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Erschienen in: Annals of Nuclear Medicine 10/2016

23.09.2016 | Original Article

Correlation of HIF-1α/HIF-2α expression with FDG uptake in lung adenocarcinoma

verfasst von: Kotaro Higashi, Toshiaki Yamagishi, Yoshimichi Ueda, Yasuhito Ishigaki, Miyako Shimasaki, Yuka Nakamura, Manabu Oguchi, Tsutomu Takegami, Motoyasu Sagawa, Hisao Tonami

Erschienen in: Annals of Nuclear Medicine | Ausgabe 10/2016

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Abstract

Objectives

Hypoxia is a key element involved in the development and progression of tumors. HIF-1α may transiently induce and mediate the response to acute and severe hypoxia, while HIF-2α may induce a longer response and may control the response to chronic and moderate hypoxia. Hypoxia increases the cellular uptake of FDG. Therefore, HIF may play an important role in the process of the cellular uptake of FDG. The aim of this study was to compare HIF-1α/HIF-2α expression with FDG uptake, Glut-1 expression, and prognosis in the patients with lung adenocarcinoma and to investigate the role of HIF-1α/HIF-2α in the uptake of FDG in lung adenocarcinoma.

Methods

In the current work, we compared the immunohistochemical expression of HIF-1α and HIF-2α in surgical specimens of 44 patients with lung adenocarcinoma. The relationships between HIF-α expression and Glut-1 expression, FDG uptake, and clinicopathological factors, including prognosis, were analyzed.

Results

There was a marginal association between HIF-1α and HIF-2α expressions (P = 0.076). We found a significant correlation between HIF-2α expression and FDG uptake (P = 0.0001). HIF-1α expression showed a marginal association with FDG uptake (P = 0.066). FDG uptake correlated more significantly with HIF-2α expression than with HIF-1α expression. A significant correlation was noticed between Glut-1 expression and both HIF-1α and HIF-2α expressions (P = 0.005 and P = 0.003, respectively). Univariate analysis of disease-free survival demonstrated that FDG uptake and HIF-2α expression, but not HIF-1α expression, were related to recurrence (P < 0.0001).

