Upregulation of Wnt signaling under hypoxia promotes lung cancer progression

Hong,Chun-Fu; Chen,Wei-You; Wu,Cheng-Wen

doi:10.3892/or.2017.5807

Upregulation of Wnt signaling under hypoxia promotes lung cancer progression

Authors:
- Chun-Fu Hong
- Wei-You Chen
- Cheng-Wen Wu
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Affiliations: Department of Long-Term Care, National Quemoy University, Kinmen County 89250, Taiwan, R.O.C., Institute of Biochemistry and Molecular Biology, National Yang Ming University, Taipei 11221, Taiwan, R.O.C.
Published online on: July 12, 2017 https://doi.org/10.3892/or.2017.5807
Pages: 1706-1714

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Abstract

The hypoxic tumor microenvironment induces epithelial-mesenchymal transition (EMT) in tumor cells and increases tumor cell malignancy. Previous studies indicated that malfunction of Wnt signaling is observed in some lung cancer patients. Athough crosstalk between hypoxia and Wnt signaling in tumor cells has recently been revealed, the detailed underlying mechanisms have not been well defined. In the present study, we demonstrated that hypoxia in lung adenocarcinoma cells can enhance Wnt signaling activity by stabilizing β-catenin and altering its localization into the nucleus. Overexpression of HIF-2α increased β-catenin expression, promoted cell mobility, and induced morphological changes to a greater degree than HIF-1α overexpression. Knockdown of HIF-2α decreased β-catenin expression and inhibited hypoxia-induced cell mobility. Moreover, we identified that phosphorylational activation of AKT1 by hypoxia and HIF-2α was required for Wnt activation upon hypoxia treatment. Downregulation of HIF-2α and β-catenin reduced colony formation when cells were exposed to long-term hypoxia treatment. Taken together, our data support that hypoxia activates PI3K/AKT as well as Wnt signaling in a HIF-2α-dependent manner, thus elevating the resistance of lung cancer cells to chronic hypoxia-induced stress.

