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Tumor Biology
Published in: Tumor Biology 4/2016

01-04-2016 | Review

Pluripotency transcription factors in lung cancer—a review

Authors: Sylwia Sławek, Krzysztof Szmyt, Maciej Fularz, Joanna Dziudzia, Maciej Boruczkowski, Jan Sikora, Mariusz Kaczmarek

Published in: Tumor Biology | Issue 4/2016

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Abstract

Lung cancer is the leading cause of cancer-related mortality worldwide. Diagnosis of lung cancer in an early stage is still a challenge due to the asymptomatic course of early stages of the disease and the lack of a standard screening program for the population. Nowadays, learning about the mechanisms that lead to cancerogenesis in the lung is crucial for the development of new diagnostic and therapeutic strategies. Recently, many studies have proved that cancer stem cells (CSCs) are responsible for the initiation, progression, metastasis, recurrence, and even resistance of chemo- and radiotherapeutic treatment in patients with lung cancer. The expression of pluripotency transcription factors is responsible for stemness properties. In this review, we summarize the current knowledge on the role of CSCs and pluripotency transcription factors in lung carcinogenesis.
Literature
1.
Gibson G, Loddenkemper R, Sibille Y, Lundbäck B. The European lung white book: sheffield; 2013. p. 224–235.
2.
3.
Qu H, Li R, Liu Z, Zhang J, Luo R. Prognostic value of cancer stem cell marker CD133 expression in non-small cell lung cancer: a systematic review. Int J Clin Exp Pathol. 2013;6(11):2644–50.PubMedPubMedCentral
4.
Tan Y, Chen B, Xu W, Zhao W, Wu J. Clinicopathological significance of CD133 in lung cancer: a meta-analysis. Mol Clin Oncol. 2014;2(1):111–5.PubMed
5.
6.
Pece S, Tosoni D, Confalonieri S, Mazzarol G, Vecchi M, Ronzoni S, et al. Biological and molecular heterogeneity of breast cancers correlates with their cancer stem cell content. Cell. 2010;140(1):62–73.CrossRefPubMed
7.
Hadjimichael C, Chanoumidou K, Papadopoulou N, Arampatzi P, Papamatheakis J, Kretsovali A. Common stemness regulators of embryonic and cancer stem cells. World J Stem Cells. 2015;7(9):1150–84.PubMedPubMedCentral
8.
Liu A, Yu X, Liu S. Pluripotency transcription factors and cancer stem cells: small genes make a big difference. Chin J Cancer. 2013;32(9):483–7.PubMedPubMedCentral
9.
Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126(4):663–76.CrossRefPubMed
10.
Zheng YW, Nie YZ, Taniguchi H. Cellular reprogramming and hepatocellular carcinoma development. World J Gastroenterol. 2014;19(47):8850–60.CrossRef
11.
Nagata S, Hirano K, Kanemori M, Sun LT, Tada T. Self-renewal and pluripotency acquired through somatic reprogramming to human cancer stem cells. PLoS One. 2012;7(11):e48699.CrossRefPubMedPubMedCentral
12.
Somervaille TC, Matheny CJ, Spencer GJ, Iwasaki M, Rinn JL, Witten DM, et al. Hierarchical maintenance of MLL myeloid leukemia stem cells employs a transcriptional program shared with embryonic rather than adult stem cells. Cell Stem Cell. 2009;4(2):129–40.CrossRefPubMedPubMedCentral
13.
Sholl LM, Barletta JA, Yeap BY, Chirieac LR, Hornick JL. Sox2 protein expression is an independent poor prognostic indicator in stage I lung adenocarcinoma. Am J Surg Pathol. 2010;34(8):1193–8.CrossRefPubMedPubMedCentral
14.
Ben-Porath I, Thomson MW, Carey VJ, Ge R, Bell GW, Regev A, et al. An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nat Genet. 2008;40(5):499–507.CrossRefPubMedPubMedCentral
15.
Ji J, Zheng PS. Expression of Sox2 in human cervical carcinogenesis. Hum Pathol. 2010;41(10):1438–47.CrossRefPubMed
16.
Fyfe B, Amazon K, Poppiti Jr RJ, Razzetti A. Intraosseous echinococcosis: a rare manifestation of echinococcal disease. South Med J. 1990;83(1):66–8.CrossRefPubMed
17.
Gadgeel SM, Wozniak A. Preclinical rationale for PI3K/Akt/mTOR pathway inhibitors as therapy for epidermal growth factor receptor inhibitor-resistant non-small-cell lung cancer. Clin Lung Cancer. 2013;14(4):322–32.CrossRefPubMed
18.