Conclusion

FDG uptake correlated more significantly with HIF-2α expression than with HIF-1α expression, and both FDG uptake and HIF-2α expression, but not HIF-1α expression was correlated with post-operative recurrence in the patients with lung adenocarcinoma. These results suggest that both FDG uptake and HIF-2α expression may represent a more aggressive phenotype and that HIF-2α may play a more important role than HIF-1α in the uptake of FDG in lung adenocarcinoma.
Literatur
1.
2.
Zurück zum Zitat Dachs GU, Patterson AV, Firth JD, Ratcliffe PJ, Townsend KM, Stratford IJ, et al. Targeting gene expression to hypoxic tumor cells. Nat Med. 1997;3:515–20.CrossRefPubMed Dachs GU, Patterson AV, Firth JD, Ratcliffe PJ, Townsend KM, Stratford IJ, et al. Targeting gene expression to hypoxic tumor cells. Nat Med. 1997;3:515–20.CrossRefPubMed
3.
Zurück zum Zitat Jiang BH, Semenza GL, Bauer C, Marti HH. Hypoxia-inducible factor 1 levels vary exponentially over a physiologically relevant range of O2 tension. Am J Physiol. 1996;271:1172–80. Jiang BH, Semenza GL, Bauer C, Marti HH. Hypoxia-inducible factor 1 levels vary exponentially over a physiologically relevant range of O2 tension. Am J Physiol. 1996;271:1172–80.
4.
Zurück zum Zitat Pugh CW, Ratcliffe PJ. Regulation of angiogenesis by hypoxia: role of the HIF system. Nat Med. 2003;9:677–84.CrossRefPubMed Pugh CW, Ratcliffe PJ. Regulation of angiogenesis by hypoxia: role of the HIF system. Nat Med. 2003;9:677–84.CrossRefPubMed
5.
Zurück zum Zitat Schofield CJ, Ratcliffe PJ. Oxygen sensing by HIF hydroxylases. Nat Rev Mol Cell Biol. 2004;5:343–54.CrossRefPubMed Schofield CJ, Ratcliffe PJ. Oxygen sensing by HIF hydroxylases. Nat Rev Mol Cell Biol. 2004;5:343–54.CrossRefPubMed
6.
Zurück zum Zitat Maxwell PH, Ratcliffe PJ. Oxygen sensors and angiogenesis. Semin Cell Dev Biol. 2002;13:29–37.CrossRefPubMed Maxwell PH, Ratcliffe PJ. Oxygen sensors and angiogenesis. Semin Cell Dev Biol. 2002;13:29–37.CrossRefPubMed
8.
Zurück zum Zitat Covello KL, Kehler J, Yu H, Gordan JD, Arsham AM, Hu CJ, et al. HIF-2 alpha regulates Oct-4: effects of hypoxia on stem cell function, embryonic development, and tumor growth. Genes Dev. 2006;20:557–70.CrossRefPubMedPubMedCentral Covello KL, Kehler J, Yu H, Gordan JD, Arsham AM, Hu CJ, et al. HIF-2 alpha regulates Oct-4: effects of hypoxia on stem cell function, embryonic development, and tumor growth. Genes Dev. 2006;20:557–70.CrossRefPubMedPubMedCentral
9.
Zurück zum Zitat Sato M, Tanaka T, Maemura K, Uchiyama T, Sato H, Maeno T, et al. The Pai-1 gene as a direct target of endothelial PAS domain protein-1 in adenocarcinoma A549 cells. Am J Respir Cell Mol Biol. 2004;31:209–15.CrossRefPubMed Sato M, Tanaka T, Maemura K, Uchiyama T, Sato H, Maeno T, et al. The Pai-1 gene as a direct target of endothelial PAS domain protein-1 in adenocarcinoma A549 cells. Am J Respir Cell Mol Biol. 2004;31:209–15.CrossRefPubMed
10.
Zurück zum Zitat Pedersen MW, Holm S, Lund EL, Højgaard L, Kristjansen PE. Coregulation of glucose uptake and vascular endothelial growth factor (VEGF) in two small-cell lung cancer (SCLC) sublines in vivo and in vitro. Neoplasia. 2001;3:80–7.CrossRefPubMedPubMedCentral Pedersen MW, Holm S, Lund EL, Højgaard L, Kristjansen PE. Coregulation of glucose uptake and vascular endothelial growth factor (VEGF) in two small-cell lung cancer (SCLC) sublines in vivo and in vitro. Neoplasia. 2001;3:80–7.CrossRefPubMedPubMedCentral
