Abstract
POU5F1B (POU domain class 5 transcription factor 1B), a processed pseudogene that is highly homologous to OCT4, was recently shown to be transcribed in cancer cells, but its clinical relevance and biological function have remained unclear. We now show that POU5F1B, which is located adjacent to MYC on human chromosome 8q24, is frequently amplified in gastric cancer (GC) cell lines. POU5F1B, but not OCT4, was also found to be expressed at a high level in GC cell lines and clinical specimens. In addition, the DNA copy number and mRNA abundance for POU5F1B showed a positive correlation in both cancer cell lines and GC specimens. Overexpression of POU5F1B in GC cells promoted colony formation in vitro as well as both tumorigenicity and tumor growth in vivo, and these effects were enhanced in the additional presence of MYC overexpression. Furthermore, knockdown of POU5F1B expression with a short hairpin RNA confirmed a role for the endogenous pseudogene in the promotion of cancer cell growth in vitro and tumor growth in vivo. POU5F1B overexpression induced upregulation of various growth factors in GC cells as well as exhibited mitogenic, angiogenic and antiapoptotic effects in GC xenografts. Finally, amplification of POU5F1B was detected in 17 (12%) of 145 cases of GC and was a significant predictor of poor prognosis in patients with stage IV disease. In conclusion, we found that the POU5F1B pseudogene is amplified and expressed at a high level in, as well as confers an aggressive phenotype on, GC, and that POU5F1B amplification is associated with a poor prognosis in GC patients.
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References
Scholer HR, Ruppert S, Suzuki N, Chowdhury K, Gruss P . New type of POU domain in germ line-specific protein Oct-4. Nature 1990; 344: 435–439.
Takahashi K, Yamanaka S . Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006; 126: 663–676.
Atlasi Y, Mowla SJ, Ziaee SA, Gokhale PJ, Andrews PW . OCT4 spliced variants are differentially expressed in human pluripotent and nonpluripotent cells. Stem Cells 2008; 26: 3068–3074.
Cauffman G, Liebaers I, Van Steirteghem A, Van de Velde H . POU5F1 isoforms show different expression patterns in human embryonic stem cells and preimplantation embryos. Stem Cells 2006; 24: 2685–2691.
Atlasi Y, Mowla SJ, Ziaee SA, Bahrami AR . OCT-4, an embryonic stem cell marker, is highly expressed in bladder cancer. Int J Cancer 2007; 120: 1598–1602.
Monk M, Holding C . Human embryonic genes re-expressed in cancer cells. Oncogene 2001; 20: 8085–8091.
Wu CL, Shieh GS, Chang CC, Yo YT, Su CH, Chang MY et al. Tumor-selective replication of an oncolytic adenovirus carrying oct-3/4 response elements in murine metastatic bladder cancer models. Clin Cancer Res 2008; 14: 1228–1238.
Pink RC, Wicks K, Caley DP, Punch EK, Jacobs L, Carter DR . Pseudogenes: pseudo-functional or key regulators in health and disease? RNA 2011; 17: 792–798.
Kalyana-Sundaram S, Kumar-Sinha C, Shankar S, Robinson DR, Wu YM, Cao X et al. Expressed pseudogenes in the transcriptional landscape of human cancers. Cell 2012; 149: 1622–1634.
Liedtke S, Enczmann J, Waclawczyk S, Wernet P, Kogler G . Oct4 and its pseudogenes confuse stem cell research. Cell Stem Cell 2007; 1: 364–366.
Suo G, Han J, Wang X, Zhang J, Zhao Y, Dai J . Oct4 pseudogenes are transcribed in cancers. Biochem Biophys Res Commun 2005; 337: 1047–1051.
Panagopoulos I, Moller E, Collin A, Mertens F . The POU5F1P1 pseudogene encodes a putative protein similar to POU5F1 isoform 1. Oncol Rep 2008; 20: 1029–1033.
Zhao S, Yuan Q, Hao H, Guo Y, Liu S, Zhang Y et al. Expression of OCT4 pseudogenes in human tumours: lessons from glioma and breast carcinoma. J Pathol 2011; 223: 672–682.
Kastler S, Honold L, Luedeke M, Kuefer R, Moller P, Hoegel J et al. POU5F1P1, a putative cancer susceptibility gene, is overexpressed in prostatic carcinoma. Prostate 70: 666–674.
Furuta K, Arao T, Sakai K, Kimura H, Nagai T, Tamura D et al. Integrated analysis of whole genome exon array and array-comparative genomic hybridization in gastric and colorectal cancer cells. Cancer Sci 2012; 103: 221–227.
Schoenhals M, Kassambara A, De Vos J, Hose D, Moreaux J, Klein B . Embryonic stem cell markers expression in cancers. Biochem Biophys Res Commun 2009; 383: 157–162.
Cantz T, Key G, Bleidissel M, Gentile L, Han DW, Brenne A et al. Absence of OCT4 expression in somatic tumor cell lines. Stem Cells 2008; 26: 692–697.
Wang X, Dai J . Concise review: isoforms of OCT4 contribute to the confusing diversity in stem cell biology. Stem Cells 2010; 28: 885–893.
Pain D, Chirn GW, Strassel C, Kemp DM . Multiple retropseudogenes from pluripotent cell-specific gene expression indicates a potential signature for novel gene identification. J Biol Chem 2005; 280: 6265–6268.