Altomare DA, Testa JR. Perturbations of the AKT signaling pathway in human cancer. Oncogene. 2005;24(50):7455–64.CrossRefPubMed
19.
Kim DH, Sarbassov DD, Ali SM, King JE, Latek RR, Erdjument-Bromage H, et al. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell. 2002;110(2):163–75.CrossRefPubMed
20.
Lei N, Peng B, Zhang JY. CIP2A regulates cell proliferation via the AKT signaling pathway in human lung cancer. Oncol Rep. 2014;32(4):1689–94.PubMed
21.
Liu CW, Li CH, Peng YJ, Cheng YW, Chen HW, Liao PL, et al. Snail regulates Nanog status during the epithelial-mesenchymal transition via the Smad1/Akt/GSK3beta signaling pathway in non-small-cell lung cancer. Oncotarget. 2014;5(11):3880–94.CrossRefPubMedPubMedCentral
22.
23.
Lin F, Lin P, Zhao D, Chen Y, Xiao L, Qin W, et al. Sox2 targets cyclinE, p27 and survivin to regulate androgen-independent human prostate cancer cell proliferation and apoptosis. Cell Prolif. 2012;45(3):207–16.CrossRefPubMed
24.
Heavey S, O’Byrne KJ, Gately K. Strategies for co-targeting the PI3K/AKT/mTOR pathway in NSCLC. Cancer Treat Rev. 2013;40(3):445–56.CrossRefPubMed
25.
Shan J, Shen J, Liu L, Xia F, Xu C, Duan G, et al. Nanog regulates self-renewal of cancer stem cells through the insulin-like growth factor pathway in human hepatocellular carcinoma. Hepatology. 2012;56(3):1004–14.CrossRefPubMed
26.
Ambady S, Malcuit C, Kashpur O, Kole D, Holmes WF, Hedblom E, et al. Expression of NANOG and NANOGP8 in a variety of undifferentiated and differentiated human cells. Int J Dev Biol. 2010;54(11–12):1743–54.CrossRefPubMedPubMedCentral
27.
Jeter CR, Badeaux M, Choy G, Chandra D, Patrawala L, Liu C, et al. Functional evidence that the self-renewal gene NANOG regulates human tumor development. Stem Cells. 2009;27(5):993–1005.CrossRefPubMedPubMedCentral
28.
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(24):10433–44.CrossRefPubMed
29.
Li L, Yu H, Wang X, Zeng J, Li D, Lu J, et al. Expression of seven stem-cell-associated markers in human airway biopsy specimens obtained via fiberoptic bronchoscopy. J Exp Clin Cancer Res. 2013;32:28.CrossRefPubMedPubMedCentral
30.
Li XQ, Yang XL, Zhang G, Wu SP, Deng XB, Xiao SJ, et al. Nuclear beta-catenin accumulation is associated with increased expression of Nanog protein and predicts poor prognosis of non-small cell lung cancer. J Transl Med. 2013;11:114.CrossRefPubMedPubMedCentral
31.
Du Y, Ma C, Wang Z, Liu Z, Liu H, Wang T. Nanog, a novel prognostic marker for lung cancer. Surg Oncol. 2013;22(4):224–9.CrossRefPubMed
32.
Peinado H, Olmeda D, Cano A. Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer. 2007;7(6):415–28.CrossRefPubMed
33.
Loh YH, Wu Q, Chew JL, Vega VB, Zhang W, Chen X, et al. The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cells. Nat Genet. 2006;38(4):431–40.CrossRefPubMed
34.
Hu T, Liu S, Breiter DR, Wang F, Tang Y, Sun S. Octamer 4 small interfering RNA results in cancer stem cell-like cell apoptosis. Cancer Res. 2008;68(16):6533–40.CrossRefPubMed
35.
Mirza AM, Gysin S, Malek N, Nakayama K, Roberts JM, McMahon M. Cooperative regulation of the cell division cycle by the protein kinases RAF and AKT. Mol Cell Biol. 2004;24(24):10868–81.CrossRefPubMedPubMedCentral
36.
Moreira AL, Gonen M, Rekhtman N, Downey RJ. Progenitor stem cell marker expression by pulmonary carcinomas. Mod Pathol. 2010;23(6):889–95.CrossRefPubMed
37.
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(3):692–7.CrossRefPubMed
38.
