Regulation of glucose metabolism-related genes and vegf by hif-1α and hif-1β, but not hif-2α, in gastric cancer

ABSTRACT Hypoxia-inducible factors (HIFs) are transcription factors that activate the transcription of target genes involved in crucial aspects of cancer development. This study investigated

the expression of HIFs and their contribution to the regulation of target genes related to angiogenesis and glucose metabolism in gastric cancer. The data showed that HIFs were

over-expressed in gastric cancer and that activation of the target genes was observed mainly in the early stages. Moreover, the results of the present study revealed that only HIF-1α, but

not HIF-2α dimerizes with HIF-1β and then regulates expression of target genes in response to hypoxia. The results of the present study demonstrate that HIF-1α and HIF-1β enhances expression

of VEGF and glucose metabolism-related genes in response to hypoxia in gastric cancer. These data offer important information regarding HIF pathways in the development of gastric cancer.

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TUMOR GROWTH IN COLORECTAL CANCER Article Open access 03 March 2025 INTRODUCTION Hypoxia is a common feature of many cancers (Ryan et al., 2000). Hypoxia-inducible factors (HIFs) are

essential components in regulating transcription in tumor cells in response to hypoxia. HIF-1α and HIF-2α dimerize with a constitutively expressed β-subunit, and exhibit distinct roles in

hypoxic expression of target genes (Hu et al., 2003; Park et al., 2003). Although HIF-1 is induced by hypoxia in almost all cell types, the expression of HIF-1 target genes induced by

hypoxia is cell type specific manner (Yu et al., 1999; Semenza, 2003). The cell type specificity is thought to be due to the functional interactions of HIFs with other transcription factors

or to activation of a subgroup of HIFs in a particular cell type during hypoxia (Ema et al., 1997; Tian et al., 1997; Brusselmans et al., 2001). Gastric cancer is one of the leading causes

of cancer related motality in East Asia, including Korea (Neugut et al., 1996). Several reports have shown that HIFs play important roles in gastric tumorigenesis (Zhong et al., 1999; Park

et al., 2003). A previous study by our group indicated that genes related to glucose metabolism, such as _PKM2_ (pyruvate kinase), _PGK1_ (phosphoglycerate kinase 1), _GLUT 1_ (glucose

transporter 1), _LDHA_ (lactate dehydrogenase A), and _ENO1_ (enolase 1), were up-regulated in gastric cancer cell lines (Kim et al., 2004). So far, the roles of HIF-1α and HIF-2α in glucose

metabolism and other HIF-regulated genes under hypoxic conditions in gastric cancer remain unclear. To identify the roles of HIFs in gastric cancer, gastric cancer tissue specimens from

human patients as well as cancer cell lines, were used to assess the contributions of HIF-1α and HIF-2α to the expression of glucose metabolism-related genes and VEGF during specific cancer

developmental stages and in response to hypoxia. RESULTS HIFS WERE OVER-EXPRESSED IN GASTRIC CANCER CELLS To confirm the relationship of the HIF pathway to the development of gastric cancer,

the expression of HIFs at the level of transcription was examined in the gastric cancer cell lines and tissues. The results of semiquantitative (Sq) RT-PCR in the gastric cancer cell lines

showed that the expression of HIF-1α and HIF-2α did not differ between gastric cancer cell lines and normal Hs 667.st cells, while HIF-1β expression was significantly increased in the

gastric cancer cell lines (Figure 1A). In contrast, Sq RT-PCR data for HIFs expression in the human gastric tissue specimens revealed up-regulation of HIF genes expression compared to

adjacent normal tissues (Figure 1B, a-c). In particular, these over-expressions were observed in the early stage of IA, although HIF-1α and HIF-2α were over-expressed in the IIIA/B stage. In

addition, immunohistochemical analysis of the human gastric tissues showed that 22 of 38 (58%) specimens showed positive staining for HIF-1α, 17 of 38 (45%) were positive for HIF-1β and 18

of 38 (47%) were positive for HIF-2α in the cancerous regions compared with adjacent normal tissues (Table 1). Interestingly, in the early stage of IA/B, these positives were mainly observed

as an over-expression of HIF-1α compared with those of HIF-1β and HIF-2α (Table 1). And the expression levels of HIFs were observed to increase in proportion to tumor grades. The

HIF-positive cells were clustered within gastric adenocarcinoma tissue, but were not detected or were expressed at very low levels in nonmalignant epithelial and stromal cells (Figure 2).

