HIF‑1α promotes the stemness of oesophageal squamous cell carcinoma by activating the Wnt/β‑catenin pathway

  • Authors:
    • Zhuan Lv
    • Rui‑Dong Liu
    • Xiao‑Qi Chen
    • Bing Wang
    • Li‑Feng Li
    • Ying‑Shu Guo
    • Xin‑Ju Chen
    • Xian‑Qing Ren
  • View Affiliations

  • Published online on: June 18, 2019     https://doi.org/10.3892/or.2019.7203
  • Pages: 726-734
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Hypoxia‑inducible‑factor 1α (HIF‑1α) is a marker for poor prognosis in the majority of the cancer types, and it has been revealed to be essential for maintaining cancer stem cells (CSCs). In the present study, it was determined that the expression of HIF‑1α and CSC‑related genes under hypoxic conditions was upregulated. Stable knockdown of HIF‑1α significantly inhibited cell proliferation, migration and tumour growth in vivo in oesophageal squamous cell carcinoma (ESCC). A previous study revealed that the Wnt/β‑catenin pathway may play a key role in maintenance and progression of CSCs. Therefore, it was also revealed that stable knockdown of HIF‑1α reduced the formation of spheroid body cells, the expression of CSC‑related genes and Wnt/β‑catenin pathway‑related target genes, as well as the activity of the Wnt/β‑catenin pathway. Collectively, the present results indicated that HIF‑1α may regulate the stemness of ESCC by activating the Wnt/β‑catenin pathway.

References

1 

Kanamoto A, Ninomiya I, Harada S, Tsukada T, Okamoto K, Nakanuma S, Sakai S, Makino I, Kinoshita J, Hayashi H, et al: Valproic acid inhibits irradiation-induced epithelial-mesenchymal transition and stem cell-like characteristics in esophageal squamous cell carcinoma. Int J Oncol. 49:1859–1869. 2016. View Article : Google Scholar : PubMed/NCBI

2 

Lin Y, Totsuka Y, He Y, Kikuchi S, Qiao Y, Ueda J, Wei W, Inoue M and Tanaka H: Epidemiology of esophageal cancer in Japan and China. J Epidemiol. 23:233–242. 2013. View Article : Google Scholar : PubMed/NCBI

3 

Alferez DG, Simões BM, Howell SJ and Clarke RB: The role of steroid hormones in breast and effects on cancer stem cells. Curr Stem Cell Rep. 4:81–94. 2018. View Article : Google Scholar : PubMed/NCBI

4 

Dalerba P and Clarke MF: Cancer stem cells and tumor metastasis: First steps into uncharted territory. Cell Stem Cell. 1:241–242. 2007. View Article : Google Scholar : PubMed/NCBI

5 

Huang SD, Yuan Y, Liu XH, Gong DJ, Bai CG, Wang F, Luo JH and Xu ZY: Self-renewal and chemotherapy resistance of p75NTR positive cells in esophageal squamous cell carcinomas. BMC Cancer. 9:92009. View Article : Google Scholar : PubMed/NCBI

6 

Rassouli FB, Matin MM, BahramiA R, Ghaffarzadegan K, Cheshomi H, Lari S, Memar B and Kan MS: Evaluating stem and cancerous biomarkers in CD15+CD44+ KYSE30 cells. Tumour Biol. 34:2909–2920. 2013. View Article : Google Scholar : PubMed/NCBI

7 

Le Bras GF, Allison GL, Richards NF, Ansari SS, Washington MK and Andl CD: CD44 upregulation in E-cadherin-negative esophageal cancers results in cell invasion. PLoS One. 6:e270632011. View Article : Google Scholar : PubMed/NCBI

8 

Ajani JA, Wang X, Song S, Suzuki A, Taketa T, Sudo K, Wadhwa R, Hofstetter WL, Komaki R, Maru DM, et al: ALDH-1 expression levels predict response or resistance to preoperative chemoradiation in resectable esophageal cancer patients. Mol Oncol. 8:142–149. 2014. View Article : Google Scholar : PubMed/NCBI

9 

Najafi M, Abbaszadegan MR, Rad A, Dastpak M, Boroumand-Noughabi S and Forghanifard MM: Crosstalk between SHH and stemness state signaling pathways in esophageal squamous cell carcinoma. J Cell Commun Signal. 11:147–153. 2017. View Article : Google Scholar : PubMed/NCBI

