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Cancer Cell International
Published in: Cancer Cell International 1/2017

Open Access 01-12-2017 | Review

Regulation of the hypoxic tumor environment in hepatocellular carcinoma using RNA interference

Authors: Sung Hoon Choi, Jun Yong Park

Published in: Cancer Cell International | Issue 1/2017

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Abstract

Objectives

Hypoxia is the condition where tumor cells have been deprived of oxygen and has been shown to have a role of tumor development in the hepatocellular carcinoma (HCC).

Methods

Using PubMed online database and Google scholar web site, the terms “angiogenesis”, “apoptosis”, “RNA interference” and/or “hepatocellular carcinoma (HCC)” were searched and analyzed.

Results

The hypoxia inducible factors (HIFs) are transcriptional regulators that affect a homeostatic response to oxidative stress and have been identified as a key transcription activator of angiogenesis, survival, and metabolism. Cytokines, such as IL-8, also controlled endothelia cells survival and angiogenesis. IL-8 was also overexpressed under hypoxia and induced tumor angiogenesis and growth.

Conclusion

Therefore, regulation of HIFs and IL-8 controlled the tumor microenvironment in terms of tumor angiogenesis and apoptosis. The review summarizes the results of regulation of the hypoxic tumor environment.
Literature
1.
2.
Wong CC, Kai AK, Ng IO. The impact of hypoxia in hepatocellular carcinoma metastasis. Front Med. 2014;8(1):33–41.CrossRefPubMed
3.
Carmeliet P, Dor Y, Herbert JM, Fukumura D, Brusselmans K, Dewerchin M, et al. Role of HIF-1α in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature. 1998;394(6692):485–90.CrossRefPubMed
4.
Alidoosti M, Ghaedi M, Soleimani A, Bakhtiyari S, Rezvanfard M, Golkhu S, et al. Study on the role of environmental parameters and HIF-1A gene polymorphism in coronary collateral formation among patients with ischemic heart disease. Clin Biochem. 2011;44(17–18):1421–4.CrossRefPubMed
5.
Feng L, Tao L, Dawei H, Xuliang L, Xiaodong L. HIF-1α expression correlates with cellular apoptosis, angiogenesis and clinical prognosis in rectal carcinoma. Pathol Oncol Res. 2014;20(3):603–10.CrossRefPubMed
6.
Hao LS, Wang G, Qian K, Luo T, Li XJ, Wu XT. HIF-1alpha expression and relationship involving tumor cell proliferation and angiogenesis in human breast carcinoma. Sichuan Da Xue Xue Bao Yi Xue Ban. 2007;38(1):60–3.PubMed
7.
Choi SH, Kwon OJ, Park JY, Kim do Y, Ahn SH, Kim SU, et al. Inhibition of tumour angiogenesis and growth by small hairpin HIF-1α and IL-8 in hepatocellular carcinoma. Liver Int. 2014;34(4):632–42.CrossRefPubMed
8.
Zhao L, Zhang C, Liao G, Long J. RNAi-mediated inhibition of PDGF-D leads to decreased cell growth, invasion and angiogenesis in the SGC-7901 gastric cancer xenograft model. Cancer Biol Ther. 2010;9(1):42–8.CrossRefPubMed
9.
Appelmann I, Liersch R, Kessler T, Mesters RM, Berdel WE. Angiogenesis inhibition in cancer therapy: platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) and their receptors: biological functions and role in malignancy. Recent Results Cancer Res. 2010;180:51–81.CrossRefPubMed
10.
Lazzeri S, Orlandi P, Piaggi P, Sartini MS, Casini G, Guidi G, et al. IL-8 and VEGFR-2 polymorphisms modulate long-term functional response to intravitreal ranibizumab in exudative age-related macular degeneration. Pharmacogenomics. 2016;17(1):35–9.CrossRefPubMed
