J Neurol Surg A Cent Eur Neurosurg 2016; 77(03): 247-257
DOI: 10.1055/s-0035-1566120
Review Article
Georg Thieme Verlag KG Stuttgart · New York

Hemoglobins, Hemorphins, and 11p15.5 Chromosomal Region in Cancer Biology and İmmunity with Special Emphasis for Brain Tumors

Meric Adil Altinoz
1   Department of Immunology, Istanbul University, DETAE - Experimental Medicine Research Institute, Istanbul, Turkey
Ilhan Elmaci
2   Department of Neurosurgery, Memorial Hospital, Istanbul, Turkey
Bahri Ince
3   Department of Psychiatry, Bakirkoy Mental Diseases Education and Training Hospital, Istanbul, Turkey
Aysel Ozpinar
4   Department of Biochemistry, Acibadem University, Istanbul, Turkey
Aydin Murat Sav
5   Department of Pathology, Acibadem University, Istanbul, Turkey
› Author Affiliations
Further Information

Publication History

30 April 2015

11 August 2015

Publication Date:
02 March 2016 (online)


In systemic cancers, increased hemolysis leads to extracellular hemoglobin (HB), and experimental studies have shown its provoking role on tumor growth and metastasis. However, investigations have shown that HB chains presented by tumor vascular pericytes or serum protein complexes of HB could also induce antitumor immunity, which may be harnessed to treat refractory cancers and brain tumors. Mounting recent evidence shows that expression of HBs is not restricted to erythrocytes and that HBs exist in the cells of lung and kidney, in macrophages, and in neurons and glia of the central nervous system (CNS). HBs mediate coping with hypoxia and free radical stress in normal and tumor cells, and they are increased in certain tumors including breast, lung, colon, and squamous cell cancers. Recent studies showed HBs in meningioma, in the cyst fluid of craniopharyngioma, in the cerebrospinal fluid (CSF) of pediatric patients with posterior fossa tumors, and in glioblastoma cell lines. Hemorphins, abundant brain peptides formed via HB-chain cleavage, exert opioid activity and antiproliferative and immunomodifier effects. Hence mutations in HBs may modify brain tumorigenesis via influencing hemorphins and perturbing regulations of immune surveillance and cell growth in the neuroectodermal tissues. The β-globin gene cluster resides in the chromosome region 11p15.5, harboring important immunity genes and IGF2, H19, PHLDA2/TSSC3, TRIM3, and SLC22A18 genes associated with cancers and gliomas. 11p15.5 is a prominent region subject to epigenetic regulation. Thus the β-globin loci may exert haplotypal interactions with these. Some clues support this theory. It is well established that iron load induces liver cancer in thalassemia major; however iron load–independent associations also exist. Enhanced rates of hematologic malignancies are associated with HB Lepore, association of hemoglobin E with cholangiocarcinoma, and enhanced gastric cancer rates in the thalassemia trait. In the African Herero population, a mutant form of δ-globin is very prevalent, and this population has higher rates of pediatric brain tumors. Globins are also expressed in healthy endothelia and in tumoral vessels, indicating potential involvement in angiogenesis. Studies on HBs and their cleavage peptides in cancers and brain tumors may lead to innovative treatment strategies.

