Prognostic impact of the combination of HIF‑1α and GLUT1 in patients with oesophageal squamous cell carcinoma

Yi,Hanjie; Han,Yongqin; Li,Qin; Lin,Runduan; Zhang,Jia; Yang,Yun; Wang,Xueping; Zhang,Lin

doi:10.3892/ol.2023.13990

Prognostic impact of the combination of HIF‑1α and GLUT1 in patients with oesophageal squamous cell carcinoma

Authors:
- Hanjie Yi
- Yongqin Han
- Qin Li
- Runduan Lin
- Jia Zhang
- Yun Yang
- Xueping Wang
- Lin Zhang
View Affiliations

Affiliations: Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330000, P.R. China, Department of Oncology, Shangrao People's Hospital, Shangrao, Jiangxi 334000, P.R. China, Department of Oncology, State Key Laboratory of Oncology in South China, Sun Yat‑Sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China, Department of Laboratory Medicine, The Third Hospital of Changsha, Changsha, Hunan 410015, P.R. China, Department of Laboratory Medicine, The 921st Hospital of The Joint Logistics Support Force of The Chinese People's Liberation Army, Changsha, Hunan 410003, P.R. China, Department of Oncology, State Key Laboratory of Oncology in South China, Sun Yat‑Sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China
Published online on: July 31, 2023 https://doi.org/10.3892/ol.2023.13990
Article Number: 404
Copyright: © Yi et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Oesophageal squamous cell carcinoma (ESCC) is a common type of carcinoma. Hypoxia is associated with chemo‑ and radio‑resistance, which may lead to a poor prognosis. Hypoxia‑inducible factor‑1α (HIF‑1α) is the main transcriptional regulator of the cellular response to low oxygen levels. Moreover, it can trigger the expression of critical genes, including glucose transporter protein type 1 (GLUT1). The aim of the present study was to evaluate the roles of HIF‑1α and GLUT1 in ESCC and their usefulness as prognostic markers. HIF‑1α and GLUT1 were measured in four ESCC cell lines, namely Eca109, KYSE150, TE‑1 and TE‑10, by western blotting following culture under normoxic and hypoxic conditions. In addition, xenograft tumors were established in mice using normoxic and hypoxic Eca109 cells and the chemosensitivity of the xenografts to 5‑fluorouracil (5‑FU) was evaluated. Furthermore, HIF‑1α and GLUT1 were analysed by immunochemistry in the tumor tissues of patients with ESCC and the associations of their expression levels with clinicopathological parameters were investigated. The results revealed that HIF‑1α and GLUT1 protein expression was weak in all four cell lines under a normoxic atmosphere but increased following culture in a hypoxic environment. In vivo, 5‑FU inhibited tumor growth more strongly in normoxic Eca109 xenografts than hypoxic Eca109 xenografts. Higher levels of apoptosis were also detected in the normoxic Eca109 xenografts via western blotting and TUNEL analysis. In patients with ESCC, HIF‑1α expression was associated with advanced ESCC while GLUT1 expression was associated with the sex of the patients. Multivariate analysis demonstrated that HIF‑1α and GLUT1 were negatively associated with progression‑free survival (PFS) and overall survival (OS). Additionally, a combination of HIF‑1α and GLUT1 expression was a predictor of RFS and OS in patients with ESCC without lymph node metastasis but not those with lymph node metastasis. The study demonstrated that HIF‑1α and GLUT1 were strongly expressed in vitro and in xenograft models when cells were exposed to hypoxia. The simultaneous high expression of HIF‑1α and GLUT1 was associated with poorer survival, and may play an important role in ESCC chemoresistance and the prognosis of ESCC.