Li XL, Jia LL, Shi MM, Li X, Li ZH, Li HF, et al. Downregulation of KPNA2 in non-small-cell lung cancer is associated with Oct4 expression. J Transl Med. 2013;11:232.CrossRefPubMedPubMedCentral
39.
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(7):e2637.CrossRefPubMedPubMedCentral
40.
Gomez-Casal R, Bhattacharya C, Ganesh N, Bailey L, Basse P, Gibson M, et al. Non-small cell lung cancer cells survived ionizing radiation treatment display cancer stem cell and epithelial-mesenchymal transition phenotypes. Mol Cancer. 2013;12(1):94.CrossRefPubMedPubMedCentral
41.
Xu C, Xie D, Yu SC, Yang XJ, He LR, Yang J, et al. beta-Catenin/POU5F1/SOX2 transcription factor complex mediates IGF-I receptor signaling and predicts poor prognosis in lung adenocarcinoma. Cancer Res. 2013;73(10):3181–9.CrossRefPubMed
42.
Chen Z, Wang T, Cai L, Su C, Zhong B, Lei Y, et al. Clinicopathological significance of non-small cell lung cancer with high prevalence of Oct-4 tumor cells. J Exp Clin Cancer Res. 2012;31:10.CrossRefPubMedPubMedCentral
43.
Yet SF, McA’Nulty MM, Folta SC, Yen HW, Yoshizumi M, Hsieh CM, et al. Human EZF, a Kruppel-like zinc finger protein, is expressed in vascular endothelial cells and contains transcriptional activation and repression domains. J Biol Chem. 1998;273(2):1026–31.CrossRefPubMed
44.
Shields JM, Yang VW. Identification of the DNA sequence that interacts with the gut-enriched Kruppel-like factor. Nucleic Acids Res. 1998;26(3):796–802.CrossRefPubMedPubMedCentral
45.
Yanagida A, Sogawa K, Yasumoto KI, Fujii-Kuriyama Y. A novel cis-acting DNA element required for a high level of inducible expression of the rat P-450c gene. Mol Cell Biol. 1990;10(4):1470–5.CrossRefPubMedPubMedCentral
46.
Hu W, Hofstetter WL, Li H, Zhou Y, He Y, Pataer A, et al. Putative tumor-suppressive function of Kruppel-like factor 4 in primary lung carcinoma. Clin Cancer Res. 2009;15(18):5688–95.CrossRefPubMedPubMedCentral
47.
Zhou Y, Hofstetter WL, He Y, Hu W, Pataer A, Wang L, et al. KLF4 inhibition of lung cancer cell invasion by suppression of SPARC expression. Cancer Biol Ther. 2010;9(7):507–13.CrossRefPubMedPubMedCentral
48.
Vaira V, Faversani A, Martin NM, Garlick DS, Ferrero S, Nosotti M, et al. Regulation of lung cancer metastasis by Klf4-Numb-like signaling. Cancer Res. 2013;73(8):2695–705.CrossRefPubMedPubMedCentral
49.
Naranjo Gomez JM, Bernal JF, Arranz PG, Fernandez SL, Roman JJ. Alterations in the expression of p53, KLF4, and p21 in neuroendocrine lung tumors. Arch Pathol Lab Med. 2014;138(7):936–42.CrossRefPubMed
50.
Su QL, Li SQ, Wang DN, Liu F, Yuan B. Effects of MicroRNA-10b on lung cancer cell proliferation and invasive metastasis and the underlying mechanism. Asian Pac J Trop Med. 2014;7(5):364–7.CrossRefPubMed
51.
Sarkar A, Hochedlinger K. The sox family of transcription factors: versatile regulators of stem and progenitor cell fate. Cell Stem Cell. 2013;12(1):15–30.CrossRefPubMedPubMedCentral
52.
Chen S, Xu Y, Chen Y, Li X, Mou W, Wang L, et al. SOX2 gene regulates the transcriptional network of oncogenes and affects tumorigenesis of human lung cancer cells. PLoS One. 2012;7(5):e36326.CrossRefPubMedPubMedCentral
53.
Rudin CM, Durinck S, Stawiski EW, Poirier JT, Modrusan Z, Shames DS, et al. Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer. Nat Genet. 2012;44(10):1111–6.CrossRefPubMedPubMedCentral
54.
Xu W, Wei Y, Tan Y, Cheng SY, Wu J. The expression and significance of stem cell transcription factor Sox2 in lung carcinoma. Zhongguo Fei Ai Za Zhi. 2013;16(11):591–5.PubMed
55.