  • References

  • 1 Dubrow R, Darefsky AS, Jacobs DI , et al. Time trends in glioblastoma multiforme survival: the role of temozolomide. Neuro Oncol 2013; 15 (12) 1750-1761
  • 2 Song CZ, Wang QW, Song CC. Hemorphin as a prognostic biomarker and potential drug for breast cancer?. Int J Cancer 2012; 131 (4) 1011-1012
  • 3 Schechter AN. Hemoglobin research and the origins of molecular medicine. Blood 2008; 112 (10) 3927-3938
  • 4 Altinoz MA, Gedikoglu G, Deniz G. β-Thalassemia trait association with autoimmune diseases: β-globin locus proximity to the immunity genes or role of hemorphins?. Immunopharmacol Immunotoxicol 2012; 34 (2) 181-190
  • 5 Newsham IF, Gorse KM, Rempel SA, Luckey J, Golden JB, Bögler O. Use of horizontal ultrathin gel electrophoresis to analyze allelic deletions in chromosome band 11p15.5 in gliomas. Neuro Oncol 2000; 2 (1) 1-5
  • 6 Liu L, Zeng M, Stamler JS. Hemoglobin induction in mouse macrophages. Proc Natl Acad Sci U S A 1999; 96 (12) 6643-6647
  • 7 Bhaskaran M, Chen H, Chen Z, Liu L. Hemoglobin is expressed in alveolar epithelial type II cells. Biochem Biophys Res Commun 2005; 333 (4) 1348-1352
  • 8 Newton DA, Rao KM, Dluhy RA, Baatz JE. Hemoglobin is expressed by alveolar epithelial cells. J Biol Chem 2006; 281 (9) 5668-5676
  • 9 Nİshi H, Inagi R, Kato H , et al. Hemoglobin is expressed by mesangial cells and reduces oxidant stress. J Am Soc Nephrol 2008; 19 (8) 1500-1508
  • 10 Tezel G, Yang X, Luo C , et al. Hemoglobin expression and regulation in glaucoma: insights into retinal ganglion cell oxygenation. Invest Ophthalmol Vis Sci 2010; 51 (2) 907-919
  • 11 Bunn HF, Forget BG. Hemoglobin: Molecular, Genetic, and Clinical Aspects. Philadelphia, PA: WB. Saunders; 1986
  • 12 Rochette J, Craig JE, Thein SL. Fetal hemoglobin levels in adults. Blood Rev 1994; 8 (4) 213-224
  • 13 Hardison RC. Globin genes on the move. J Biol 2008; 7 (9) 35
  • 14 Cosby K, Partovi KS, Crawford JH , et al. Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation. Nat Med 2003; 9 (12) 1498-1505
  • 15 Huang Z, Shiva S, Kim-Shapiro DB , et al. Enzymatic function of hemoglobin as a nitrite reductase that produces NO under allosteric control. J Clin Invest 2005; 115 (8) 2099-2107
  • 16 Masuoka N, Kodama H, Abe T, Wang DH, Nakano T. Characterization of hydrogen peroxide removal reaction by hemoglobin in the presence of reduced pyridine nucleotides. Biochim Biophys Acta 2003; 1637 (1) 46-54
  • 17 Goldstein S, Samuni A. Intra- and intermolecular oxidation of oxymyoglobin and oxyhemoglobin induced by hydroxyl and carbonate radicals. Free Radic Biol Med 2005; 39 (4) 511-519
  • 18 Chung AS, Lee J, Ferrara N. Targeting the tumour vasculature: insights from physiological angiogenesis. Nat Rev Cancer 2010; 10 (7) 505-514
  • 19 Betsholtz C, Armulik A. Homeostatic functions of vascular endothelial growth factor in adult microvasculature. Am J Physiol Heart Circ Physiol 2006; 290 (2) H509-H511
  • 20 Fukumura D, Jain RK. Tumor microenvironment abnormalities: causes, consequences, and strategies to normalize. J Cell Biochem 2007; 101 (4) 937-949
  • 21 Folberg R, Rummelt V, Parys-Van Ginderdeuren R , et al. The prognostic value of tumor blood vessel morphology in primary uveal melanoma. Ophthalmology 1993; 100 (9) 1389-1398
  • 22 Maniotis AJ, Folberg R, Hess A , et al. Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry. Am J Pathol 1999; 155 (3) 739-752
  • 23 Kucera T, Lammert E. Ancestral vascular tube formation and its adoption by tumors. Biol Chem 2009; 390 (10) 985-994