11.
Zurück zum Zitat Clavo AC, Brown RS, Wahl RL. Fluorodeoxyglucose uptake in human cancer cell lines is increased by hypoxia. J Nucl Med. 1995;36:1625–32.PubMed Clavo AC, Brown RS, Wahl RL. Fluorodeoxyglucose uptake in human cancer cell lines is increased by hypoxia. J Nucl Med. 1995;36:1625–32.PubMed
12.
Zurück zum Zitat Guo J, Higashi K, Ueda Y, Oguchi M, Takegami T, Toga H, et al. Microvessel density: correlation with 18F-FDG uptake and prognostic impact in lung adenocarcinomas. J Nucl Med. 2006;47:419–25.PubMed Guo J, Higashi K, Ueda Y, Oguchi M, Takegami T, Toga H, et al. Microvessel density: correlation with 18F-FDG uptake and prognostic impact in lung adenocarcinomas. J Nucl Med. 2006;47:419–25.PubMed
13.
Zurück zum Zitat Guo J, Higashi K, Ueda Y, Ishigaki Y, Sakuma T, Oguchi M, et al. VEGF-A and its isoform VEGF121 mRNA expression measured by quantitative real-time RT-PCR: correlation with F-18 FDG uptake and aggressiveness of lung adenocarcinoma: preliminary study. Ann Nucl Med. 2011;25:29–36.CrossRefPubMed Guo J, Higashi K, Ueda Y, Ishigaki Y, Sakuma T, Oguchi M, et al. VEGF-A and its isoform VEGF121 mRNA expression measured by quantitative real-time RT-PCR: correlation with F-18 FDG uptake and aggressiveness of lung adenocarcinoma: preliminary study. Ann Nucl Med. 2011;25:29–36.CrossRefPubMed
14.
Zurück zum Zitat van Baardwijk A, Dooms C, van Suylen RJ, Verbeken E, Hochstenbag M, Dehing-Oberije C, et al. The maximum uptake of (18)F-deoxyglucose on positron emission tomography scan correlates with survival, hypoxia inducible factor-1α and GLUT-1 in non-small cell lung cancer. Eur J Cancer. 2007;43:1392–8.CrossRefPubMed van Baardwijk A, Dooms C, van Suylen RJ, Verbeken E, Hochstenbag M, Dehing-Oberije C, et al. The maximum uptake of (18)F-deoxyglucose on positron emission tomography scan correlates with survival, hypoxia inducible factor-1α and GLUT-1 in non-small cell lung cancer. Eur J Cancer. 2007;43:1392–8.CrossRefPubMed
15.
Zurück zum Zitat Dooms C, Verbeken E, Stroobants S, Vansteenkiste J. Biological correlates of the maximum 18-fluoro-2-deoxy-glucose uptake on positron emission tomography in non-small cell lung carcinoma after induction chemotherapy. J Thorac Oncol. 2009;4:1221–5.CrossRefPubMed Dooms C, Verbeken E, Stroobants S, Vansteenkiste J. Biological correlates of the maximum 18-fluoro-2-deoxy-glucose uptake on positron emission tomography in non-small cell lung carcinoma after induction chemotherapy. J Thorac Oncol. 2009;4:1221–5.CrossRefPubMed
16.
Zurück zum Zitat Kaira K, Endo M, Abe M, Nakagawa K, Ohde Y, Okumura T, et al. Biologic correlates of 18F-FDG uptake on PET in pulmonary pleomorphic carcinoma. Lung Cancer. 2011;71:144–50.CrossRefPubMed Kaira K, Endo M, Abe M, Nakagawa K, Ohde Y, Okumura T, et al. Biologic correlates of 18F-FDG uptake on PET in pulmonary pleomorphic carcinoma. Lung Cancer. 2011;71:144–50.CrossRefPubMed
17.
Zurück zum Zitat Yokoyama Y, Charnock-Jones DS, Licence D, Yanaihara A, Hastings JM, Holland CM, et al. Expression of vascular endothelial growth factor (VEGF)-D and its receptor, VEGF receptor 3, as a prognostic factor in endometrial carcinoma. Clin Cancer Res. 2003;9:1361–9.PubMed Yokoyama Y, Charnock-Jones DS, Licence D, Yanaihara A, Hastings JM, Holland CM, et al. Expression of vascular endothelial growth factor (VEGF)-D and its receptor, VEGF receptor 3, as a prognostic factor in endometrial carcinoma. Clin Cancer Res. 2003;9:1361–9.PubMed