HIF-1α and HIF-2α was located in the cytosol and nucleus, while HIF-1β was limited to the nucleus. These data indicate that HIFs are commonly over-expressed in gastric cancer, and that

HIF-1α plays a particularly important role in its early stages. OVER-EXPRESSION OF GLUCOSE METABOLISM-RELATED GENES AND VEGF IS COMMON IN GASTRIC CANCER CELLS, ESPECIALLY IN THE EARLY STAGES

To further confirm the activation of HIF pathways, the expression of glucose metabolism-related genes and VEGF also was investigated in gastric cancer cell lines and tissues. The results

shown in Figure 1A reveal that glucose metabolism-related target genes, as well as the VEGF, were over-expressed in gastric cancer cell lines compared with normal Hs 677.st cells. In

addition, results of the Sq RT-PCR in gastric tumor tissues show that VEGF was over-expressed only during stage IA (Figure 1B, d). Interestingly, over-expression of glucose metabolism

related target genes was mainly observed during stage I, although GLUT1 and ENO1 also were over-expressed during stage II (Figure 1B, e-h). These results indicate that the effective

activation of HIF related angiogenesis and glucose metabolism pathways may play important roles in the progression of gastric cancer. THE HETERODIMER OF HIF-1Α AND HIF-1Β, BUT NOT OF HIF-2Α

DIRECTLY REGULATES THE EXPRESSION OF GLUCOSE METABOLISM-RELATED TARGET GENES AND VEGF To examine the contribution of HIF members to the expression of genes related to glucose metabolism and

VEGF, expression of these genes in response to hypoxia was examined in SNU-638 cells. As shown in Figure 3A and B, expression of HIFs at both the transcriptional and translational levels was

increased under hypoxic conditions compared with normoxia. In particular, an HIF-1α expression in gastric cancer cell line under hypoxic conditions was revealed to be regulated more in the

translational level than in the transcriptional level. In addition, the increased transcriptional levels of glucose metabolism-related genes, as well as of the VEGF, were confirmed under

hypoxic conditions (Figure 3A). Among them, immunoblot analysis of GLUT1 and ENO1 protein levels also revealed over-expression at the translational level (Figure 3B). However, when SNU-638

cells were transfected with siRNA to HIFs, HIF-1α and HIF-1β but not HIF-2α resulted in the down regulation of target genes related to glucose metabolism and of VEGF at both the

transcriptional and translational levels (Figure 3A and B). On the other hands, when the transcriptional activity of HIFs in SNU-638 cells under hypoxic condition was examined using a HRE

(hypoxic response element)-luciferase reporter construct, the siRNA of HIF-1α and HIF-1β were shown to reduce the relative luciferase activity induced by CoCl2 stimulation whereas siRNA of

HIF-2α had no effect (Figure 3C). These data indicate that HIF-2α was not required to the expression of glucose metabolism-related genes in gastric cancer cells under hypoxic conditions. To

confirm which heterodimer of HIF-1α and -2α directly regulates these genes, an immunoprecipitation assay with HIF-1β antibody was performed. As shown in Figure 3D, HIF-1β interacted only

with HIF-1α in SNU-638 cells under hypoxic conditions. This interaction was also confirmed in immunoprecipitation result with the antibody against HIF-1α. This result explains why HIF-2α had

no effect on regulation of expression of target genes related to glucose metabolism and of VEGF, although HIF-2α was over-expressed in SNU-638 cells under hypoxic conditions. Taken

together, these data strongly suggest that not only HIF-1α but also HIF-1β play significant roles in the regulation of glucose metabolism and angiogenesis related genes in gastric cancer.