  • 24 Kamba T, Tam BY, Hashizume H , et al. VEGF-dependent plasticity of fenestrated capillaries in the normal adult microvasculature. Am J Physiol Heart Circ Physiol 2006; 290 (2) H560-H576
  • 25 Terwilliger NB. Functional adaptations of oxygen-transport proteins. J Exp Biol 1998; 201 (Pt 8): 1085-1098
  • 26 Mangum CP. Oxygen transport in invertebrates. Am J Physiol 1985; 248 (5 Pt 2): R505-R514
  • 27 Folberg R, Maniotis AJ. Vasculogenic mimicry. APMIS 2004; 112 (7–8) 508-525
  • 28 Bürgers AC, Lammert E. Extraerythrocytic hemoglobin—a possible oxygen transporter in human malignant tumors. Med Hypotheses 2011; 77 (4) 580-583
  • 29 Faivre-Fiorina B, Caron A, Fassot C , et al. Presence of hemoglobin inside aortic endothelial cells after cell-free hemoglobin administration in guinea pigs. Am J Physiol 1999; 276 (2 Pt 2): H766-H770
  • 30 Siddiqui FA, Amirkhosravi A, Amaya M , et al. Hemoglobin enhances tissue factor expression on human malignant cells. Blood Coagul Fibrinolysis 2001; 12 (3) 171-177
  • 31 Siddiqui FA, Siddiqui TF, Francis JL. Hemoglobin induces the production and release of matrix metalloproteinase-9 from human malignant cells. Blood Coagul Fibrinolysis 2003; 14 (5) 449-455
  • 32 Siddiqui FA, Desai H, Siddiqui TF, Francis JL. Hemoglobin induces the expression and secretion of vascular endothelial growth factor from human malignant cells. Hematol J 2002; 3 (5) 264-270
  • 33 Harshman LC, Kuo CJ, Wong BY, Vogelzang NJ, Srinivas S. Increased hemoglobin associated with VEGF inhibitors in advanced renal cell carcinoma. Cancer Invest 2009; 27 (8) 851-856
  • 34 Borgan E, Lindholm EM, Moestue S , et al. Subtype-specific response to bevacizumab is reflected in the metabolome and transcriptome of breast cancer xenografts. Mol Oncol 2013; 7 (1) 130-142
  • 35 Kawai N, Kunimatsu M, Tozawa K, Sasaki M, Kohri K. Human prostate cancer cells adhere specifically to hemoglobin: a possible role in bone-specific metastasis. Cancer Lett 2001; 171 (2) 201-207
  • 36 van Rossen ME, Sluiter W, Bonthuis F, Jeekel H, Marquet RL, van Eijck CH. Scavenging of reactive oxygen species leads to diminished peritoneal tumor recurrence. Cancer Res 2000; 60 (20) 5625-5629
  • 37 Wen WN. Methemoglobin contributes to the growth of human tumor cells. Life Sci 2002; 70 (8) 907-916
  • 38 Roth AD, Elmer J, Harris DR , et al. Hemoglobin regulates the migration of glioma cells along poly(ε-caprolactone)-aligned nanofibers. Biotechnol Prog 2014; 30 (5) 1214-1220
  • 39 Yu Y, Wong J, Lovejoy DB, Kalinowski DS, Richardson DR. Chelators at the cancer coalface: desferrioxamine to Triapine and beyond. Clin Cancer Res 2006; 12 (23) 6876-6883
  • 40 Neubauer H, Clare SE, Kurek R , et al. Breast cancer proteomics by laser capture microdissection, sample pooling, 54-cm IPG IEF, and differential iodine radioisotope detection. Electrophoresis 2006; 27 (9) 1840-1852
  • 41 Mueck AO, Ruan X, Seeger H, Fehm T, Neubauer H. Genomic and non-genomic actions of progestogens in the breast. J Steroid Biochem Mol Biol 2014; 142: 62-67
  • 42 Chang SC, Chen HF, Chou MH, Wang HC, Su HY, Wong ML. Haemoglobin in normal and neoplastic canine mammary glands. Vet Comp Oncol 2010; 8 (4) 302-309
  • 43 Wang HW, Jiang JK, Lin CH, Lin JK, Huang GJ, Yu JS. Diffuse reflectance spectroscopy detects increased hemoglobin concentration and decreased oxygenation during colon carcinogenesis from normal to malignant tumors. Opt Express 2009; 17 (4) 2805-2817
  • 44 Choi JW, Liu H, Shin DH , et al. Proteomic and cytokine plasma biomarkers for predicting progression from colorectal adenoma to carcinoma in human patients. Proteomics 2013; 13 (15) 2361-2374