Friesen C, Herr I, Krammer PH, Debatin KM . Involvement of the CD95 (APO-1/FAS) receptor/ligand system in drug-induced apoptosis in leukemia cells. Nat Med 1996; 2: 574–577.
Calcagno DQ, Leal MF, Assumpcao PP, Smith MA, Burbano RR . MYC and gastric adenocarcinoma carcinogenesis. World J Gastroenterol 2008; 14: 5962–5968.
Fletcher O, Johnson N, Gibson L, Coupland B, Fraser A, Leonard A et al. Association of genetic variants at 8q24 with breast cancer risk. Cancer Epidemiol Biomarkers Prev 2008; 17: 702–705.
Gudmundsson J, Sulem P, Manolescu A, Amundadottir LT, Gudbjartsson D, Helgason A et al. Genome-wide association study identifies a second prostate cancer susceptibility variant at 8q24. Nat Genet 2007; 39: 631–637.
Haiman CA, Le Marchand L, Yamamato J, Stram DO, Sheng X, Kolonel LN et al. A common genetic risk factor for colorectal and prostate cancer. Nat Genet 2007; 39: 954–956.
Schumacher FR, Feigelson HS, Cox DG, Haiman CA, Albanes D, Buring J et al. A common 8q24 variant in prostate and breast cancer from a large nested case-control study. Cancer Res 2007; 67: 2951–2956.
Yeager M, Orr N, Hayes RB, Jacobs KB, Kraft P, Wacholder S et al. Genome-wide association study of prostate cancer identifies a second risk locus at 8q24. Nat Genet 2007; 39: 645–649.
Zanke BW, Greenwood CM, Rangrej J, Kustra R, Tenesa A, Farrington SM et al. Genome-wide association scan identifies a colorectal cancer susceptibility locus on chromosome 8q24. Nat Genet 2007; 39: 989–994.
Amundadottir LT, Sulem P, Gudmundsson J, Helgason A, Baker A, Agnarsson BA et al. A common variant associated with prostate cancer in European and African populations. Nat Genet 2006; 38: 652–658.
Bier A, Oviedo-Landaverde I, Zhao J, Mamane Y, Kandouz M, Batist G . Connexin43 pseudogene in breast cancer cells offers a novel therapeutic target. Mol Cancer Ther 2009; 8: 786–793.
Yu H, Zhao X, Su B, Li D, Xu Y, Luo S et al. Expression of NF1 pseudogenes. Hum Mutat 2005; 26: 487–488.
Zhang J, Wang X, Li M, Han J, Chen B, Wang B et al. NANOGP8 is a retrogene expressed in cancers. FEBS J 2006; 273: 1723–1730.
Poliseno L, Salmena L, Zhang J, Carver B, Haveman WJ, Pandolfi PP . A coding-independent function of gene and pseudogene mRNAs regulates tumour biology. Nature 2010; 465: 1033–1038.
Matsumoto K, Arao T, Hamaguchi T, Shimada Y, Kato K, Oda I et al. FGFR2 gene amplification and clinicopathological features in gastric cancer. Br J Cancer 2012; 106: 727–732.
Graziano F, Galluccio N, Lorenzini P, Ruzzo A, Canestrari E, D'Emidio S et al. Genetic activation of the MET pathway and prognosis of patients with high-risk, radically resected gastric cancer. J Clin Oncol 2011; 29: 4789–4795.
Klapper W, Stoecklein H, Zeynalova S, Ott G, Kosari F, Rosenwald A et al. Structural aberrations affecting the MYC locus indicate a poor prognosis independent of clinical risk factors in diffuse large B-cell lymphomas treated within randomized trials of the German High-Grade Non-Hodgkin's Lymphoma Study Group (DSHNHL). Leukemia 2008; 22: 2226–2229.
Kaneda H, Arao T, Tanaka K, Tamura D, Aomatsu K, Kudo K et al. FOXQ1 is overexpressed in colorectal cancer and enhances tumorigenicity and tumor growth. Cancer Res 2010; 70: 2053–2063.
Tanaka K, Arao T, Maegawa M, Matsumoto K, Kaneda H, Kudo K et al. SRPX2 is overexpressed in gastric cancer and promotes cellular migration and adhesion. Int J Cancer 2009; 124: 1072–1080.
Takeda M, Arao T, Yokote H, Komatsu T, Yanagihara K, Sasaki H et al. AZD2171 shows potent antitumor activity against gastric cancer over-expressing fibroblast growth factor receptor 2/keratinocyte growth factor receptor. Clin Cancer Res 2007; 13: 3051–3057.
Yamada Y, Arao T, Gotoda T, Taniguchi H, Oda I, Shirao K et al. Identification of prognostic biomarkers in gastric cancer using endoscopic biopsy samples. Cancer Sci 2008; 99: 2193–2199.
Acknowledgements
This study was supported by the Third-Term Comprehensive 10-Year Strategy for Cancer Control and a Grant-in-Aid for Cancer Research from the Ministry of Health, Labor and Welfare of Japan. We thank Shinji Kurashimo, Yoshihiro Mine, Ayaka Kurumatani and Tomoko Kitayama for technical assistance.
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Hayashi, H., Arao, T., Togashi, Y. et al. The OCT4 pseudogene POU5F1B is amplified and promotes an aggressive phenotype in gastric cancer. Oncogene 34, 199–208 (2015). https://doi.org/10.1038/onc.2013.547
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DOI: https://doi.org/10.1038/onc.2013.547
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