Abstract
Hypoxia, the reduction of oxygen levels in cells or tissues, elicits a set of genes to adjust physiological and pathological demands during normal development and cancer progression. OCT4, a homeobox transcription factor, is essential for self-renewal of embryonic stem cells, but little is known about the role of OCT4 in non-germ-cell tumorigenesis. Here, we report that hypoxia stimulates a short isoform of OCT4, called OCT4B, via a HIF2α-dependent pathway to induce the epithelial–mesenchymal transition (EMT) and facilitate cancer dissemination. OCT4B overexpression decreased epithelial barrier properties, which led to an increase in cell migration and invasion in lung cancer cells. OCT4B knockdown attenuated HIF2α-induced EMT and inhibited cancer dissemination in cell-line and animal models. We observed that OCT4B bound the SLUG promoter and enhanced its expression, and SLUG silencing inhibited OCT4B-mediated EMT, accompanied with decreased cell migration and invasion. Correlation analysis revealed that OCT4B expression was significantly associated with the SLUG level in lung tumors. These results provide novel insights into OCT4B-mediated oncogenesis in cancer dissemination.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Pani G, Galeotti T, Chiarugi P. Metastasis: cancer cell’s escape from oxidative stress. Cancer Metastas Rev. 2010;29:351–78.
Crino L, Weder W, van Meerbeeck J, Felip E, Group EGW. Early stage and locally advanced (non-metastatic) non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010;21(Suppl 5):v103–115.
Bollineni VR, Wiegman EM, Pruim J, Groen HJ, Langendijk JA. Hypoxia imaging using Positron Emission Tomography in non-small cell lung cancer: implications for radiotherapy. Cancer Treat Rev. 2012;38:1027–32.
Keith B, Simon MC. Hypoxia-inducible factors, stem cells, and cancer. Cell. 2007;129:465–72.
Wiesener MS, Jurgensen JS, Rosenberger C, Scholze CK, Horstrup JH, Warnecke C, et al. Widespread hypoxia-inducible expression of HIF-2alpha in distinct cell populations of different organs. FASEB J. 2003;17:271–3.
Hu CJ, Wang LY, Chodosh LA, Keith B, Simon MC. Differential roles of hypoxia-inducible factor 1alpha (HIF-1alpha) and HIF-2alpha in hypoxic gene regulation. Mol Cell Biol. 2003;23:9361–74.
Boiani M, Eckardt S, Scholer HR, McLaughlin KJ. Oct4 distribution and level in mouse clones: consequences for pluripotency. Genes Dev. 2002;16:1209–19.
Pan GJ, Chang ZY, Scholer HR, Pei D. Stem cell pluripotency and transcription factor Oct4. Cell Res. 2002;12:321–9.
Covello KL, Kehler J, Yu H, Gordan JD, Arsham AM, Hu CJ, et al. HIF-2alpha regulates Oct-4: effects of hypoxia on stem cell function, embryonic development, and tumor growth. Genes Dev. 2006;20:557–70.
Lee J, Kim HK, Rho JY, Han YM, Kim J. The human OCT-4 isoforms differ in their ability to confer self-renewal. J Biol Chem. 2006;281:33554–65.
Wang X, Zhao Y, Xiao Z, Chen B, Wei Z, Wang B, et al. Alternative translation of OCT4 by an internal ribosome entry site and its novel function in stress response. Stem Cells. 2009;27:1265–75.
Gao Y, Wei J, Han J, Wang X, Su G, Zhao Y, et al. The novel function of OCT4B isoform-265 in genotoxic stress. Stem Cells. 2012;30:665–72.
Jiang J, Tang YL, Liang XH. EMT: a new vision of hypoxia promoting cancer progression. Cancer Biol Ther. 2011;11:714–23.
Radisky ES, Radisky DC. Matrix metalloproteinase-induced epithelial-mesenchymal transition in breast cancer. J Mammary Gland Biol Neoplasia. 2010;15:201–12.
Shih JY, Tsai MF, Chang TH, Chang YL, Yuan A, Yu CJ, et al. Transcription repressor slug promotes carcinoma invasion and predicts outcome of patients with lung adenocarcinoma. Clin Cancer Res. 2005;11:8070–8.
Bolos V, Peinado H, Perez-Moreno MA, Fraga MF, Esteller M, Cano A. The transcription factor Slug represses E-cadherin expression and induces epithelial to mesenchymal transitions: a comparison with Snail and E47 repressors. J Cell Sci. 2003;116:499–511.
Bhat-Nakshatri P, Appaiah H, Ballas C, Pick-Franke P, Goulet R Jr., Badve S, et al. SLUG/SNAI2 and tumor necrosis factor generate breast cells with CD44+/CD24- phenotype. BMC Cancer. 2010;10:411.
Bhattacharya S, Michels CL, Leung MK, Arany ZP, Kung AL, Livingston DM. Functional role of p35srj, a novel p300/CBP binding protein, during transactivation by HIF-1. Genes Dev. 1999;13:64–75.
Papamichos SI, Lambropoulos AF, Kotoula V. OCT4B expression in PBMNCs suggests the existence of an alternative OCT4 promoter. Genes Chromosomes Cancer. 2009;48:1112–4.