  • 45 Chatterji B, Borlak J. Serum proteomics of lung adenocarcinomas induced by targeted overexpression of c-raf in alveolar epithelium identifies candidate biomarkers. Proteomics 2007; 7 (21) 3980-3991
  • 46 Woong-Shick A, Sung-Pil P, Su-Mi B , et al. Identification of hemoglobin-alpha and -beta subunits as potential serum biomarkers for the diagnosis and prognosis of ovarian cancer. Cancer Sci 2005; 96 (3) 197-201
  • 47 Li X, Wu Z, Wang Y, Mei Q, Fu X, Han W. Characterization of adult α- and β-globin elevated by hydrogen peroxide in cervical cancer cells that play a cytoprotective role against oxidative insults. PLoS ONE 2013; 8 (1) e54342
  • 48 Roesch-Ely M, Nees M, Karsai S , et al. Proteomic analysis reveals successive aberrations in protein expression from healthy mucosa to invasive head and neck cancer. Oncogene 2007; 26 (1) 54-64
  • 49 Thiel UJ, Feltens R, Adryan B , et al. Analysis of differentially expressed proteins in oral squamous cell carcinoma by MALDI-TOF MS. J Oral Pathol Med 2011; 40 (5) 369-379
  • 50 Straub AC, Lohman AW, Billaud M , et al. Endothelial cell expression of haemoglobin α regulates nitric oxide signalling. Nature 2012; 491 (7424) 473-477
  • 51 Gorr TA, Wichmann D, Pilarsky C , et al. Old proteins--new locations: myoglobin, haemoglobin, neuroglobin and cytoglobin in solid tumours and cancer cells. Acta Physiol (Oxf) 2011; 202 (3) 563-581
  • 52 Komita H, Zhao X, Taylor JL , et al. CD8+ T-cell responses against hemoglobin-beta prevent solid tumor growth. Cancer Res 2008; 68 (19) 8076-8084
  • 53 Sitdikova SM, Amandzholov BS, Serebryakova MV, Zhdanovich MY, Kiselevskii MV, Donenko FV. Peculiarities of hemoglobin interaction with serum proteins of mice with Ehrlich carcinoma. Bull Exp Biol Med 2006; 141 (5) 624-627
  • 54 Donenko FV, Sitdikova SM, Amandzholov BS, Kiselevskii MV. Biological activity of hemoglobin-containing complex isolated from blood serum of mice with Ehrlich carcinoma. Bull Exp Biol Med 2006; 142 (3) 347-350
  • 55 Donenko FV, Sitdikova SM, Syrtsev AV , et al. Hemoglobin-associated proteins isolated from blood serum of Ehrlich carcinoma-bearing mice. Int J Oncol 2008; 32 (4) 885-893
  • 56 Schelshorn DW, Schneider A, Kuschinsky W , et al. Expression of hemoglobin in rodent neurons. J Cereb Blood Flow Metab 2009; 29 (3) 585-595
  • 57 He Y, Hua Y, Liu W, Hu H, Keep RF, Xi G. Effects of cerebral ischemia on neuronal hemoglobin. J Cereb Blood Flow Metab 2009; 29 (3) 596-605
  • 58 Biagioli M, Pinto M, Cesselli D , et al. Unexpected expression of alpha- and beta-globin in mesencephalic dopaminergic neurons and glial cells. Proc Natl Acad Sci U S A 2009; 106 (36) 15454-15459
  • 59 Richter F, Meurers BH, Zhu C, Medvedeva VP, Chesselet MF. Neurons express hemoglobin alpha- and beta-chains in rat and human brains. J Comp Neurol 2009; 515 (5) 538-547
  • 60 Broadwater L, Pandit A, Clements R , et al. Analysis of the mitochondrial proteome in multiple sclerosis cortex. Biochim Biophys Acta 2011; 1812 (5) 630-641
  • 61 Ferrer I, Gómez A, Carmona M , et al. Neuronal hemoglobin is reduced in Alzheimer's disease, argyrophilic grain disease, Parkinson's disease, and dementia with Lewy bodies. J Alzheimers Dis 2011; 23 (3) 537-550
  • 62 Russo R, Zucchelli S, Codrich M, Marcuzzi F, Verde C, Gustincich S. Hemoglobin is present as a canonical α2β2 tetramer in dopaminergic neurons. Biochim Biophys Acta 2013; 1834 (9) 1939-1943
  • 63 Blishchenko EY, Sazonova OV, Kalinina OA , et al. Family of hemorphins: co-relations between amino acid sequences and effects in cell cultures. Peptides 2002; 23 (5) 903-910