View Figures

View References

1	Zheng RS, Zhang SW, Sun KX, Chen R, Wang SM, Li L, Zeng HM, Wei WW and He J: Cancer statistics in China, 2016. Zhonghua Zhong Liu Za Zhi. 45:212–220. 2023.(In Chinese). PubMed/NCBI
2	Kamangar F, Dores GM and Anderson WF: Patterns of cancer incidence, mortality, and prevalence across five continents: Defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol. 24:2137–2150. 2006. View Article : Google Scholar : PubMed/NCBI
3	Brahimi-Horn MC, Chiche J and Pouyssegur J: Hypoxia and cancer. J Mol Med (Berl). 85:1301–1307. 2007. View Article : Google Scholar : PubMed/NCBI
4	Lee JW, Bae SH, Jeong JW, Kim SH and Kim KW: Hypoxia-inducible factor (HIF-1)alpha: Its protein stability and biological functions. Exp Mol Med. 36:1–12. 2004. View Article : Google Scholar : PubMed/NCBI
5	Chen C, Pore N, Behrooz A, Ismail-Beigi F and Maity A: Regulation of glut1 mRNA by hypoxia-inducible factor-1. Interaction between H-ras and hypoxia. J Biol Chem. 276:9519–9525. 2001. View Article : Google Scholar : PubMed/NCBI
6	Airley RE and Mobasheri A: Hypoxic regulation of glucose transport, anaerobic metabolism and angiogenesis in cancer: Novel pathways and targets for anticancer therapeutics. Chemotherapy. 53:233–256. 2007. View Article : Google Scholar : PubMed/NCBI
7	Song K, Li M, Xu XJ, Xuan L, Huang GN, Song XL and Liu QF: HIF-1α and GLUT1 gene expression is associated with chemoresistance of acute myeloid leukemia. Asian Pac J Cancer Prev. 15:1823–1829. 2014. View Article : Google Scholar : PubMed/NCBI
8	Coleman CN: Modulating the radiation response. Stem Cells. 14:10–15. 1996. View Article : Google Scholar : PubMed/NCBI
9	Kaira K, Murakami H, Endo M, Ohde Y, Naito T, Kondo H, Nakajima T, Yamamoto N and Takahashi T: Biological correlation of ¹⁸F-FDG uptake on PET in pulmonary neuroendocrine tumors. Anticancer Res. 33:4219–4228. 2013.PubMed/NCBI
10	Chen B, Tang H, Liu X, Liu P, Yang L, Xie X, Ye F, Song C, Xie X and Wei W: miR-22 as a prognostic factor targets glucose transporter protein type 1 in breast cancer. Cancer Lett. 356:410–417. 2015. View Article : Google Scholar : PubMed/NCBI
11	Kim BW, Cho H, Chung JY, Conway C, Ylaya K, Kim JH and Hewitt SM: Prognostic assessment of hypoxia and metabolic markers in cervical cancer using automated digital image analysis of immunohistochemistry. J Transl Med. 11:1852013. View Article : Google Scholar : PubMed/NCBI
12	Osugi J, Yamaura T, Muto S, Okabe N, Matsumura Y, Hoshino M, Higuchi M, Suzuki H and Gotoh M: Prognostic impact of the combination of glucose transporter 1 and ATP citrate lyase in node-negative patients with non-small lung cancer. Lung Cancer. 88:310–318. 2015. View Article : Google Scholar : PubMed/NCBI
13	Tohma T, Okazumi S, Makino H, Cho A, Mochizuki R, Shuto K, Kudo H, Matsubara K, Gunji H, Matsubara H and Ochiai T: Overexpression of glucose transporter 1 in esophageal squamous cell carcinomas: A marker for poor prognosis. Dis Esophagus. 18:185–189. 2005. View Article : Google Scholar : PubMed/NCBI
14	Chiba I, Ogawa K, Morioka T, Shimoji H, Sunagawa N, Iraha S, Nishimaki T, Yoshimi N and Murayama S: Clinical significance of GLUT-1 expression in patients with esophageal cancer treated with concurrent chemoradiotherapy. Oncol Lett. 2:21–28. 2011. View Article : Google Scholar : PubMed/NCBI
15	Waters JK and Reznik SI: Update on management of squamous cell esophageal cancer. Curr Oncol Rep. 24:375–385. 2022. View Article : Google Scholar : PubMed/NCBI
16	He S, Xu J, Liu X and Zhen Y: Advances and challenges in the treatment of esophageal cancer. Acta Pharm Sin B. 11:3379–3392. 2021. View Article : Google Scholar : PubMed/NCBI
17	Ajduković J: HIF-1-a big chapter in the cancer tale. Exp Oncol. 38:9–12. 2016. View Article : Google Scholar : PubMed/NCBI
18	Tang K, Toyozumi T, Murakami K, Sakata H, Kano M, Endo S, Matsumoto Y, Suito H, Takahashi M, Sekino N, et al: HIF-1α stimulates the progression of oesophageal squamous cell carcinoma by activating the Wnt/β-catenin signalling pathway. Br J Cancer. 127:474–487. 2022. View Article : Google Scholar : PubMed/NCBI
19	Dhani N, Fyles A, Hedley D and Milosevic M: The clinical significance of hypoxia in human cancers. Semin Nucl Med. 45:110–121. 2015. View Article : Google Scholar : PubMed/NCBI
20	Liu H, Zhang Z, Zhou S, Liu X, Li G, Song B and Xu W: Claudin-1/4 as directly target gene of HIF-1α can feedback regulating HIF-1α by PI3K-AKT-mTOR and impact the proliferation of esophageal squamous cell though Rho GTPase and p-JNK pathway. Cancer Gene Ther. 29:665–682. 2022. View Article : Google Scholar : PubMed/NCBI