Yuan P, Kadara H, Behrens C, Tang X, Woods D, Solis LM, et al. Sex determining region Y-Box 2 (SOX2) is a potential cell-lineage gene highly expressed in the pathogenesis of squamous cell carcinomas of the lung. PLoS One. 2010;5(2):e9112.CrossRefPubMedPubMedCentral
56.
57.
Cortes-Dericks L, Galetta D, Spaggiari L, Schmid RA, Karoubi G. High expression of octamer-binding transcription factor 4A, prominin-1 and aldehyde dehydrogenase strongly indicates involvement in the initiation of lung adenocarcinoma resulting in shorter disease-free intervals. Eur J Cardiothorac Surg. 2012;41(6):e173–81.CrossRefPubMed
58.
Toschi L, Finocchiaro G, Nguyen TT, Skokan MC, Giordano L, Gianoncelli L, et al. Increased SOX2 gene copy number is associated with FGFR1 and PIK3CA gene gain in non-small cell lung cancer and predicts improved survival in early stage disease. PLoS One. 2014;9(4):e95303.CrossRefPubMedPubMedCentral
59.
Bass AJ, Watanabe H, Mermel CH, Yu S, Perner S, Verhaak RG, et al. SOX2 is an amplified lineage-survival oncogene in lung and esophageal squamous cell carcinomas. Nat Genet. 2009;41(11):1238–42.CrossRefPubMedPubMedCentral
60.
Hussenet T, Dali S, Exinger J, Monga B, Jost B, Dembele D, et al. SOX2 is an oncogene activated by recurrent 3q26.3 amplifications in human lung squamous cell carcinomas. PLoS One. 2010;5(1):e8960.CrossRefPubMedPubMedCentral
61.
Chen S, Li X, Lu D, Xu Y, Mou W, Wang L, et al. SOX2 regulates apoptosis through MAP4K4-survivin signaling pathway in human lung cancer cells. Carcinogenesis. 2014;35(3):613–23.CrossRefPubMed
62.
Fang WT, Fan CC, Li SM, Jang TH, Lin HP, Shih NY, et al. Downregulation of a putative tumor suppressor BMP4 by SOX2 promotes growth of lung squamous cell carcinoma. Int J Cancer. 2014;135(4):809–19.CrossRefPubMed
63.
Singh S, Trevino J, Bora-Singhal N, Coppola D, Haura E, Altiok S, et al. EGFR/Src/Akt signaling modulates Sox2 expression and self-renewal of stem-like side-population cells in non-small cell lung cancer. Mol Cancer. 2012;11:73.CrossRefPubMedPubMedCentral
64.
65.
Viswanathan SR, Powers JT, Einhorn W, Hoshida Y, Ng TL, Toffanin S, et al. Lin28 promotes transformation and is associated with advanced human malignancies. Nat Genet. 2009;41(7):843–8.CrossRefPubMedPubMedCentral
66.
Kumar MS, Erkeland SJ, Pester RE, Chen CY, Ebert MS, Sharp PA, et al. Suppression of non-small cell lung tumor development by the let-7 microRNA family. Proc Natl Acad Sci U S A. 2008;105(10):3903–8.CrossRefPubMedPubMedCentral
67.
Oh JS, Kim JJ, Byun JY, Kim IA. Lin28-let7 modulates radiosensitivity of human cancer cells with activation of K-Ras. Int J Radiat Oncol Biol Phys. 2010;76(1):5–8.CrossRefPubMed
68.
Wen J, Liu H, Wang Q, Liu Z, Li Y, Xiong H, et al. Genetic variants of the LIN28B gene predict severe radiation pneumonitis in patients with non-small cell lung cancer treated with definitive radiation therapy. Eur J Cancer. 2014;50(10):1706–16.CrossRefPubMedPubMedCentral
69.
70.
Karachaliou N, Papadaki C, Lagoudaki E, Trypaki M, Sfakianaki M, Koutsopoulos A, et al. Predictive value of BRCA1, ERCC1, ATP7B, PKM2, TOPOI, TOPOmicron-IIA, TOPOIIB and C-MYC genes in patients with small cell lung cancer (SCLC) who received first line therapy with cisplatin and etoposide. PLoS One. 2013;8(9):e74611.CrossRefPubMedPubMedCentral
71.
Sato M, Larsen JE, Lee W, Sun H, Shames DS, Dalvi MP, et al. Human lung epithelial cells progressed to malignancy through specific oncogenic manipulations. Mol Cancer Res. 2013;11(6):638–50.CrossRefPubMedPubMedCentral
72.