DISCUSSION Over-expression of HIFs is thought to correlate with cancer progression (Semenza, 2003; Carroll and Ashcroft, 2005). However, the roles of HIF-1α and HIF-2α in regulating

expression of HIF target genes, such as glucose metabolism-related genes and VEGF, in gastric cancer under hypoxic conditions remain unclear. The present study, we investigated HIF

expression as well as their relationship to expression of glucose metabolism-related genes and VEGF in gastric cancer cells. The resulting data provide new clues to understanding the

molecular mechanisms of the HIF pathway in gastric cancer development. The HIF expression data showed that mRNA and protein of HIFs, HIF-1α, HIF-1β and -2α were over-expressed in gastric

cancer tissues. This result was coincident with others observation in which HIF-1α was over-expressed, as assessed by immunochemical histological analysis, in 2 gastric cancer tissue

specimens (Zhong et al., 1999). In addition, it was partially supported by a previous study that the combination of a HIF-1α protein over-expression with nonfunctional p53 tends to indicate

a dismal prognosis in gastric cancer (Sumiyoshi et al., 2006). Furthermore, the results of the present study revealed that the activation of glucose metabolism-related genes and VEGF was

mainly observed in the early stages of gastric cancer, especially in stage I. These data offer valuable evidence that therapeutic strategies targeting angiogenesis and glucose metabolism

pathways should be implemented during the early stages of gastric cancer. Moreover, it was determined that HIF-1α but not HIF-2α primarily dimerizes with HIF-1β and regulates expression of

VEGF and glucose metabolism-related genes in response to hypoxia. It is well-known that HIF-1α but not HIF-1β plays important roles in the HIF-1 pathway. It also has been reported that HIF

target genes are regulated by HIF-1α in prostate, ovarian, breast, and lung cancers (Volm and Koomagi, 2000; Schindl et al., 2002). Taking these reports into account, the data from the

present study offer strong evidence that, at least in gastric cancer, not only HIF-1α but also HIF-1β play crucial roles in HIF pathway. In other words, under the hypoxic condition, HIF-1α

heterodimerizes with HIF-1β in nucleus, the heterodimmer binds to an enhancer element called the HRE in target genes involved in glucose metabolism and angiogenesis and then regulates

expression of these genes. In addition, HIF-2α has been reported to contribute to HIF target gene expression in renal carcinoma cells (Carroll and Ashcroft, 2006), suggesting that the

contributions of HIF-1α and HIF-2α to HIF target gene expression induced by hypoxia are regulated in a cell type specific manner in which dimerization with HIF-1β is an important factor. The

results of the present study demonstrate that HIF-1α and HIF-1β but not HIF-2α enhances expression of glucose metabolism-related genes and VEGF in response to hypoxia in gastric cancer.

These data offer important information relevant to therapies that target angiogenesis and glucose metabolism using the HIF pathway in gastric cancer. METHODS PATIENT TISSUE SAMPLES

Twenty-seven tissues with pairs of gastric tumors and adjacent non-tumor tissue for gene expression examination and 38 gastric cancer blocks for immunohistochemical staining analysis were

obtained from the College of Medicine, Chungnam National University, and from the Department of Pathology, Eulji University School of Medicine, Korea with informed consent, respectively. The

gastric tumors were staged according to tumor-node-metastasis classification of Union Internationale Contre le Cancer. CELL CULTURE AND SEMIQUANTITATIVE (SQ) RT-PCR ANALYSIS Human gastric

cancer cell lines (SNU-216, -484, -601, -638) were obtained from the Korean Cell Line Bank (Seoul, Korea) (Park et al., 1997; Choi et al., 2007) and normal gastric cell line (Hs677.st) was

obtained from ATCC. All cell lines were maintained in RPMI1640 supplemented with 10% FBS (Hyclone Laboratories) and gentamicin (10 µg/ml) at 37℃ in a 5% CO2 humidified atmosphere.

