Hypoxia promotes migration/invasion and glycolysis in head and neck squamous cell carcinoma via an HIF-1α-MTDH loop

Zhu,Gangcai; Peng,Fusen; Gong,Wei; She,Li; Wei,Ming; Tan,Haolei; Chen,Changhan; Zhang,Diekuo; Li,Guo; Huang,Donghai; Zhang,Xin; Liu,Yong

doi:10.3892/or.2017.5949

Hypoxia promotes migration/invasion and glycolysis in head and neck squamous cell carcinoma via an HIF-1α-MTDH loop

Authors:
- Gangcai Zhu
- Fusen Peng
- Wei Gong
- Li She
- Ming Wei
- Haolei Tan
- Changhan Chen
- Diekuo Zhang
- Guo Li
- Donghai Huang
- Xin Zhang
- Yong Liu
View Affiliations

Affiliations: Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China, Department of Otolaryngology Head and Neck Surgery, Loudi Central Hospital, Loudi, Hunan 417011, P.R. China, Department of Head and Neck Surgery, Hunan Cancer Hospital, The Affiliated Tumour Hospital of Xiangya Medical School, Central South University, Changsha, Hunan 410013, P.R. China
Published online on: September 7, 2017 https://doi.org/10.3892/or.2017.5949
Pages: 2893-2900

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

Hypoxia is a hallmark of progressive cancer. Hypoxic cancer cells trigger glycolysis in response to a decreased O2 supply to meet metabolic and bioenergetic demands. Meanwhile, these responses to hypoxia and alterations of the microenvironment promote cancer cell metastasis by increasing transcription of hypoxia-inducible factor (HIF)-regulated genes. However, the detailed mechanism by which hypoxia regulates cancer cell metastasis and glycolysis remains to be investigated. In the present study, we identified that metadherin (MTDH), a multifaceted oncogene, is involved in the regulation of head and neck squamous cell carcinoma (HNSCC) metastasis and invasion under hypoxic conditions. Furthermore, the study indicated that there is a positive feedback loop between HIF-1α and MTDH in HNSCC cells, and that hypoxia promotes HNSCC cell metastasis and epithelial-mesenchymal transition by mediating the HIF-1α-MTDH loop. These findings implicate HIF-1α-MTDH as a promising target for anticancer drugs in solid tumors, and help to explain the pro-tumorigenic and unfavorable effect of MTDH on HNSCC observed in our previous studies.