18.
Zurück zum Zitat Hu CJ, Wang LY, Chodosh LA, Keith B, Simon MC. Differential roles of hypoxia-inducible factor 1α (HIF-1α) and HIF-2α in hypoxic gene regulation. Mol Cell Biol. 2003;23:9361–74.CrossRefPubMedPubMedCentral Hu CJ, Wang LY, Chodosh LA, Keith B, Simon MC. Differential roles of hypoxia-inducible factor 1α (HIF-1α) and HIF-2α in hypoxic gene regulation. Mol Cell Biol. 2003;23:9361–74.CrossRefPubMedPubMedCentral
19.
Zurück zum Zitat Giatromanolaki A, Koukourakis MI, Sivridis E, Turley H, Talks K, Pezzella F, et al. Relation of hypoxia inducible factor 1α and 2α in operable non-small cell lung cancer to angiogenic/molecular profile of tumours and survival. Br J Cancer. 2001;85:881–90.CrossRefPubMedPubMedCentral Giatromanolaki A, Koukourakis MI, Sivridis E, Turley H, Talks K, Pezzella F, et al. Relation of hypoxia inducible factor 1α and 2α in operable non-small cell lung cancer to angiogenic/molecular profile of tumours and survival. Br J Cancer. 2001;85:881–90.CrossRefPubMedPubMedCentral
20.
Zurück zum Zitat Wu XH, Qian C, Yuan K. Correlations of hypoxia-inducible factor-1α/hypoxia-inducible factor-2α expression with angiogenesis factors expression and prognosis in non-small cell lung cancer. Chin Med J. 2011;124:11–8.PubMed Wu XH, Qian C, Yuan K. Correlations of hypoxia-inducible factor-1α/hypoxia-inducible factor-2α expression with angiogenesis factors expression and prognosis in non-small cell lung cancer. Chin Med J. 2011;124:11–8.PubMed
21.
Zurück zum Zitat Higashi K, Ito K, Hiramatsu Y, Ishikawa T, Sakuma T, Matsunari I, et al. 18F-FDG uptake by primary tumor as a predictor of intratumoral lymphatic vessel invasion and lymph node involvement in non-small cell lung cancer: analysis of a multicenter study. J Nucl Med. 2005;46:267–73.PubMed Higashi K, Ito K, Hiramatsu Y, Ishikawa T, Sakuma T, Matsunari I, et al. 18F-FDG uptake by primary tumor as a predictor of intratumoral lymphatic vessel invasion and lymph node involvement in non-small cell lung cancer: analysis of a multicenter study. J Nucl Med. 2005;46:267–73.PubMed
22.
Zurück zum Zitat Tsutani Y, Miyata Y, Misumi K, Ikeda T, Mimura T, Hihara J, et al. Difference in prognostic significance of maximum standardized uptake value on [18F]-fluoro-2-deoxyglucose positron emission tomography between adenocarcinoma and squamous cell carcinoma of the lung. Jpn J Clin Oncol. 2011;41:890–6.CrossRefPubMed Tsutani Y, Miyata Y, Misumi K, Ikeda T, Mimura T, Hihara J, et al. Difference in prognostic significance of maximum standardized uptake value on [18F]-fluoro-2-deoxyglucose positron emission tomography between adenocarcinoma and squamous cell carcinoma of the lung. Jpn J Clin Oncol. 2011;41:890–6.CrossRefPubMed
23.
Zurück zum Zitat Nguyen XC, Lee WW, Chung JH, Park SY, Sung SW, Kim YK, et al. FDG uptake, glucose transporter type 1, and Ki-67 expressions in non-small-cell lung cancer: correlations and prognostic values. Eur J Radiol. 2007;62:214–9.CrossRefPubMed Nguyen XC, Lee WW, Chung JH, Park SY, Sung SW, Kim YK, et al. FDG uptake, glucose transporter type 1, and Ki-67 expressions in non-small-cell lung cancer: correlations and prognostic values. Eur J Radiol. 2007;62:214–9.CrossRefPubMed
24.