11.
Fulda S, Debatin KM. HIF-1-regulated glucose metabolism: a key to apoptosis resistance? Cell Cycle. 2007;6(7):790–2.CrossRefPubMed
12.
Tzouvelekis A, Ntolios P, Karameris A, Koutsopoulos A, Boglou P, Koulelidis A, et al. Expression of hypoxia-inducible factor (HIF)-1a-vascular endothelial growth factor (VEGF)-inhibitory growth factor (ING)-4-axis in sarcoidosis patients. BMC Res Notes. 2012;5:654.CrossRefPubMedPubMedCentral
13.
Eckle T, Kewley EM, Brodsky KS, Tak E, Bonney S, Gobel M, et al. Identification of hypoxia-inducible factor HIF-1A as transcriptional regulator of the A2B adenosine receptor during acute lung injury. J Immunol. 2014;192(3):1249–56.CrossRefPubMedPubMedCentral
14.
Kitajima Y, Miyazaki K. The critical impact of HIF-1a on gastric cancer biology. Cancers (Basel). 2013;5(1):15–26.CrossRef
15.
Minet E, Michel G, Remacle J, Michiels C. Role of HIF-1 as a transcription factor involved in embryonic development, cancer progression and apoptosis (review). Int J Mol Med. 2000;5(3):253–9.PubMed
16.
Yu JX, Cui L, Zhang QY, Chen H, Ji P, Wei HJ, et al. Expression of NOS and HIF-1alpha in human colorectal carcinoma and implication in tumor angiogenesis. World J Gastroenterol. 2006;12(29):4660–4.CrossRefPubMedPubMedCentral
17.
Nguyen LK, Cavadas MA, Scholz CC, Fitzpatrick SF, Bruning U, Cummins EP, et al. A dynamic model of the hypoxia-inducible factor 1a (HIF-1a) network. J Cell Sci. 2015;128(2):422.CrossRefPubMed
18.
Nishimoto A, Kugimiya N, Hosoyama T, Enoki T, Li TS, Hamano K. HIF-1α activation under glucose deprivation plays a central role in the acquisition of anti-apoptosis in human colon cancer cells. Int J Oncol. 2014;44(6):2077–84.PubMed
19.
Pan XY, Zhang ZH, Wu LX, Wang ZC. Effect of HIF-1a/VEGF signaling pathway on plasma progesterone and ovarian prostaglandin F(2)a secretion during luteal development of pseudopregnant rats. Genet Mol Res. 2015;14(3):8796–809.CrossRefPubMed
20.
Jones MK, Szabo IL, Kawanaka H, Husain SS, Tarnawski AS. von Hippel Lindau tumor suppressor and HIF-1α: new targets of NSAIDs inhibition of hypoxia-induced angiogenesis. FASEB J. 2002;16(2):264–6.PubMed
21.
Zhang W, Chen H. The study on the interleukin-8 (IL-8). Sheng Wu Yi Xue Gong Cheng Xue Za Zhi. 2002;19(4):697–702.PubMed
22.
Sakamoto Y, Harada T, Horie S, Iba Y, Taniguchi F, Yoshida S, et al. Tumor necrosis factor-alpha-induced interleukin-8 (IL-8) expression in endometriotic stromal cells, probably through nuclear factor-kappa B activation: gonadotropin-releasing hormone agonist treatment reduced IL-8 expression. J Clin Endocrinol Metab. 2003;88(2):730–5.CrossRefPubMed
23.
Schraufstatter IU, Trieu K, Zhao M, Rose DM, Terkeltaub RA, Burger M. IL-8-mediated cell migration in endothelial cells depends on cathepsin B activity and transactivation of the epidermal growth factor receptor. J Immunol. 2003;171(12):6714–22.CrossRefPubMed
24.
Wang L, Tang C, Cao H, Li K, Pang X, Zhong L, et al. Activation of IL-8 via PI3K/Akt-dependent pathway is involved in leptin-mediated epithelial-mesenchymal transition in human breast cancer cells. Cancer Biol Ther. 2015;16(8):1220–30.CrossRefPubMedPubMedCentral
25.
Xie Q, Sun Z, Chen M, Zhong Q, Yang T, Yi J. IL-8 up-regulates proliferative angiogenesis in ischemic myocardium in rabbits through phosphorylation of Akt/GSK-3beta(ser9) dependent pathways. Int J Clin Exp Med. 2015;8(8):12498–508.PubMedPubMedCentral