10 

Izadpanah MH, Abbaszadegan MR, Fahim Y and Forghanifard MM: Ectopic expression of TWIST1 upregulates the stemness marker OCT4 in the esophageal squamous cell carcinoma cell line KYSE30. Cell Mol Biol Lett. 22:332017. View Article : Google Scholar : PubMed/NCBI

11 

Lv Z, Yu JJ, Zhang WJ, Xiong L, Wang F, Li LF, Zhou XL, Gao XY, Ding XF, Han L, et al: Expression and functional regulation of stemness gene Lgr5 in esophageal squamous cell carcinoma. Oncotarget. 8:26492–26504. 2017.PubMed/NCBI

12 

Mohyeldin A, Garzón-Muvdi T and Quiñones-Hinojosa A: Oxygen in stem cell biology: A critical component of the stem cell niche. Cell Stem Cell. 7:150–161. 2010. View Article : Google Scholar : PubMed/NCBI

13 

Shin S, Im HJ, Kwon YJ, Ye DJ, Baek HS, Kim D, Choi HK and Chun YJ: Human steroid sulfatase induces Wnt/β-catenin signaling and epithelial-mesenchymal transition by upregulating Twist1 and HIF-1α in human prostate and cervical cancer cells. Oncotarget. 8:61604–61617. 2017. View Article : Google Scholar : PubMed/NCBI

14 

Semenza GL: The hypoxic tumor microenvironment: A driving force for breast cancer metastasis. Biochim Biophys Acta. 1863:382–391. 2016. View Article : Google Scholar : PubMed/NCBI

15 

Schwab LP, Peacock DL, Majumdar D, Ingels JF, Jensen LC, Smith KD, Cushing RC and Seagroves TN: Hypoxia-inducible factor 1α promotes primary tumor growth and tumor-initiating cell activity in breast cancer. Breast Cancer Res. 14:R62012. View Article : Google Scholar : PubMed/NCBI

16 

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. Nature Cell Biol. 12:1007–1013. 2010. View Article : Google Scholar : PubMed/NCBI

17 

Santoyo-Ramos P, Likhatcheva M, García-Zepeda EA, Castañeda-Patlán MC and Robles-Flores M: Hypoxia-inducible factors modulate the stemness and malignancy of colon cancer cells by playing opposite roles in canonical Wnt signaling. PLoS One. 9:e1125802014. View Article : Google Scholar : PubMed/NCBI

18 

Wend P, Holland JD, Ziebold U and Birchmeier W: Wnt signaling in stem and cancer stem cells. Semin Cell Dev Biol. 21:855–863. 2010. View Article : Google Scholar : PubMed/NCBI

19 

Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI

20 

Semenza GL: Hypoxia-inducible factors: Mediators of cancer progression and targets for cancer therapy. Trends Pharmacol Sci. 33:207–214. 2012. View Article : Google Scholar : PubMed/NCBI

21 

Wenger RH: Cellular adaptation to hypoxia: O2-sensing protein hydroxylases, hypoxia-inducible transcription factors, and O2-regulated gene expression. FASEB J. 16:1151–1162. 2012. View Article : Google Scholar

22 

Jubb AM, Buffa FM and Harris AL: Assessment of tumour hypoxia for prediction of response to therapy and cancer prognosis. J Cell Mol Med. 14:18–29. 2010. View Article : Google Scholar : PubMed/NCBI

23 

Wang GL and Semenza GL: Purification and characterization of hypoxia-inducible factor 1. J Biol Chem. 270:1230–1237. 1995. View Article : Google Scholar : PubMed/NCBI

24 

Conley SJ, Gheordunescu E, Kakarala P, Newman B, Korkaya H, Heath AN, Clouthier SG and Wicha MS: Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia. Proc Natl Acad Sci USA. 109:2784–2789. 2012. View Article : Google Scholar : PubMed/NCBI

25 

Imamura T, Kikuchi H, Herraiz MT, Park DY, Mizukami Y, Mino-Kenduson M, Lynch MP, Rueda BR, Benita Y, Xavier RJ and Chung DC: HIF-1alpha and HIF-2alpha have divergent roles in colon cancer. Int J Cancer. 124:763–771. 2009. View Article : Google Scholar : PubMed/NCBI

