Expression of hypoxia inducible factor-1α (HIF-1α) and glucose transporter-1 (GLUT-1) in ovarian adenocarcinomas: Difference in hypoxic status depending on histological character

Abstract

Abstract. The expression of hypoxia inducible factor-1α (HIF-1α) and glucose transporter-1 (GLUT-1) was immunohistochemically analyzed in ovarian adenocarcinomas with the aim of elucidating whether hypoxic status is associated with histological type or structural character. The following ovarian adenocarcinomas were used: serous adenocarcinoma (SEA), 21 cases; mucinous adenocarcinoma (MUA), 19 cases; endometrioid adenocarcinoma (ENA), 16 cases; clear cell adenocarcinoma (CLA), 19 cases. High-level expression (3+) of HIF-1α was observed in 100% of SEAs, 58% of MUAs, 100% of ENAs and 89% of CLAs, and high-level expression of GLUT-1 in 76% of SEAs, 26% of MUAs, 50% of ENAs and 67% of CLAs. Heterogeneous or localized staining was relatively evident for GLUT-1. Immunohistochemical profiles were in accord with the immunoblotting and mRNA levels of both markers. ELISA for the detection of active HIF-1 demonstrated that HIF-1 is strongly activated in SEAs, ENAs and CLAs as compared to MUAs. Our results show that GLUT-1 overexpression is to some extent regulated by HIF-1α and is also strongly associated with histological features, i.e., papillary or stratified structure accompanied by little or no vascular stroma. In conclusion, hypoxic status differs according to the histological type of ovarian adenocarcinoma and the micro-environmental conditions of each type. IntroductionMalignant tumors are considered to be in a more or less hypoxic state, with highly malignant tumors being especially hypoxia-resistant (1). Hypoxia inducible factor-1 (HIF-1), which is a heterodimer made up of an α and ß subunit, is one of the interesting recently discovered factors involved in tumor development and histogenesis (1). The heterodimer of HIF-1 in the nucleus is biologically functional when it is bound to hypoxia response elements (HREs). It is known that pathophysiological phenomena, including glucose transport, glycolysis, angiogenesis, erythropoiesis and the inhibition of apoptosis, are usually regulated by transcription factors such as HIF-1α (2). In this regulation, the expression level of the HIF-1α subunit is a determinant of HIF-1 transcription activity (2) and the loss of the von Hippel-Lindau tumor suppressor gene results in constitutive high-level expression of HIF-1α (3). In general, when compared to non-malignant tumor cells or normal tissue cells the glucose utilization rate is increased in malignant tumor cells (4). One or more members of the glucose transporter (GLUT) gene family are expressed in all mammalian cells. GLUTs are integral membrane glycoproteins that play a key role in facilitating glucose transport (5). GLUT-1 is a representative member of the family and is widely distributed in normal tissues such as erythrocytes and endothelial cells at the blood-brain barrier (6-8). Various studies have shown a close relationship between GLUT-1 expression and carcinogenesis, tumor development or the unfavorable prognosis of various malignancies (9-12).We have observed a progressive increase in HIF-1α and GLUT-1 expressio...

Expression and significance of hypoxia-inducible factor-1α and glucose transporter-1 in laryngeal carcinoma

“…Hypoxia-inducible factor-1α (HIF-1α), a transcription factor associated with the cellular response to hypoxia (12), upregulates the expression of several hypoxia response genes, including GLUT-1 (1). The overexpression of GLUT-1 increases glucose transport to meet the energy requirements of malignant tumour cells.…”

“…Malignant tumours are considered to be in a hypoxic state (1). Under hypoxic conditions, cancer cells switch from oxygen-dependent glucose metabolism to oxygen-independent glycolysis (2).…”

Molecular typing of epithelial ovarian carcinomas using inflammatory markers

“…15 HIF-1alpha is activated by hypoxia involving the PI-3K/AKT/mTOR signaling pathway. Glut-1 expression has been correlated with malignant transformation, histological characteristics, 8 and tumor angiogenesis. 16 Because it promotes malignant transformation and development of histological tumor characteristics 7 including angiogenesis, 16 inhibition of Glut-1 is currently being evaluated as a therapeutic strategy.…”

“…7 Glut-1 is a glucose transporter-1 molecule essential for tumor cells to survive, especially in a severely hypoxic microenvironment. 8 iNOS synthesizes nitric oxide (NO), which causes NO-mediated apoptosis in the presence of inflammatory mediators like bacterial endotoxins. 9 Cyclooxygenase enzyme (COX) is a key regulatory enzyme in the prostaglandin/eicosanoid synthetic pathway.…”

Immunohistochemical Expression of Glut-1 in Epithelial Ovarian Tumors: Correlation With the Clinicopathological Factors and Tumor Proliferative Marker Pcna.

“…Glut-1 is a prototype of the Glut family and is widely distributed in normal tissues including RBCs [25]. Studies on ovarian cancer have suggested that Glut-1 is overexpressed and correlated with tumor aggressiveness and poor prognosis [15,26].…”