Zurück zum Zitat Uchida T, Rossignol F, Matthay MA, Mounier R, Couette S, Clottes E, et al. Prolonged hypoxia differentially regulates hypoxia-inducible factor (HIF)-1α and HIF-2α expression in lung epithelial cells: implication of natural antisense HIF-1α. J Biol Chem. 2004;279:14871–8.CrossRefPubMed Uchida T, Rossignol F, Matthay MA, Mounier R, Couette S, Clottes E, et al. Prolonged hypoxia differentially regulates hypoxia-inducible factor (HIF)-1α and HIF-2α expression in lung epithelial cells: implication of natural antisense HIF-1α. J Biol Chem. 2004;279:14871–8.CrossRefPubMed
25.
Zurück zum Zitat Mottet D, Dumont V, Deccache Y, Demazy C, Ninane N, Raes M, et al. Regulation of hypoxia-inducible factor-1α protein level during hypoxic conditions by the phosphatidylinositol 3-kinase/Akt/glycogen synthase kinase 3β pathway in HepG2 cells. J Biol Chem. 2003;278:31277–85.CrossRefPubMed Mottet D, Dumont V, Deccache Y, Demazy C, Ninane N, Raes M, et al. Regulation of hypoxia-inducible factor-1α protein level during hypoxic conditions by the phosphatidylinositol 3-kinase/Akt/glycogen synthase kinase 3β pathway in HepG2 cells. J Biol Chem. 2003;278:31277–85.CrossRefPubMed
26.
Zurück zum Zitat Holmquist-Mengelbier L, Fredlund E, Löfstedt T, Noguera R, Navarro S, Nilsson H, et al. Recruitment of HIF-1α and HIF-2α to common target genes is differentially regulated in neuroblastoma: HIF-2α promotes an aggressive phenotype. Cancer Cell. 2006;10:413–23.CrossRefPubMed Holmquist-Mengelbier L, Fredlund E, Löfstedt T, Noguera R, Navarro S, Nilsson H, et al. Recruitment of HIF-1α and HIF-2α to common target genes is differentially regulated in neuroblastoma: HIF-2α promotes an aggressive phenotype. Cancer Cell. 2006;10:413–23.CrossRefPubMed
27.
Zurück zum Zitat Kim WY, Perera S, Zhou B, Carretero J, Yeh JJ, Heathcote SA, et al. HIF2α cooperates with RAS to promote lung tumorigenesis in mice. J Clin Invest. 2009;119:2160–70.CrossRefPubMedPubMedCentral Kim WY, Perera S, Zhou B, Carretero J, Yeh JJ, Heathcote SA, et al. HIF2α cooperates with RAS to promote lung tumorigenesis in mice. J Clin Invest. 2009;119:2160–70.CrossRefPubMedPubMedCentral
28.
Zurück zum Zitat Pàez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H, Viñals F, et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell. 2009;15:220–31.CrossRefPubMedPubMedCentral Pàez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H, Viñals F, et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell. 2009;15:220–31.CrossRefPubMedPubMedCentral
29.
Zurück zum Zitat Kamlah F, Eul BG, Li S, Lang N, Marsh LM, Seeger W, et al. Intravenous injection of siRNA directed against hypoxia-inducible factors prolongs survival in a Lewis lung carcinoma cancer model. Cancer Gene Ther. 2009;16:195–205.PubMed Kamlah F, Eul BG, Li S, Lang N, Marsh LM, Seeger W, et al. Intravenous injection of siRNA directed against hypoxia-inducible factors prolongs survival in a Lewis lung carcinoma cancer model. Cancer Gene Ther. 2009;16:195–205.PubMed
Metadaten
Titel
Correlation of HIF-1α/HIF-2α expression with FDG uptake in lung adenocarcinoma
verfasst von
Kotaro Higashi
Toshiaki Yamagishi
Yoshimichi Ueda
Yasuhito Ishigaki
Miyako Shimasaki
Yuka Nakamura
Manabu Oguchi
Tsutomu Takegami
Motoyasu Sagawa
Hisao Tonami
Publikationsdatum
23.09.2016
Verlag
Springer Japan
Erschienen in
Annals of Nuclear Medicine / Ausgabe 10/2016
Print ISSN: 0914-7187
Elektronische ISSN: 1864-6433
DOI
https://doi.org/10.1007/s12149-016-1116-5

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