  • 64 Gelman JS, Sironi J, Castro LM, Ferro ES, Fricker LD. Hemopressins and other hemoglobin-derived peptides in mouse brain: comparison between brain, blood, and heart peptidome and regulation in Cpefat/fat mice. J Neurochem 2010; 113 (4) 871-880
  • 65 Ivanov VT, Karelin AA, Philippova MM, Nazimov IV, Pletnev VZ. Hemoglobin as a source of endogenous bioactive peptides: the concept of tissue-specific peptide pool. Biopolymers 1997; 43 (2) 171-188
  • 66 Nyberg F, Sanderson K, Glämsta EL. The hemorphins: a new class of opioid peptides derived from the blood protein hemoglobin. Biopolymers 1997; 43 (2) 147-156
  • 67 Lammerich HP, Busmann A, Kutzleb C , et al. Identification and functional characterization of hemorphins VV-H-7 and LVV-H-7 as low-affinity agonists for the orphan bombesin receptor subtype 3. Br J Pharmacol 2003; 138 (8) 1431-1440
  • 68 Cerpa-Poljak A, Lahnstein J, Mason KE, Smythe GA, Duncan MW. Mass spectrometric identification and quantification of hemorphins extracted from human adrenal and pheochromocytoma tissue. J Neurochem 1997; 68 (4) 1712-1719
  • 69 Blishchenko E, Sazonova O, Surovoy A , et al. Antiproliferative action of valorphin in cell cultures. J Pept Sci 2002; 8 (8) 438-452
  • 70 Blishchenko EY, Sazonova OV, Kalinina OA , et al. Antitumor effect of valorphin in vitro and in vivo: combined action with cytostatic drugs. Cancer Biol Ther 2005; 4 (1) 118-124
  • 71 Cohen M, Fruitier-Arnaudin I, Sauvan R, Birnbaum D, Piot JM. Serum levels of Hemorphin-7 peptides in patients with breast cancer. Clin Chim Acta 2003; 337 (1–2) 59-67
  • 72 Moeller I, Albiston AL, Lew RA, Mendelsohn FA, Chai SY. A globin fragment, LVV-hemorphin-7, induces [3H]thymidine incorporation in a neuronal cell line via the AT4 receptor. J Neurochem 1999; 73 (1) 301-308
  • 73 Mustafa T, Chai SY, Mendelsohn FA, Moeller I, Albiston AL. Characterization of the AT(4) receptor in a human neuroblastoma cell line (SK-N-MC). J Neurochem 2001; 76 (6) 1679-1687
  • 74 Liang TS, Gao JL, Fatemi O, Lavigne M, Leto TL, Murphy PM. The endogenous opioid spinorphin blocks fMet-Leu-Phe-induced neutrophil chemotaxis by acting as a specific antagonist at the N-formylpeptide receptor subtype FPR. J Immunol 2001; 167 (11) 6609-6614
  • 75 Barkhudaryan N, Gambarov S, Gyulbayazyan T, Nahapetyan K. LVV-hemorphin-4 modulates Ca2+/calmodulin-dependent pathways in the immune system by the same mechanism as in the brain. J Mol Neurosci 2002; 18 (3) 203-210
  • 76 Yamamoto Y, Ono H, Ueda A, Shimamura M, Nishimura K, Hazato T. Spinorphin as an endogenous inhibitor of enkephalin-degrading enzymes: roles in pain and inflammation. Curr Protein Pept Sci 2002; 3 (6) 587-599
  • 77 Tecchio C, Cassatella MA. Neutrophil-derived cytokines involved in physiological and pathological angiogenesis. Chem Immunol Allergy 2014; 99: 123-137
  • 78 Giardine B, Borg J, Viennas E , et al. Updates of the HbVar database of human hemoglobin variants and thalassemia mutations. Nucleic Acids Res 2014; 42 (Database issue): D1063-D1069
  • 79 Modell B, Darlison M. Global epidemiology of haemoglobin disorders and derived service indicators. Available at: http://www.who.int/bulletin/volumes/86/6/06-036673/en/ . Accessed April 23, 2015
  • 80 Cousens NE, Gaff CL, Metcalfe SA, Delatycki MB. Carrier screening for beta-thalassaemia: a review of international practice. Eur J Hum Genet 2010; 18 (10) 1077-1083
  • 81 Ntaios G, Chatzinikolaou A, Saouli Z , et al. Discrimination indices as screening tests for beta-thalassemic trait. Ann Hematol 2007; 86 (7) 487-491