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1	Herbst RS, Heymach JV and Lippman SM: Lung cancer. N Engl J Med. 359:1367–1380. 2008. View Article : Google Scholar : PubMed/NCBI
2	Rohwer N and Cramer T: Hypoxia-mediated drug resistance: Novel insights on the functional interaction of HIFs and cell death pathways. Drug Resist Updat. 14:191–201. 2011. View Article : Google Scholar : PubMed/NCBI
3	Semenza GL: Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 3:721–732. 2003. View Article : Google Scholar : PubMed/NCBI
4	Bertout JA, Patel SA and Simon MC: The impact of O₂ availability on human cancer. Nat Rev Cancer. 8:967–975. 2008. View Article : Google Scholar : PubMed/NCBI
5	Semenza GL: Evaluation of HIF-1 inhibitors as anticancer agents. Drug Discov Today. 12:853–859. 2007. View Article : Google Scholar : PubMed/NCBI
6	Semenza GL: Oxygen homeostasis. Wiley Interdiscip Rev Syst Biol Med. 2:336–361. 2010. View Article : Google Scholar : PubMed/NCBI
7	Jain RK: Normalization of tumor vasculature: An emerging concept in antiangiogenic therapy. Science. 307:58–62. 2005. View Article : Google Scholar : PubMed/NCBI
8	Du R, Lu KV, Petritsch C, Liu P, Ganss R, Passegué E, Song H, Vandenberg S, Johnson RS, Werb Z, et al: HIF1α induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell. 13:206–220. 2008. View Article : Google Scholar : PubMed/NCBI
9	Hu CJ, Wang LY, Chodosh LA, Keith B and Simon MC: Differential roles of hypoxia-inducible factor 1α (HIF-1α) and HIF-2α in hypoxic gene regulation. Mol Cell Biol. 23:9361–9374. 2003. View Article : Google Scholar : PubMed/NCBI
10	Warnecke C, Zaborowska Z, Kurreck J, Erdmann VA, Frei U, Wiesener M and Eckardt KU: Differentiating the functional role of hypoxia-inducible factor (HIF)-1α and HIF-2α (EPAS-1) by the use of RNA interference: Erythropoietin is a HIF-2α target gene in Hep3B and Kelly cells. FASEB J. 18:1462–1464. 2004.PubMed/NCBI
11	Rankin EB, Higgins DF, Walisser JA, Johnson RS, Bradfield CA and Haase VH: Inactivation of the arylhydrocarbon receptor nuclear translocator (Arnt) suppresses von Hippel-Lindau disease-associated vascular tumors in mice. Mol Cell Biol. 25:3163–3172. 2005. View Article : Google Scholar : PubMed/NCBI
12	Hu CJ, Iyer S, Sataur A, Covello KL, Chodosh LA and Simon MC: Differential regulation of the transcriptional activities of hypoxia-inducible factor 1 alpha (HIF-1alpha) and HIF-2alpha in stem cells. Mol Cell Biol. 26:3514–3526. 2006. View Article : Google Scholar : PubMed/NCBI
13	Logan CY and Nusse R: The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol. 20:781–810. 2004. View Article : Google Scholar : PubMed/NCBI
14	MacDonald BT, Tamai K and He X: Wnt/β-catenin signaling: Components, mechanisms, and diseases. Dev Cell. 17:9–26. 2009. View Article : Google Scholar : PubMed/NCBI
15	Hecht A, Vleminckx K, Stemmler MP, van Roy F and Kemler R: The p300/CBP acetyltransferases function as transcriptional coactivators of beta-catenin in vertebrates. EMBO J. 19:1839–1850. 2000. View Article : Google Scholar : PubMed/NCBI
16	Takemaru KI and Moon RT: The transcriptional coactivator CBP interacts with beta-catenin to activate gene expression. J Cell Biol. 149:249–254. 2000. View Article : Google Scholar : PubMed/NCBI
17	Barker N, Hurlstone A, Musisi H, Miles A, Bienz M and Clevers H: The chromatin remodelling factor Brg-1 interacts with β-catenin to promote target gene activation. EMBO J. 20:4935–4943. 2001. View Article : Google Scholar : PubMed/NCBI
18	Clevers H: Wnt/β-catenin signaling in development and disease. Cell. 127:469–480. 2006. View Article : Google Scholar : PubMed/NCBI
19	Mazumdar J, O'Brien WT, Johnson RS, LaManna JC, Chavez JC, Klein PS and Simon MC: O₂ regulates stem cells through Wnt/β-catenin signalling. Nat Cell Biol. 12:1007–1013. 2010. View Article : Google Scholar : PubMed/NCBI
20	Choi H, Chun YS, Kim TY and Park JW: HIF-2α enhances β-catenin/TCF-driven transcription by interacting with β-catenin. Cancer Res. 70:10101–10111. 2010. View Article : Google Scholar : PubMed/NCBI
21	Hong C-F, Lin S-Y, Chou Y-T and Wu C-W: MicroRNA-7 compromises p53 protein-dependent apoptosis by controlling the expression of the chromatin remodeling factor SMARCD1. J Biol Chem. 291:1877–1889. 2016. View Article : Google Scholar : PubMed/NCBI
22	Li S, Yang B, Teguh D, Zhou L, Xu J and Rong L: Amyloid β peptide enhances RANKL-induced osteoclast activation through NF-κB, ERK, and calcium oscillation signaling. Int J Mol Sci. 17:16832016. View Article : Google Scholar :
23	Cormier N, Yeo A, Fiorentino E and Paxson J: Optimization of the wound scratch assay to detect changes in murine mesenchymal stromal cell migration after damage by soluble cigarette smoke extract. J Vis Exp. 106:e534142015.
24	Alvarez-Tejado M, Naranjo-Suarez S, Jiménez C, Carrera AC, Landázuri MO and del Peso L: Hypoxia induces the activation of the phosphatidylinositol 3-kinase/Akt cell survival pathway in PC12 cells: Protective role in apoptosis. J Biol Chem. 276:22368–22374. 2001. View Article : Google Scholar : PubMed/NCBI
25	Deguchi JO, Yamazaki H, Aikawa E and Aikawa M: Chronic hypoxia activates the Akt and β-catenin pathways in human macrophages. Arterioscler Thromb Vasc Biol. 29:1664–1670. 2009. View Article : Google Scholar : PubMed/NCBI
26	Beitner-Johnson D, Rust RT, Hsieh TC and Millhorn DE: Hypoxia activates Akt and induces phosphorylation of GSK-3 in PC12 cells. Cell Signal. 13:23–27. 2001. View Article : Google Scholar : PubMed/NCBI
27	Zhong H, De Marzo AM, Laughner E, Lim M, Hilton DA, Zagzag D, Buechler P, Isaacs WB, Semenza GL and Simons JW: Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. Cancer Res. 59:5830–5835. 1999.PubMed/NCBI
28	Lu X and Kang Y: Hypoxia and hypoxia-inducible factors: Master regulators of metastasis. Clin Cancer Res. 16:5928–5935. 2010. View Article : Google Scholar : PubMed/NCBI
29	Yang MH, Wu MZ, Chiou SH, Chen PM, Chang SY, Liu CJ, Teng SC and Wu KJ: Direct regulation of TWIST by HIF-1α promotes metastasis. Nat Cell Biol. 10:295–305. 2008. View Article : Google Scholar : PubMed/NCBI
30	Ouyang G, Liu M, Ruan K, Song G, Mao Y and Bao S: Upregulated expression of periostin by hypoxia in non-small-cell lung cancer cells promotes cell survival via the Akt/PKB pathway. Cancer Lett. 281:213–219. 2009. View Article : Google Scholar : PubMed/NCBI
31	Graeber TG, Osmanian C, Jacks T, Housman DE, Koch CJ, Lowe SW and Giaccia AJ: Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature. 379:88–91. 1996. View Article : Google Scholar : PubMed/NCBI
32	Araya R, Uehara T and Nomura Y: Hypoxia induces apoptosis in human neuroblastoma SK-N-MC cells by caspase activation accompanying cytochrome c release from mitochondria. FEBS Lett. 439:168–172. 1998. View Article : Google Scholar : PubMed/NCBI
33	Steinbach JP, Wolburg H, Klumpp A, Probst H and Weller M: Hypoxia-induced cell death in human malignant glioma cells: Energy deprivation promotes decoupling of mitochondrial cytochrome c release from caspase processing and necrotic cell death. Cell Death Differ. 10:823–832. 2003. View Article : Google Scholar : PubMed/NCBI
34	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
35	Zhang N, Ji N, Jiang W-M, Li ZY, Wang M, Wen JM, Li Y, Chen X and Chen JM: Hypoxia-induced autophagy promotes human prostate stromal cells survival and ER-stress. Biochem Biophys Res Commun. 464:1107–1112. 2015. View Article : Google Scholar : PubMed/NCBI
36	Musgrove EA, Lee CS, Buckley MF and Sutherland RL: Cyclin D1 induction in breast cancer cells shortens G1 and is sufficient for cells arrested in G1 to complete the cell cycle. Proc Natl Acad Sci USA. 91:8022–8026. 1994. View Article : Google Scholar : PubMed/NCBI
37	Santarius T, Shipley J, Brewer D, Stratton MR and Cooper CS: A census of amplified and overexpressed human cancer genes. Nat Rev Cancer. 10:59–64. 2010. View Article : Google Scholar : PubMed/NCBI