Li R, Liang J, Ni S, Zhou T, Qing X, Li H, et al. A mesenchymal-to-epithelial transition initiates and is required for the nuclear reprogramming of mouse fibroblasts. Cell Stem Cell. 2010;7:51–63.
Keese CR, Bhawe K, Wegener J, Giaever I. Real-time impedance assay to follow the invasive activities of metastatic cells in culture. Biotechniques. 2002;33:842–4. 846, 848–50
Shih JY, Yang PC. The EMT regulator slug and lung carcinogenesis. Carcinogenesis. 2011;32:1299–304.
Vaupel P. The role of hypoxia-induced factors in tumor progression. Oncologist. 2004;9(Suppl 5):10–17.
Koh MY, Lemos R Jr., Liu X, Powis G. The hypoxia-associated factor switches cells from HIF-1alpha- to HIF-2alpha-dependent signaling promoting stem cell characteristics, aggressive tumor growth and invasion. Cancer Res. 2011;71:4015–27.
Kumar SM, Liu S, Lu H, Zhang H, Zhang PJ, Gimotty PA, et al. Acquired cancer stem cell phenotypes through Oct4-mediated dedifferentiation. Oncogene. 2012;31:4898–911.
Chiou SH, Wang ML, Chou YT, Chen CJ, Hong CF, Hsieh WJ, et al. Coexpression of Oct4 and Nanog enhances malignancy in lung adenocarcinoma by inducing cancer stem cell-like properties and epithelial-mesenchymal transdifferentiation. Cancer Res. 2010;70:10433–44.
Beltran AS, Rivenbark AG, Richardson BT, Yuan X, Quian H, Hunt JP, et al. Generation of tumor-initiating cells by exogenous delivery of OCT4 transcription factor. Breast Cancer Res. 2011;13:R94.
Chen YC, Hsu HS, Chen YW, Tsai TH, How CK, Wang CY, et al. Oct-4 expression maintained cancer stem-like properties in lung cancer-derived CD133-positive cells. PLoS ONE. 2008;3:e2637.
Wenger RH. Cellular adaptation to hypoxia: O2-sensing protein hydroxylases, hypoxia-inducible transcription factors, and O2-regulated gene expression. FASEB J. 2002;16:1151–62.
Kim WY, Perera S, Zhou B, Carretero J, Yeh JJ, Heathcote SA, et al. HIF2alpha cooperates with RAS to promote lung tumorigenesis in mice. J Clin Invest. 2009;119:2160–70.
Karoubi G, Gugger M, Schmid R, Dutly A. OCT4 expression in human non-small cell lung cancer: implications for therapeutic intervention. Interact Cardiovasc Thorac Surg. 2009;8:393–7.
Gao Y, Wang X, Han J, Xiao Z, Chen B, Su G, et al. The novel OCT4 spliced variant OCT4B1 can generate three protein isoforms by alternative splicing into OCT4B. J Genet Genom. 2010;37:461–5.
Brehm A, Ohbo K, Scholer H. The carboxy-terminal transactivation domain of Oct-4 acquires cell specificity through the POU domain. Mol Cell Biol. 1997;17:154–62.
Guo CL, Liu L, Jia YD, Zhao XY, Zhou Q, Wang L. A novel variant of Oct3/4 gene in mouse embryonic stem cells. Stem Cell Res. 2012;9:69–76.
Theodorou E, Dalembert G, Heffelfinger C, White E, Weissman S, Corcoran L, et al. A high throughput embryonic stem cell screen identifies Oct-2 as a bifunctional regulator of neuronal differentiation. Genes Dev. 2009;23:575–88.
Li Z, Bao S, Wu Q, Wang H, Eyler C, Sathornsumetee S, et al. Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells. Cancer Cell. 2009;15:501–13.
Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 2008;133:704–15.
Chu YW, Yang PC, Yang SC, Shyu YC, Hendrix MJ, Wu R, et al. Selection of invasive and metastatic subpopulations from a human lung adenocarcinoma cell line. Am J Respir Cell Mol Biol. 1997;17:353–60.
Chou YT, Hsieh CH, Chiou SH, Hsu CF, Kao YR, Lee CC, et al. CITED2 functions as a molecular switch of cytokine-induced proliferation and quiescence. Cell Death Differ. 2012;19:2015–28.
Acknowledgements
This work was supported by National Tsing Hua University, National Yang-Ming University, Institute of Biomedical Science at Academia Sinica, Ministry of Science and Technology (NSC 102-2320-B-007-010, MOST104-2321-B-010-007, MOST 105–2325-B-010-003, MOST 106-2320-B-007-005-MY3), and Ministry of Health and Welfare (MOHW105-TDU-B-211–134003), Executive Yuan, Taiwan.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Electronic supplementary material
Rights and permissions
About this article
Cite this article
Lin, SC., Chung, CH., Chung, CH. et al. OCT4B mediates hypoxia-induced cancer dissemination. Oncogene 38, 1093–1105 (2019). https://doi.org/10.1038/s41388-018-0487-6
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41388-018-0487-6