26.
Sasabe E, Tatemoto Y, Li D, Yamamoto T, Osaki T. Mechanism of HIF-1α-dependent suppression of hypoxia-induced apoptosis in squamous cell carcinoma cells. Cancer Sci. 2005;96(7):394–402.CrossRefPubMed
27.
28.
Chen QR, Zhang L, Gasper W, Mixson AJ. Targeting tumor angiogenesis with gene therapy. Mol Genet Metab. 2001;74(1–2):120–7.CrossRefPubMed
29.
Varda-Bloom N, Shaish A, Gonen A, Levanon K, Greenbereger S, Ferber S, et al. Tissue-specific gene therapy directed to tumor angiogenesis. Gene Ther. 2001;8(11):819–27.CrossRefPubMed
30.
Cho SW, Kitisin K, Buck D, Steel J, Brufsky A, Gillespie R, et al. Transcatheter arterial chemoembolization is a feasible palliative locoregional therapy for breast cancer liver metastases. Int J Surg Oncol. 2010;2010:251621.PubMedPubMedCentral
31.
Goda N, Dozier SJ, Johnson RS. HIF-1 in cell cycle regulation, apoptosis, and tumor progression. Antioxid Redox Signal. 2003;5(4):467–73.CrossRefPubMed
32.
Choi SH, Park JY, Kang W, Kim SU, Kim DY, Ahn SH, et al. Knockdown of HIF-1α and IL-8 induced apoptosis of hepatocellular carcinoma triggers apoptosis of vascular endothelial cells. Apoptosis. 2015. doi:10.​1007/​s10495-015-1185-2.PubMed
33.
Choi SH, Chung AR, Kang W, Park JY, Lee MS, Hwang SW, et al. Silencing of hypoxia-inducible factor-1β induces anti-tumor effects in hepatoma cell lines under tumor hypoxia. PLoS ONE. 2014;9(7):e103304.CrossRefPubMedPubMedCentral
34.
35.
Semenza GL. Vasculogenesis, angiogenesis, and arteriogenesis: mechanisms of blood vessel formation and remodeling. J Cell Biochem. 2007;102(4):840–7.CrossRefPubMed
36.
Zagzag D, Friedlander DR, Margolis B, Grumet M, Semenza GL, Zhong H, et al. Molecular events implicated in brain tumor angiogenesis and invasion. Pediatr Neurosurg. 2000;33(1):49–55.CrossRefPubMed
37.
Hirota K, Semenza GL. Regulation of angiogenesis by hypoxia-inducible factor 1. Crit Rev Oncol Hematol. 2006;59(1):15–26.CrossRefPubMed
38.
39.
Plate KH. Gene therapy of malignant glioma via inhibition of tumor angiogenesis. Cancer Metastasis Rev. 1996;15(2):237–40.CrossRefPubMed
40.
Sato Y. Molecular diagnosis of tumor angiogenesis and anti-angiogenic cancer therapy. Int J Clin Oncol. 2003;8(4):200–6.CrossRefPubMed
41.
Natarajan R, Fisher BJ, Fowler AA 3rd. Hypoxia inducible factor-1 modulates hemin-induced IL-8 secretion in microvascular endothelium. Microvasc Res. 2007;73(3):163–72.CrossRefPubMed
42.
Fernando RI, Castillo MD, Litzinger M, Hamilton DH, Palena C. IL-8 signaling plays a critical role in the epithelial-mesenchymal transition of human carcinoma cells. Cancer Res. 2011;71(15):5296–306.CrossRefPubMedPubMedCentral
43.
Xie TX, Xia Z, Zhang N, Gong W, Huang S. Constitutive NF-kappaB activity regulates the expression of VEGF and IL-8 and tumor angiogenesis of human glioblastoma. Oncol Rep. 2010;23(3):725–32.PubMed
44.
Bohensky J, Shapiro IM, Leshinsky S, Terkhorn SP, Adams CS, Srinivas V. HIF-1 regulation of chondrocyte apoptosis: induction of the autophagic pathway. Autophagy. 2007;3(3):207–14.CrossRefPubMed
45.
Volm M, Koomagi R. Hypoxia-inducible factor (HIF-1) and its relationship to apoptosis and proliferation in lung cancer. Anticancer Res. 2000;20(3A):1527–33.PubMed
46.
Xu K, Ding Q, Fang Z, Zheng J, Gao P, Lu Y, et al. Silencing of HIF-1α suppresses tumorigenicity of renal cell carcinoma through induction of apoptosis. Cancer Gene Ther. 2010;17(3):212–22.CrossRefPubMed