Johnson BE, Russell E, Simmons AM, Phelps R, Steinberg SM, Ihde DC, et al. MYC family DNA amplification in 126 tumor cell lines from patients with small cell lung cancer. J Cell Biochem Suppl. 1996;24:210–7.CrossRefPubMed
73.
74.
D’Angelo SP, Pietanza MC. The molecular pathogenesis of small cell lung cancer. Cancer Biol Ther. 2010;10(1):1–10.CrossRefPubMed
75.
Castro IC, Breiling A, Luetkenhaus K, Ceteci F, Hausmann S, Kress S, et al. MYC-induced epigenetic activation of GATA4 in lung adenocarcinoma. Mol Cancer Res. 2012;11(2):161–72.CrossRefPubMed
76.
Liao P, Wang W, Shen M, Pan W, Zhang K, Wang R, et al. A positive feedback loop between EBP2 and c-Myc regulates rDNA transcription, cell proliferation, and tumorigenesis. Cell Death Dis. 2014;5:e1032.CrossRefPubMedPubMedCentral
77.
Jiang L, Li J, Song L. Bmi-1, stem cells and cancer. Acta Biochim Biophys Sin (Shanghai). 2009;41(7):527–34.CrossRef
78.
Glinsky GV, Berezovska O, Glinskii AB. Microarray analysis identifies a death-from-cancer signature predicting therapy failure in patients with multiple types of cancer. J Clin Invest. 2005;115(6):1503–21.CrossRefPubMedPubMedCentral
79.
Lowe SW, Sherr CJ. Tumor suppression by Ink4a-Arf: progress and puzzles. Curr Opin Genet Dev. 2003;13(1):77–83.CrossRefPubMed
80.
Bhattacharya R, Mustafi SB, Street M, Dey A, Dwivedi SK. Bmi-1: at the crossroads of physiological and pathological biology. Genes Dis. 2015;2(3):225–39.CrossRefPubMedPubMedCentral
81.
Chen T, Xu C, Chen J, Ding C, Xu Z, Li C, et al. MicroRNA-203 inhibits cellular proliferation and invasion by targeting Bmi1 in non-small cell lung cancer. Oncol Lett. 2015;9(6):2639–46.PubMedPubMedCentral
82.
Hu J, Liu YL, Piao SL, Yang DD, Yang YM, Cai L. Expression patterns of USP22 and potential targets BMI-1, PTEN, p-AKT in non-small-cell lung cancer. Lung Cancer. 2012;77(3):593–9.CrossRefPubMed
83.
Shao Y, Geng Y, Gu W, Ning Z, Jiang J, Pei H. Prognostic role of high Bmi-1 expression in Asian and Caucasian patients with solid tumors: a meta-analysis. Biomed Pharmacother. 2014;68(8):969–77.CrossRefPubMed
84.
Zhang XY, Dong QG, Huang JS, Huang AM, Shi CL, Jin B, et al. The expression of stem cell-related indicators as a prognostic factor in human lung adenocarcinoma. J Surg Oncol. 2010;102(7):856–62.CrossRefPubMed
85.
He Z, Xia Y, Pan C, Ma T, Liu B, Wang J, et al. Upregulation of MiR-452 inhibits metastasis of non-small-cell lung cancer by regulating BMI1. Cell Physiol Biochem. 2015;37(1):387–98.CrossRefPubMed
86.
Zhang Y, Li X, Chen Z, Bepler G. Ubiquitination and degradation of ribonucleotide reductase M1 by the polycomb group proteins RNF2 and Bmi1 and cellular response to gemcitabine. PLoS One. 2014;9(3):e91186.CrossRefPubMedPubMedCentral
87.
Udagawa H, Ishii G, Morise M, Umemura S, Matsumoto S, Yoh K, et al. Comparison of the expression levels of molecular markers among the peripheral area and central area of primary tumor and metastatic lymph node tumor in patients with squamous cell carcinoma of the lung. J Cancer Res Clin Oncol. 2015;141(8):1417–25.CrossRefPubMed
Metadata
Title
Pluripotency transcription factors in lung cancer—a review
Authors
Sylwia Sławek
Krzysztof Szmyt
Maciej Fularz
Joanna Dziudzia
Maciej Boruczkowski
Jan Sikora
Mariusz Kaczmarek
Publication date
01-04-2016
Publisher
Springer Netherlands
Published in
Tumor Biology / Issue 4/2016
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-015-4407-x

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