TNF-α, NF-κB, TGF-β, MMP-7, COX-2, EGFR, HER2/neu, ER, and HIF-1α] and clinical outcomes following curative chemoradiation therapy in 10 patients with esophageal squamous cell carcinoma. Oncol Lett 5(3):903–910CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Sohda M, Ishikawa H, Masuda N, Kato H, Miyazaki T, Nakajima M, … Kuwano H (2004) Pretreatment evaluation of combined HIF-1α, p53 and p21 expression is a useful and sensitive indicator of response to radiation and chemotherapy in esophageal cancer. Int J Cancer 110(6):838–844CrossRefPubMedGoogle Scholar
  79. 79.
    Stoeltzing O, McCarty MF, Wey JS, Fan F, Liu W, Belcheva A, … Ellis LM (2004) Role of hypoxia-inducible factor 1α in gastric cancer cell growth, angiogenesis, and vessel maturation. J Natl Cancer Inst 96(12):946–956CrossRefPubMedGoogle Scholar
  80. 80.
    Sudo T, Iwaya T, Nishida N, Sawada G, Takahashi Y, Ishibashi M, … Mimori K (2013) Expression of mesenchymal markers vimentin and fibronectin: the clinical significance in esophageal squamous cell carcinoma. Ann Surg Oncol 20(3):324–335CrossRefGoogle Scholar
  81. 81.
    Sun H, Li XB, Meng Y, Fan L, Li M, Fang J (2013) TRAF6 upregulates expression of HIF-1α and promotes tumor angiogenesis. Cancer Res 73(15):4950–4959CrossRefPubMedGoogle Scholar
  82. 82.
    Suzuki H, Tomida A, Tsuruo T (2001) Dephosphorylated hypoxia-inducible factor 1α as a mediator of p53-dependent apoptosis during hypoxia. Oncogene 20(41):5779–5788CrossRefPubMedGoogle Scholar
  83. 83.
    Tachezy M, Zander H, Gebauer F, von Loga K, Pantel K, Izbicki JR, Bockhorn M (2013) CXCR7 expression in esophageal cancer. J Transl Med 11:238CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Takaoka M, Kim SH, Okawa T, Michaylira CZ, Stairs D, Johnston C, … El-Deiry WS (2007) IGFBP-3 regulates esophageal tumor growth through IGF-dependent and independent mechanisms. Cancer Biol Ther 6(4):534–540CrossRefGoogle Scholar
  85. 85.
    Takii Y, Abiru S, Fujioka H, Nakamura M, Komori A, Ito M, … Yano K (2007) Expression of microsomal prostaglandin E synthase-1 in human hepatocellular carcinoma. Liver Int 27(7):989–996CrossRefPubMedGoogle Scholar
  86. 86.
    Tetsu O, McCormick F (1999) β-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature 398(6726):422–426CrossRefGoogle Scholar
  87. 87.
    Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A (2015) Global cancer statistics, 2012. CA Cancer J Clin 65(2):87–108CrossRefGoogle Scholar
  88. 88.
    Tzao C, Lee SC, Tung HJ, Hsu HS, Hsu WH, Sun GH, … Cheng YL (2008) Expression of hypoxia-inducible factor (HIF)-1α and vascular endothelial growth factor (VEGF)-D as outcome predictors in resected esophageal squamous cell carcinoma. Dis Markers 25(3):141–148CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    van Rees BP, Sivula A, Thorén S, Yokozaki H, Jakobsson PJ, Offerhaus GJA, Ristimäki A (2003) Expression of microsomal prostaglandin E synthase-1 in intestinal type gastric adenocarcinoma and in gastric cancer cell lines. Int J Cancer 107(4):551–556CrossRefPubMedGoogle Scholar
  90. 90.
    Versmold B, Felsberg J, Mikeska T et al (2007) Epigenetic silencing of the candidate tumor suppressor gene PROX1 in sporadic breast cancer. Int J Cancer 121(3):547–554CrossRefPubMedGoogle Scholar
  91. 91.
    Wang D, Plukker JTM, Coppes RP (2017) Cancer stem cells with increased metastatic potential as a therapeutic target for esophageal cancer. In: Seminars in cancer biology. AcademicCrossRefPubMedGoogle Scholar
  92. 92.
    Wang N, Zhang CQ, He JH, Duan XF, Wang YY, Ji X, … Zhao GQ (2013) MiR-21 down-regulation suppresses cell growth, invasion and induces cell apoptosis by targeting FASL, TIMP3, and RECK genes in esophageal carcinoma. Dig Dis Sci 58(7):1863–1870CrossRefPubMedGoogle Scholar
  93. 93.