View Figures

View References

1	Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J and Jemal A: Global cancer statistics, 2012. CA Cancer J Clin. 65:87–108. 2015. View Article : Google Scholar : PubMed/NCBI
2	Mamelle G, Pampurik J, Luboinski B, Lancar R, Lusinchi A and Bosq J: Lymph node prognostic factors in head and neck squamous cell carcinomas. Am J Surg. 168:494–498. 1994. View Article : Google Scholar : PubMed/NCBI
3	Quail DF and Joyce JA: Microenvironmental regulation of tumor progression and metastasis. Nat Med. 19:1423–1437. 2013. View Article : Google Scholar : PubMed/NCBI
4	Vaupel P and Mayer A: Hypoxia in cancer: Significance and impact on clinical outcome. Cancer Metastasis Rev. 26:225–239. 2007. View Article : Google Scholar : PubMed/NCBI
5	Rankin EB and Giaccia AJ: Hypoxic control of metastasis. Science. 352:175–180. 2016. View Article : Google Scholar : PubMed/NCBI
6	Palazon A, Goldrath AW, Nizet V and Johnson RS: HIF transcription factors, inflammation, and immunity. Immunity. 41:518–528. 2014. View Article : Google Scholar : PubMed/NCBI
7	Liu W, Shen SM, Zhao XY and Chen GQ: Targeted genes and interacting proteins of hypoxia inducible factor-1. Int J Biochem Mol Biol. 3:165–178. 2012.PubMed/NCBI
8	Kim JW, Tchernyshyov I, Semenza GL and Dang CV: HIF-1-mediated expression of pyruvate dehydrogenase kinase: A metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 3:177–185. 2006. View Article : Google Scholar : PubMed/NCBI
9	Lu J, Tan M and Cai Q: The Warburg effect in tumor progression: Mitochondrial oxidative metabolism as an anti-metastasis mechanism. Cancer Lett. 356:156–164. 2015. View Article : Google Scholar : PubMed/NCBI
10	Verdone JE, Zarif JC and Pienta KJ: Aerobic glycolysis, motility, and cytoskeletal remodeling. Cell Cycle. 14:169–170. 2015. View Article : Google Scholar : PubMed/NCBI
11	Emdad L, Das SK, Hu B, Kegelman T, Kang DC, Lee SG, Sarkar D and Fisher PB: AEG-1/MTDH/LYRIC: A promiscuous protein partner critical in cancer, obesity, and CNS diseases. Adv Cancer Res. 131:97–132. 2016. View Article : Google Scholar : PubMed/NCBI
12	Liu Y, Su Z, Li G, Yu C, Ren S, Huang D, Fan S, Tian Y, Zhang X and Qiu Y: Increased expression of metadherin protein predicts worse disease-free and overall survival in laryngeal squamous cell carcinoma. Int J Cancer. 133:671–679. 2013. View Article : Google Scholar : PubMed/NCBI
13	Yu C, Liu Y, Tan H, Li G, Su Z, Ren S, Zhu G, Tian Y, Qiu Y and Zhang X: Metadherin regulates metastasis of squamous cell carcinoma of the head and neck via AKT signalling pathway-mediated epithelial-mesenchymal transition. Cancer Lett. 343:258–267. 2014. View Article : Google Scholar : PubMed/NCBI
14	Zhu GC, Yu CY, She L, Tan HL, Li G, Ren SL, Su ZW, Wei M, Huang DH, Tian YQ, et al: Metadherin regulation of vascular endothelial growth factor expression is dependent upon the PI3K/Akt pathway in squamous cell carcinoma of the head and neck. Medicine. 94:e5022015. View Article : Google Scholar : PubMed/NCBI
15	Noch E, Bookland M and Khalili K: Astrocyte-elevated gene-1 (AEG-1) induction by hypoxia and glucose deprivation in glioblastoma. Cancer Biol Ther. 11:32–39. 2011. View Article : Google Scholar : PubMed/NCBI
16	Zhu G, Cai G, Liu Y, Tan H, Yu C, Huang M, Wei M, Li S, Cui X, Huang D, et al: Quantitative iTRAQ LC-MS/MS proteomics reveals transcription factor crosstalk and regulatory networks in hypopharyngeal squamous cell carcinoma. J Cancer. 5:525–536. 2014. View Article : Google Scholar : PubMed/NCBI
17	Pouysségur J, Dayan F and Mazure NM: Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature. 441:437–443. 2006. View Article : Google Scholar : PubMed/NCBI
18	Shan Y, Li X, You B, Shi S, Zhang Q and You Y: MicroRNA-338 inhibits migration and proliferation by targeting hypoxia-induced factor 1α in nasopharyngeal carcinoma. Oncol Rep. 34:1943–1952. 2015. View Article : Google Scholar : PubMed/NCBI
19	Yee Koh M, Spivak-Kroizman TR and Powis G: HIF-1 regulation: Not so easy come, easy go. Trends Biochem Sci. 33:526–534. 2008. View Article : Google Scholar : PubMed/NCBI