26 

Ezashi T, Das P and Roberts RM: Low O2 tensions and the prevention of differentiation of hES cells. Proc Natl Acad Sci USA. 102:4783–4788. 2005. View Article : Google Scholar : PubMed/NCBI

27 

Yoshida Y, Takahashi K, Okita K, Ichisaka T and Yamanaka S: Hypoxia enhances the generation of induced pluripotent stem cells. Cell Stem Cell. 5:237–241. 2009. View Article : Google Scholar : PubMed/NCBI

28 

Louie E, Nik S, Chen JS, Schmidt M, Song B, Pacson C, Chen XF, Park S, Ju J and Chen EI: Identification of a stem-like cell population by exposing metastatic breast cancer cell lines to repetitive cycles of hypoxia and reoxygenation. Breast Cancer Res. 12:R942010. View Article : Google Scholar : PubMed/NCBI

29 

Xiang L, Gilkes DM, Hu H, Takano N, Luo W, Lu H, Bullen JW, Samanta D, Liang H and Semenza GL: Hypoxia-inducible factor 1 mediates TAZ expression and nuclear localization to induce the breast cancer stem cell phenotype. Oncotarget. 5:12509–12527. 2014. View Article : Google Scholar : PubMed/NCBI

30 

Qiang L, Wu T, Zhang HW, Lu N, Hu R, Wang YJ, Zhao L, Chen FH, Wang XT, You QD and Guo QL: HIF-1α is critical for hypoxia-mediated maintenance of glioblastoma stem cells by activating Notch signaling pathway. Cell Death Differ. 19:284–294. 2012. View Article : Google Scholar : PubMed/NCBI

31 

Sato T and Clevers H: Primary mouse small intestinal epithelial cell cultures. Methods Mol Biol. 945:319–328. 2013. View Article : Google Scholar : PubMed/NCBI

32 

Yue D, Zhang Z, Li J, Chen X, Ping Y, Liu S, Shi X, Li L, Wang L, Huang L, et al: Transforming growth factor-beta1 promotes the migration and invasion of sphere-forming stem-like cell subpopulations in esophageal cancer. Exp Cell Res. 336:141–149. 2015. View Article : Google Scholar : PubMed/NCBI

33 

Clevers H, Loh KM and Nusse R: Stem cell signaling. An integral program for tissue renewal and regeneration: Wnt signaling and stem cell control. Science. 346:12480122014. View Article : Google Scholar : PubMed/NCBI

34 

He TC, Sparks AB, Rago C, Hermeking H, Zawel L, da Costa LT, Morin PJ, Vogelstein B and Kinzler KW: Identification of c-MYC as a target of the APC pathway. Science. 281:1509–1512. 1998. View Article : Google Scholar : PubMed/NCBI

35 

Tetsu O and McCormick F: Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature. 398:422–426. 1999. View Article : Google Scholar : PubMed/NCBI

36 

Klaus A; Birchmeier, : Wnt signalling and its impact on development and cancer. Nat Rev Cancer. 8:387–398. 2008. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

August 2019
Volume 42 Issue 2

Print ISSN: 1021-335X
Online ISSN:1791-2431

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Lv, Z., Liu, R., Chen, X., Wang, B., Li, L., Guo, Y. ... Ren, X. (2019). HIF‑1α promotes the stemness of oesophageal squamous cell carcinoma by activating the Wnt/β‑catenin pathway. Oncology Reports, 42, 726-734. https://doi.org/10.3892/or.2019.7203
MLA
Lv, Z., Liu, R., Chen, X., Wang, B., Li, L., Guo, Y., Chen, X., Ren, X."HIF‑1α promotes the stemness of oesophageal squamous cell carcinoma by activating the Wnt/β‑catenin pathway". Oncology Reports 42.2 (2019): 726-734.
Chicago
Lv, Z., Liu, R., Chen, X., Wang, B., Li, L., Guo, Y., Chen, X., Ren, X."HIF‑1α promotes the stemness of oesophageal squamous cell carcinoma by activating the Wnt/β‑catenin pathway". Oncology Reports 42, no. 2 (2019): 726-734. https://doi.org/10.3892/or.2019.7203