Environmental hypoxic conditions (2%) were achieved in an airtight humidified chamber continuously flushed with a gas mixture containing 5% CO2 and 95% N2. The culture of human normal and

gastric cancer cell lines, as well as Sq RT-PCR analysis using total RNAs from these cell lines, were performed as previously described (Kim et al., 2004). The primers used in Sq RT-PCR are

indicated in Supplemental Data Table S1 and the size of PCR products ranged from 300 to 600 bp. The PCR cycle numbers were varied from 25 to 35 according to the exponential part of the

amplification curve of target genes. SIRNA TREATMENT siRNA targeted to HIF-1α, (5'-CUGAUGACCAGCAACUUGATT-3' and 5'-UCAAGUUGCUGGUCAUCAGTT-3'), HIF-1β,

(5'-CAAUGCGGAUCAGAGUAAATT-3' and 5'-UUUACUCUGAUCCGCAUUGTT-3'), and HIF-2α, (5'-CAGCAUCUUUGAUAGCAGUTT-3' and 5'-ACUGCUAUCAAAGAUGCUGTT-3') were designed

using programs such as Dharmacon-siDESIGN and Invitrogen BOCK-iT RNAi designer, and synthesized from Samchully Pharm (Korea). The human gastric cancer SNU-638 cells were plated at 40%

confluency (8 × 105 cells/dish) in 10 cm plates and transfected with oligonucleotide duplexes (100 nM) that had been premixed with Oligofectamine (Invitrogen) in Opti-MEM-I (Invitrogen) for

4 h. An siRNA targeted to an irrelevant mRNA of GFP served as the nonspecific control. IMMUNOPRECIPITATION AND IMMUNOBLOT ANALYSIS The SNU-638 cells were treated for 4 h under hypoxic or

normoxic conditions, rinsed once with cold PBS, and lysed in lysis buffer A [20 mM HEPES (pH 7.5), 150 mM NaCl, 1 mM EDTA, 2 mM EGTA, 1% Triton X-100, 10% glycerol, 1 mM AEBSF, 1 mM Na3VO4,

5 mM NaF, 10 µg/ml aprotinin and leupeptin]. The cell lysates were pre-cleared with 10 µl protein A/G agarose beads (Amersham Biosciences) for 1 h. The cleared lysates were incubated with 6

µg HIF-1β or HIF-1α antibodies (Santa Cruz Biotechnology, Inc.) overnight at 4℃. The lysates were mixed with 30 µl protein A/G agarose beads for 2 h at 4℃. The beads were washed three times

with 1 ml lysis buffer A. The final protein precipitates were subjected to immunoblot analysis. Proteins resolved by 6% SDS-PAGE were transferred to nitrocellulose membranes and nonspecific

binding sites were blocked by incubation in TBS containing 0.5% Tween-20 and 5% (w/v) dry milk. Immunoblot analysis was performed with the indicated antibodies in figure. A mouse monoclonal

antibody against HIF-1α antibody was purchased from BD Transduction Laboratories. Antibodies to α-tubulin, GLUT1, HIF-1β, and ENO1 were obtained from Santa Cruz Biotechnology. A mouse

monoclonal antibody to HIF-2α was purchased from Abcam Inc. The bound primary antibodies were visualized with HRP-conjugated goat anti rabbit-IgG, goat anti-mouse-IgG (Pierce), or donkey

anti-goat IgG (Santa Cruz Biotechnology Inc.), and enhanced with a chemiluminescence kit (AB Frontier, Korea). IMMUNOHISTOCHEMISTRY Immunohistochemical staining for HIF-1α, HIF-2α, and