  • 82 Usman M, Moinuddin M, Ahmed SA. Role of iron deficiency anemia in the propagation of beta thalssemia gene. Korean J Hepatol 2011; 46 (1) 41-44
  • 83 Quattrin N, Mastrobouni A, Laudisio FL, Brancaccio V, Pagnini D. Hb Lepore and (haemo-) blastomata. Folia Haematol Int Mag Klin Morphol Blutforsch 1976; 103 (6) 915-919
  • 84 Gallerani M, Pulga A, Bottini E, Dall'Ara G, Battaglia G, Tessari R. Heterozygous beta thalassemia and gastrointestinal pathology [in Italian]. Minerva Med 1986; 77 (17) 709-712
  • 85 Gallerani M, Pulga A, Martinelli L , et al. Heterozygote beta-thalassemia and neoplastic pathology [in Italian]. Minerva Med 1990; 81 (3) 175-180
  • 86 Insiripong S, Thaisamakr S, Amatachaya C. Hemoglobin typing in cholangiocarcinoma. Southeast Asian J Trop Med Public Health 1997; 28 (2) 424-427
  • 87 Kim JH, Lee SK, Yoo YC , et al. Proteome analysis of human cerebrospinal fluid as a diagnostic biomarker in patients with meningioma. Med Sci Monit 2012; 18 (11) BR450-BR460
  • 88 Mais DD, Boxer LA, Gulbranson RD, Keren DF. Hemoglobin Ypsilanti: a high-oxygen-affinity hemoglobin demonstrated by two automated high-pressure liquid chromatography systems. Am J Clin Pathol 2007; 128 (5) 850-853
  • 89 Martelli C, Iavarone F, Vincenzoni F , et al. Proteomic characterization of pediatric craniopharyngioma intracystic fluid by LC-MS top-down/bottom-up integrated approaches. Electrophoresis 2014; 35 (15) 2172-2183
  • 90 Desiderio C, D'Angelo L, Rossetti DV , et al. Cerebrospinal fluid top-down proteomics evidenced the potential biomarker role of LVV- and VV-hemorphin-7 in posterior cranial fossa pediatric brain tumors. Proteomics 2012; 12 (13) 2158-2166
  • 91 Emara M, Salloum N, Allalunis-Turner J. Expression and hypoxic up-regulation of neuroglobin in human glioblastoma cells. Mol Oncol 2009; 3 (1) 45-53
  • 92 Emara M, Turner AR, Allalunis-Turner J. Hypoxic regulation of cytoglobin and neuroglobin expression in human normal and tumor tissues. Cancer Cell Int 2010; 10: 33
  • 93 Emara M, Turner AR, Allalunis-Turner J. Adult, embryonic and fetal hemoglobin are expressed in human glioblastoma cells. Int J Oncol 2014; 44 (2) 514-520
  • 94 Emara M, Turner AR, Allalunis-Turner J. Hypoxia differentially upregulates the expression of embryonic, fetal and adult hemoglobin in human glioblastoma cells. Int J Oncol 2014; 44 (3) 950-958
  • 95 He Z, Russell JE. Expression, purification, and characterization of human hemoglobins Gower-1 (zeta(2)epsilon(2)), Gower-2 (alpha(2)epsilon(2)), and Portland-2 (zeta(2)beta(2)) assembled in complex transgenic-knockout mice. Blood 2001; 97 (4) 1099-1105
  • 96 Durany N, Joseph J, Campo E, Molina R, Carreras J. Phosphoglycerate mutase, 2,3-bisphosphoglycerate phosphatase and enolase activity and isoenzymes in lung, colon and liver carcinomas. Br J Cancer 1997; 75 (7) 969-977
  • 97 Hoogewijs D, Ebner B, Germani F , et al. Androglobin: a chimeric globin in metazoans that is preferentially expressed in Mammalian testes. Mol Biol Evol 2012; 29 (4) 1105-1114
  • 98 Huang B, Lu YS, Li X , et al. Androglobin knockdown inhibits growth of glioma cell lines. Int J Clin Exp Pathol 2014; 7 (5) 2179-2184
  • 99 Titulaer MK, Mustafa DA, Siccama I , et al. A software application for comparing large numbers of high resolution MALDI-FTICR MS spectra demonstrated by searching candidate biomarkers for glioma blood vessel formation. BMC Bioinformatics 2008; 9: 133
  • 100 Qu Y, Zhang L, Rong Z, He T, Zhang S. Number of glioma polyploid giant cancer cells (PGCCs) associated with vasculogenic mimicry formation and tumor grade in human glioma. J Exp Clin Cancer Res 2013; 32: 75