21	Moreno-Acosta P, Vallard A, Carrillo S, Gamboa O, Romero-Rojas A, Molano M, Acosta J, Mayorga D, Rancoule C, Garcia MA, et al: Biomarkers of resistance to radiation therapy: A prospective study in cervical carcinoma. Radiat Oncol. 12:1202017. View Article : Google Scholar : PubMed/NCBI
22	Chen SW, Shen WC, Lin YC, Chen RY, Hsieh TC, Yen KY and Kao CH: Correlation of pretreatment ¹⁸F-FDG PET tumor textural features with gene expression in pharyngeal cancer and implications for radiotherapy-based treatment outcomes. Eur J Nucl Med Mol Imaging. 44:567–580. 2017. View Article : Google Scholar : PubMed/NCBI
23	Batchelor TT, Sorensen AG, di Tomaso E, Zhang WT, Duda DG, Cohen KS, Kozak KR, Cahill DP, Chen PJ, Zhu M, et al: AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell. 11:83–95. 2007. View Article : Google Scholar : PubMed/NCBI
24	Yu M, Yongzhi H, Chen S, Luo X, Lin Y, Zhou Y, Jin H, Hou B, Deng Y, Tu L and Jian Z: The prognostic value of GLUT1 in cancers: A systematic review and meta-analysis. Oncotarget. 8:43356–43367. 2017. View Article : Google Scholar : PubMed/NCBI
25	Carvalho KC, Cunha IW, Rocha RM, Ayala FR, Cajaíba MM, Begnami MD, Vilela RS, Paiva GR, Andrade RG and Soares FA: GLUT1 expression in malignant tumors and its use as an immunodiagnostic marker. Clinics (Sao Paulo). 66:965–972. 2011. View Article : Google Scholar : PubMed/NCBI
26	Brown RS and Wahl RL: Overexpression of Glut-1 glucose transporter in human breast cancer. An immunohistochemical study. Cancer. 72:2979–2985. 1993. View Article : Google Scholar : PubMed/NCBI
27	Wang J, Ye C, Chen C, Xiong H, Xie B, Zhou J, Chen Y, Zheng S and Wang L: Glucose transporter GLUT1 expression and clinical outcome in solid tumors: A systematic review and meta-analysis. Oncotarget. 8:16875–16886. 2017. View Article : Google Scholar : PubMed/NCBI
28	Ping W, Sun W, Zu Y, Chen W and Fu X: Clinicopathological and prognostic significance of hypoxia-inducible factor-1α in esophageal squamous cell carcinoma: A meta-analysis. Tumour Biol. 35:4401–4409. 2014. View Article : Google Scholar : PubMed/NCBI
29	Jun YJ, Jang SM, Han HL, Lee KH, Jang KS and Paik SS: Clinicopathologic significance of GLUT1 expression and its correlation with Apaf-1 in colorectal adenocarcinomas. World J Gastroenterol. 17:1866–1873. 2011. View Article : Google Scholar : PubMed/NCBI
30	Sun G, Hu W, Lu Y and Wang Y: A meta-analysis of HIF-1α and esophageal squamous cell carcinoma (ESCC) risk. Pathol Oncol Res. 19:685–693. 2013. View Article : Google Scholar : PubMed/NCBI
31	Esteban MA, Tran MG, Harten SK, Hill P, Castellanos MC, Chandra A, Raval R, O'brien TS and Maxwell PH: Regulation of E-cadherin expression by VHL and hypoxia-inducible factor. Cancer Res. 66:3567–3575. 2006. View Article : Google Scholar : PubMed/NCBI
32	Fillies T, Werkmeister R, van Diest PJ, Brandt B, Joos U and Buerger H: HIF1-alpha overexpression indicates a good prognosis in early stage squamous cell carcinomas of the oral floor. BMC Cancer. 5:842005. View Article : Google Scholar : PubMed/NCBI
33	Shao N, Han Y, Song L and Song W: Clinical significance of hypoxia-inducible factor 1α, and its correlation with p53 and vascular endothelial growth factor expression in resectable esophageal squamous cell carcinoma. J Cancer Res Ther. 16:269–275. 2020. View Article : Google Scholar : PubMed/NCBI
34	Zimna A and Kurpisz M: Hypoxia-inducible factor-1 in physiological and pathophysiological angiogenesis: Applications and therapies. Biomed Res Int. 2015:5494122015. View Article : Google Scholar : PubMed/NCBI
35	Zhang L, Ye SB, Li ZL, Ma G, Chen SP, He J, Liu WL, Xie D, Zeng YX and Li J: Increased HIF-1alpha expression in tumor cells and lymphocytes of tumor microenvironments predicts unfavorable survival in esophageal squamous cell carcinoma patients. Int J Clin Exp Pathol. 7:3887–3897. 2014.PubMed/NCBI
36	Cheng J, Yang HL, Gu CJ, Liu YK, Shao J, Zhu R, He YY, Zhu XY and Li MQ: Melatonin restricts the viability and angiogenesis of vascular endothelial cells by suppressing HIF-1α/ROS/VEGF. Int J Mol Med. 43:945–955. 2019.PubMed/NCBI
37	Xie L, Wang Y, Li Q, Ji X, Tu Y, Du S, Lou H, Zeng X, Zhu L, Zhang J and Zhu M: The HIF-1α/p53/miRNA-34a/Klotho axis in retinal pigment epithelial cells promotes subretinal fibrosis and exacerbates choroidal neovascularization. J Cell Mol Med. 25:1700–1711. 2021. View Article : Google Scholar : PubMed/NCBI