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

Abstract

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.

A heterodimer of α and β hemoglobin chains functions as an innate anticancer agent

“…An HBB‐derived peptide exerted cytotoxicity to human neuroblastoma cells in vitro and inhibited metastasis formation of neuroblastoma xenografts in vivo 11 . The present study and other studies 44‐48 indicated that hemoglobin and hemoglobin‐derived fragments could be classified as moonlighting proteins characterized by their capacity to perform multiple physiologic tasks, including anticancer functions.…”

Investigating the Protein Signature of Adamantinomatous Craniopharyngioma Pediatric Brain Tumor Tissue: Towards the Comprehension of Its Aggressive Behavior

“…This peptide holds multiple biological activities including a role in the maintenance of homeostasis [28]. Recently, the expression of hemoglobin chains in neurons and glial cells, in endothelial and tumor vessels, and the potential role of hemoglobin and hemorphin peptides within brain tumors [29] shed a new light on the investigation of this nonepithelial protein and its fragment. The fragment 25-48 of serum albumin was detected in four samples, and given its frequent identification in biological fluids and tissues [25], this fragment could have a biological significance.…”

Advances in the antitumor mechanisms of tripartite motif-containing protein 3

“…A study demonstrated significantly lower expression levels of TRIM3 in lung cancer tissue compared to normal lung tissue, with its expression level closely correlating with the clinical and pathological characteristics of lung cancer. Further experiments evidenced TRIM3’s ability to inhibit lung cancer cell proliferation and invasion and induce apoptosis (Altinoz et al 2016 ). Additionally, TRIM3 can also regulate the metabolism of lung cancer cells, curtailing metabolic pathways such as glycolysis and oxidative phosphorylation, thus hindering the growth and invasion of lung cancer cells.…”