  • 101 Zhang S, Mercado-Uribe I, Liu J. Generation of erythroid cells from fibroblasts and cancer cells in vitro and in vivo. Cancer Lett 2013; 333 (2) 205-212
  • 102 Sheng G. Primitive and definitive erythropoiesis in the yolk sac: a bird's eye view. Int J Dev Biol 2010; 54 (6–7) 1033-1043
  • 103 Peters J. The role of genomic imprinting in biology and disease: an expanding view. Nat Rev Genet 2014; 15 (8) 517-530
  • 104 Nusrat M, Moiz B, Nasir A, Rasool Hashmi M. An insight into the suspected HbA2′ cases detected by high performance liquid chromatography in Pakistan. BMC Res Notes 2011; 4: 103
  • 105 Bennani M, Mombo LE, Chaventre A , et al. Origin of Hb A2′ (Hb B2) [delta16(A13)Gly —> Arg (GGC —> CGC)]. [delta16(A13)Gly–> Arg (GGC–> CGC)] Hemoglobin 2003; 27 (2) 105-110
  • 106 Spurdle AB, Krause A, Ramsay M, Jenkins T. The high frequency of the Hb B2 variant in the Herero population: a founder effect?. Hemoglobin 1994; 18 (4–5) 317-323
  • 107 Wessels G, Hesseling PB. Unusual distribution of childhood cancer in Namibia. Pediatr Hematol Oncol 1996; 13 (1) 9-20
  • 108 Wessels G, Hesseling PB. Incidence and frequency rates of childhood cancer in Namibia. S Afr Med J 1997; 87 (7) 885-889
  • 109 Harpending HC, Pennington R. Age structure and sex-biased mortality among Herero pastoralists. Hum Biol 1991; 63 (3) 329-353
  • 110 Klymenko TM. Accounting for sexual dimorphism in neonatology [in Ukrainian]. Lik Sprava 1999; 6 (6) 73-75
  • 111 İnce B, Guloksuz S, Altınbaş K, Oral ET, Alpkan LR, Altinoz MA. Minor hemoglobins HbA2 and HbF associate with disease severity in bipolar disorder with a likely protective role of HbA2 against post-partum episodes. J Affect Disord 2013; 151 (1) 405-408
  • 112 Weroha SJ, Haluska P. The insulin-like growth factor system in cancer. Endocrinol Metab Clin North Am 2012; 41 (2) 335-350 , vi
  • 113 Uyeno S, Aoki Y, Nata M , et al. IGF2 but not H19 shows loss of imprinting in human glioma. Cancer Res 1996; 56 (23) 5356-5359
  • 114 Soroceanu L, Kharbanda S, Chen R , et al. Identification of IGF2 signaling through phosphoinositide-3-kinase regulatory subunit 3 as a growth-promoting axis in glioblastoma. Proc Natl Acad Sci U S A 2007; 104 (9) 3466-3471
  • 115 Gabory A, Ripoche MA, Yoshimizu T, Dandolo L. The H19 gene: regulation and function of a non-coding RNA. Cytogenet Genome Res 2006; 113 (1–4) 188-193
  • 116 Shi Y, Wang Y, Luan W , et al. Long non-coding RNA H19 promotes glioma cell invasion by deriving miR-675. PLoS ONE 2014; 9 (1) e86295
  • 117 Feinberg AP. Imprinting of a genomic domain of 11p15 and loss of imprinting in cancer: an introduction. Cancer Res 1999; 59 (7, Suppl): 1743s-1746s
  • 118 Müller S, van den Boom D, Zirkel D , et al. Retention of imprinting of the human apoptosis-related gene TSSC3 in human brain tumors. Hum Mol Genet 2000; 9 (5) 757-763
  • 119 Chen G, Kong J, Tucker-Burden C , et al. Human Brat ortholog TRIM3 is a tumor suppressor that regulates asymmetric cell division in glioblastoma. Cancer Res 2014; 74 (16) 4536-4548
  • 120 Liu Y, Raheja R, Yeh N , et al. TRIM3, a tumor suppressor linked to regulation of p21(Waf1/Cip1.). Oncogene 2014; 33 (3) 308-315
  • 121 Chu SH, Feng DF, Ma YB , et al. Promoter methylation and downregulation of SLC22A18 are associated with the development and progression of human glioma. J Transl Med 2011; 9: 156
  • 122 Chu SH, Ma YB, Feng DF, Li ZQ, Jiang PC. Predictive value of the SLC22A18 protein expression in glioblastoma patients receiving temozolomide therapy. J Transl Med 2013; 11: 69