20	Gupta T, Master Z, Kannan S, Agarwal JP, Ghsoh-Laskar S, Rangarajan V, Murthy V and Budrukkar A: Diagnostic performance of post-treatment FDG PET or FDG PET/CT imaging in head and neck cancer: A systematic review and meta-analysis. Eur J Nucl Med Mol Imaging. 38:2083–2095. 2011. View Article : Google Scholar : PubMed/NCBI
21	Blatt S, Voelxen N, Sagheb K, Pabst AM, Walenta S, Schroeder T, Mueller-Klieser W and Ziebart T: Lactate as a predictive marker for tumor recurrence in patients with head and neck squamous cell carcinoma (HNSCC) post radiation: A prospective study over 15 years. Clin Oral Investig. 20:2097–2104. 2016. View Article : Google Scholar : PubMed/NCBI
22	Koukourakis MI, Giatromanolaki A, Winter S, Leek R, Sivridis E and Harris AL: Lactate dehydrogenase 5 expression in squamous cell head and neck cancer relates to prognosis following radical or postoperative radiotherapy. Oncology. 77:285–292. 2009. View Article : Google Scholar : PubMed/NCBI
23	Payen VL, Porporato PE, Baselet B and Sonveaux P: Metabolic changes associated with tumor metastasis, part 1: Tumor pH, glycolysis and the pentose phosphate pathway. Cell Mol Life Sci. 73:1333–1348. 2016. View Article : Google Scholar : PubMed/NCBI
24	Doherty JR and Cleveland JL: Targeting lactate metabolism for cancer therapeutics. J Clin Invest. 123:3685–3692. 2013. View Article : Google Scholar : PubMed/NCBI
25	Pinheiro C, Longatto-Filho A, Ferreira L, Pereira SM, Etlinger D, Moreira MA, Jubé LF, Queiroz GS, Schmitt F and Baltazar F: Increasing expression of monocarboxylate transporters 1 and 4 along progression to invasive cervical carcinoma. Int J Gynecol Pathol. 27:568–574. 2008. View Article : Google Scholar : PubMed/NCBI
26	Levenson AS, Thurn KE, Simons LA, Veliceasa D, Jarrett J, Osipo C, Jordan VC, Volpert OV, Satcher RL Jr and Gartenhaus RB: MCT-1 oncogene contributes to increased in vivo tumorigenicity of MCF7 cells by promotion of angiogenesis and inhibition of apoptosis. Cancer Res. 65:10651–10656. 2005. View Article : Google Scholar : PubMed/NCBI
27	Gallagher SM, Castorino JJ, Wang D and Philp NJ: Monocarboxylate transporter 4 regulates maturation and trafficking of CD147 to the plasma membrane in the metastatic breast cancer cell line MDA-MB-231. Cancer Res. 67:4182–4189. 2007. View Article : Google Scholar : PubMed/NCBI
28	Lee S-G, Kang D-C, DeSalle R, Sarkar D and Fisher PB: AEG-1/MTDH/LYRIC, the beginning: Initial cloning, structure, expression profile, and regulation of expression. Adv Cancer Res. 120:1–38. 2013. View Article : Google Scholar : PubMed/NCBI
29	Podar K and Anderson KC: A therapeutic role for targeting c-Myc/Hif-1-dependent signaling pathways. Cell Cycle. 9:1722–1728. 2010. View Article : Google Scholar : PubMed/NCBI
30	Lee SG, Su ZZ, Emdad L, Sarkar D and Fisher PB: Astrocyte elevated gene-1 (AEG-1) is a target gene of oncogenic Ha-ras requiring phosphatidylinositol 3-kinase and c-Myc. Proc Natl Acad Sci USA. 103:pp. 17390–17395. 2006; View Article : Google Scholar : PubMed/NCBI
31	Emdad L, Das SK, Dasgupta S, Hu B, Sarkar D and Fisher PB: AEG-1/MTDH/LYRIC: Signaling pathways, downstream genes, interacting proteins, and regulation of tumor angiogenesis. Adv Cancer Res. 120:75–111. 2013. View Article : Google Scholar : PubMed/NCBI
32	Mottet D, Dumont V, Deccache Y, Demazy C, Ninane N, Raes M and Michiels C: Regulation of hypoxia-inducible factor-1alpha protein level during hypoxic conditions by the phosphatidylinositol 3-kinase/Akt/glycogen synthase kinase 3beta pathway in HepG2 cells. J Biol Chem. 278:31277–31285. 2003. View Article : Google Scholar : PubMed/NCBI
33	Rius J, Guma M, Schachtrup C, Akassoglou K, Zinkernagel AS, Nizet V, Johnson RS, Haddad GG and Karin M: NF-kappaB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1alpha. Nature. 453:807–811. 2008. View Article : Google Scholar : PubMed/NCBI
34	Yang MH, Wu MZ, Chiou SH, Chen PM, Chang SY, Liu CJ, Teng SC and Wu KJ: Direct regulation of TWIST by HIF-1alpha promotes metastasis. Nat Cell Biol. 10:295–305. 2008. View Article : Google Scholar : PubMed/NCBI
35	Liang Y, Hu J, Li J, Liu Y, Yu J, Zhuang X, Mu L, Kong X, Hong D, Yang Q, et al: Epigenetic activation of TWIST1 by MTDH promotes cancer stem-like cell traits in breast cancer. Cancer Res. 75:3672–3680. 2015. View Article : Google Scholar : PubMed/NCBI