    Yang X, Yang B, Cai J, Zhang C, Zhang Q, Xu L, … Cheng H (2013) Berberine enhances radiosensitivity of esophageal squamous cancer by targeting HIF-1α in vitro and in vivo. Cancer Biol Ther 14(11):1068–1073CrossRefGoogle Scholar
  94. 94.
    Yokobori T, Bao P, Fukuchi M, Altan B, Ozawa D, Rokudai S, … Sakai M (2015) Nuclear PROX1 is associated with hypoxia-inducible factor 1α expression and cancer progression in esophageal squamous cell carcinoma. Ann Surg Oncol 22(3):1566–1573CrossRefGoogle Scholar
  95. 95.
    Yusup G, Akutsu Y, Mutallip M, Qin W, Hu X, Komatsu-Akimoto A, … Isozaki Y (2014) A COX-2 inhibitor enhances the antitumor effects of chemotherapy and radiotherapy for esophageal squamous cell carcinoma. Int J Oncol 44(4):1146–1152CrossRefPubMedGoogle Scholar
  96. 96.
    Zhang C, Yang X, Zhang Q, Guo Q, He J, Qin Q, … Liu Z (2014a) STAT3 inhibitor NSC74859 radiosensitizes esophageal cancer via the downregulation of HIF-1α. Tumor Biol 35(10):9793–9799CrossRefPubMedGoogle Scholar
  97. 97.
    Zhang F, Yang Z, Cao M, Xu Y, Li J, Chen X, … Yang Y (2014b) MiR-203 suppresses tumor growth and invasion and down-regulates MiR-21 expression through repressing ran in esophageal cancer. Cancer Lett 342(1):121–129CrossRefPubMedGoogle Scholar
  98. 98.
    Zhang L, Ye SB, Li ZL, Ma G, Chen SP, He J, … Li J (2014c) Increased HIF-1alpha expression in tumor cells and lymphocytes of tumor microenvironments predicts unfavourable survival in esophageal squamous cell carcinoma patients. Int J Clin Exp Pathol 7(7):3887Google Scholar
  99. 99.
    Zhang L, Ye SB, Ma G, Tang XF, Chen SP, He J, … Li J (2013) The expressions of MIF and CXCR4 protein in tumor microenvironment are adverse prognostic factors in patients with esophageal squamous cell carcinoma. J Transl Med 11:60CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Zhao H, Iwasaki M, Yang J, Savage S, Ma D (2014) Hypoxia-inducible factor-1: a possible link between inhalational anesthetics and tumor progression? Acta Anaesthesiol Taiwan 52(2):70–76CrossRefPubMedGoogle Scholar
  101. 101.
    Zheng T, Hong X, Wang J, Pei T, Liang Y, Yin D, … Liu J (2014) Gankyrin promotes tumor growth and metastasis through activation of IL-6/STAT3 signalling in human cholangiocarcinoma. Hepatology 59(3):935–946CrossRefPubMedGoogle Scholar
  102. 102.
    Zhong H, Chiles K, Feldser D, Laughner E, Hanrahan C, Georgescu MM, … Semenza GL (2000) Modulation of hypoxia-inducible factor 1α expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics. Cancer Res 60(6):1541–1545Google Scholar
  103. 103.
    Zhong Z, Dong Z, Yang L, Gong Z (2012) miR-21 induces cell cycle at S phase and modulates cell proliferation by down-regulating hMSH2 in lung cancer. J Cancer Res Clin Oncol 138(10):1781–1788CrossRefPubMedGoogle Scholar
  104. 104.
    Zhu H, Feng Y, Zhang J, Zhou X, Hao B, Zhang G, Shi R (2011) Inhibition of hypoxia inducible factor 1α expression suppresses the progression of esophageal squamous cell carcinoma. Cancer Biol Ther 11(11):981–987CrossRefPubMedGoogle Scholar
  105. 105.
    Zhu H, Yang X, Ding Y, Liu J, Lu J, Zhan L, … Yang Y (2015) Recombinant human endostatin enhances the radioresponse in esophageal squamous cell carcinoma by normalizing tumor vasculature and reducing hypoxia. Sci Rep 5:14503Google Scholar
  106. 106.
    Zimmermann KC, Sarbia M, Weber AA, Borchard F, Gabbert HE, Schrör K (1999) Cyclooxygenase-2 expression in human esophageal carcinoma. Cancer Res 59(1):198–204PubMedGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd 2017

Authors and Affiliations

  • A. M. V. N. Prathyusha
    • 1
  • Godi Raghu
    • 1
  • Pallaval Veera Bramhachari
    • 1
    Email author
  1. 1.Department of BiotechnologyKrishna UniversityMachilipatnamIndia

Personalised recommendations