HIF-1β was performed using the previously described procedures (Kim et al., 2005; Choi et al., 2007). The primary antibodies used in the immunohistochemical staining were as followings: a

rabbit polyclonal antibody against HIF-1α at a 1:200 dilution; a mouse monoclonal anti-HIF-1β at a 1:200 dilution (Santa Cruz Biotechnology, Inc.); a mouse monoclonal antibody against HIF-2α

at a 1:1000 dilution (Abcam Inc.). LUCIFERASE REPORTER ASSAY SNU-638 cells were transfected by Fugene 6 liposome technique (Boehringer Mannheim) according to protocol of the supplier. For

reporter assays in HIF-1α, HIF-1β, or HIF-2α knocked-down cells, SNU-638 cells were cotransfected with siRNA of HIFs and HRE-Luciferase reporter. At 48 h post-transfection, the cells were

incubated with 200 µM of CoCl2 in complete medium for 12 h. Relative luciferase activities were determined by normalizing the β-galactosidase activities of the cell lysates. The luciferase

assay carried out by the method using enhanced luciferase assay kit (Promega) according to the manufacture's instruction. STATISTICS Data were analyzed using a Student's _t_-test

on SigmaPlot 8.0 software. _P_-values were assessed to derive the statistical significance. SUPPLEMENTAL DATA Supplemental Data include a table and can be found with this article online.

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PubMed  Google Scholar  Download references ACKNOWLEDGEMENTS We thank Prof. Kyu-Sang Song, School College of Medicine, ChungNam National University, Korea, for the gift of human gastric

cancer tissues. This work was supported by a grant from the 21C Frontier Functional Human Genome Project, and by the Drug Target Discovery Project from the Ministry of Science and Technology

of Korea, and by the Korea Research Institute of Bioscience and Biotechnology (KRIBB) Research Initiative Program. AUTHOR INFORMATION Author notes * In-Sung Song and Ai-Guo Wang: These

authors contributed equally to this work. AUTHORS AND AFFILIATIONS * Genome Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806, Korea., In-Sung Song, 

Ai-Guo Wang, Sun Young Yoon, Jeong-Min Kim & Nam-Soon Kim * Department of Pathology, Eulji University School of Medicine, Daejeon 301-746, Korea., Joo Heon Kim * School of Life Sciences

and Biotechnology, College of Natural Sciences, Kyungpook National University, Daegu 702-701, Korea., Dong-Seok Lee Authors * In-Sung Song View author publications You can also search for

this author inPubMed Google Scholar * Ai-Guo Wang View author publications You can also search for this author inPubMed Google Scholar * Sun Young Yoon View author publications You can also

search for this author inPubMed Google Scholar * Jeong-Min Kim View author publications You can also search for this author inPubMed Google Scholar * Joo Heon Kim View author publications

You can also search for this author inPubMed Google Scholar * Dong-Seok Lee View author publications You can also search for this author inPubMed Google Scholar * Nam-Soon Kim View author

publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Nam-Soon Kim. ADDITIONAL INFORMATION Supplementary Information accompanies the

paper on the Experimental & Molecular Medicine website SUPPLEMENTARY INFORMATION SUPPLEMENTARY INFORMATION (PDF 263 KB) RIGHTS AND PERMISSIONS This is an Open Access article distributed

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reproduction in any medium, provided the original work is properly cited. Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Song, IS., Wang, AG., Yoon, S. _et al._ Regulation of

glucose metabolism-related genes and VEGF by HIF-1α and HIF-1β, but not HIF-2α, in gastric cancer. _Exp Mol Med_ 41, 51–58 (2009). https://doi.org/10.3858/emm.2009.41.1.007 Download citation

* Accepted: 19 September 2008 * Published: 31 January 2009 * Issue Date: January 2009 * DOI: https://doi.org/10.3858/emm.2009.41.1.007 SHARE THIS ARTICLE Anyone you share the following link

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content-sharing initiative KEYWORDS * glucose metabolism disorders * hypoxia-inducible factor 1 * neovascularization, pathologic * stomach neoplasms * vascular endothelial growth factor A