47.
Jawahir M, Nicholas SA, Coughlan K, Sumbayev VV. Apoptosis signal-regulating kinase 1 (ASK1) and HIF-1α protein are essential factors for nitric oxide-dependent accumulation of p53 in THP-1 human myeloid macrophages. Apoptosis. 2008;13(12):1410–6.CrossRefPubMed
48.
49.
Sendoel A, Kohler I, Fellmann C, Lowe SW, Hengartner MO. HIF-1 antagonizes p53-mediated apoptosis through a secreted neuronal tyrosinase. Nature. 2010;465(7298):577–83.CrossRefPubMedPubMedCentral
50.
Xia L, Mo P, Huang W, Zhang L, Wang Y, Zhu H, et al. The TNF-α/ROS/HIF-1-induced upregulation of FoxMI expression promotes HCC proliferation and resistance to apoptosis. Carcinogenesis. 2012;33(11):2250–9.CrossRefPubMed
51.
Khan MN, Bhattacharyya T, Andrikopoulos P, Esteban MA, Barod R, Connor T, et al. Factor inhibiting HIF (FIH-1) promotes renal cancer cell survival by protecting cells from HIF-1α-mediated apoptosis. Br J Cancer. 2011;104(7):1151–9.CrossRefPubMedPubMedCentral
52.
Horree N, Groot AJ, van Hattem WA, Heintz AP, Vooijs M, van Diest PJ. HIF-1A gene mutations associated with higher microvessel density in endometrial carcinomas. Histopathology. 2008;52(5):637–9.CrossRefPubMed
53.
Cursio R, Miele C, Filippa N, Van Obberghen E, Gugenheim J. Liver HIF-1 alpha induction precedes apoptosis following normothermic ischemia-reperfusion in rats. Transpl Proc. 2008;40(6):2042–5.CrossRef
54.
Gupta-Saraf P, Miller CL. HIF-1α downregulation and apoptosis in hypoxic prostate tumor cells infected with oncolytic mammalian orthoreovirus. Oncotarget. 2014;5(2):561–74.CrossRefPubMedPubMedCentral
55.
Ueda M, Ueki K, Kumagai K, Terai Y, Okamoto Y, Ueki M, et al. Apoptosis and tumor angiogenesis in cervical cancer after preoperative chemotherapy. Cancer Res. 1998;58(11):2343–6.PubMed
56.
Albertsson P, Lennernas B, Norrby K. On metronomic chemotherapy: modulation of angiogenesis mediated by VEGE-A. Acta Oncol. 2006;45(2):144–55.CrossRefPubMed
57.
Gasparini G, Biganzoli E, Bonoldi E, Morabito A, Fanelli M, Boracchi P. Angiogenesis sustains tumor dormancy in patients with breast cancer treated with adjuvant chemotherapy. Breast Cancer Res Treat. 2001;65(1):71–5.CrossRefPubMed
58.
Jijon HB, Buret A, Hirota CL, Hollenberg MD, Beck PL. The EGF receptor and HER2 participate in TNF-α-dependent MAPK activation and IL-8 secretion in intestinal epithelial cells. Mediators Inflamm. 2012;2012:207398.CrossRefPubMedPubMedCentral
59.
Petzelbauer P, Watson CA, Pfau SE, Pober JS. IL-8 and angiogenesis: evidence that human endothelial cells lack receptors and do not respond to IL-8 in vitro. Cytokine. 1995;7(3):267–72.CrossRefPubMed
60.
Rao DD, Vorhies JS, Senzer N, Nemunaitis J. siRNA vs. shRNA: similarities and differences. Adv Drug Deliv Rev. 2009;61(9):746–59.CrossRefPubMed
61.
Chen C, Yu Z. siRNA targeting HIF-1α induces apoptosis of pancreatic cancer cells through NF-kappaB-independent and -dependent pathways under hypoxic conditions. Anticancer Res. 2009;29(4):1367–72.PubMed
Metadata
Title
Regulation of the hypoxic tumor environment in hepatocellular carcinoma using RNA interference
Authors
Sung Hoon Choi
Jun Yong Park
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2017
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-016-0374-6

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