CD44 Is Associated with the Aggressive Phenotype of Nasopharyngeal Carcinoma through Redox Regulation

International Journal of Molecular Sciences - Tập 14 Số 7 - Trang 13266-13281
Chien‐Hung Lin1,2, Peir‐Haur Hung3, Yann‐Jang Chen4,5,2
1Department of Pediatrics, Zhongxing Branch, Taipei City Hospital, Taipei 103, Taiwan
2Institute of Clinical Medicine, National Yang-Ming University, Taipei, 112, Taiwan
3Department of Medical Research, Ditmanson Medical Foundation Chia-yi Christian Hospital, Chia-yi 600, Taiwan
4Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei 112, Taiwan
5Department of Pediatrics, Renai Branch, Taipei City Hospital, Taipei 106, Taiwan

Tóm tắt

Recent studies have shown that cancer stem-like cells (CSCs) within a tumor have the capacity for self-renewal and differentiation, and are associated with an aggressive phenotype and therapeutic resistance. Studies have also associated tumor progression with alterations in the levels of intracellular reactive oxygen species (ROS). In this study, we cultured nasopharyngeal carcinoma (NPC) CSCs in conditions that allowed sphere formation. The resulting sphere cells displayed stemness properties, characteristics of the epithelial–mesenchymal transition (EMT), and increased expression of the CSC surface marker CD44. We further evaluated the association between CD44 expression and EMT marker expression, and any correlation with redox status, in these CSCs. We showed that the EMT in sphere cells is associated with the upregulation of CD44 expression and increased ROS generation, which might promote NPC aggressiveness. We also identified the coexpression of CD44 with the EMT marker N-cadherin in sphere cells, and downregulated CD44 expression after the addition of the antioxidant N-acetyl cysteine. Our results indicate that CD44 plays a role in the EMT phenotype of CSCs in NPC, and suggest its involvement in EMT-associated ROS production. These findings might facilitate the development of a novel therapy for the prevention of NPC recurrence and metastasis.

Từ khóa


Tài liệu tham khảo

Gu, 2012, The criteria to confirm the role of epstein-barr virus in nasopharyngeal carcinoma initiation, Int. J. Mol. Sci, 13, 13737, 10.3390/ijms131013737

Lo, 2004, Focus on nasopharyngeal carcinoma, Cancer Cell, 5, 423, 10.1016/S1535-6108(04)00119-9

Ksiazkiewicz, 2012, Epithelial-mesenchymal transition: A hallmark in metastasis formation linking circulating tumor cells and cancer stem cells, Pathobiology, 79, 195, 10.1159/000337106

Hollier, 2009, The epithelial-to-mesenchymal transition and cancer stem cells: A coalition against cancer therapies, J. Mammary Gland Biol. Neoplasia, 14, 29, 10.1007/s10911-009-9110-3

Guo, 2012, Cancer stem-like side population cells in the human nasopharyngeal carcinoma cell line cne-2 possess epithelial mesenchymal transition properties in association with metastasis, Oncol. Rep, 28, 241

Su, 2011, Identification of cancer stem-like CD44+ cells in human nasopharyngeal carcinoma cell line, Arch. Med. Res, 42, 15, 10.1016/j.arcmed.2011.01.007

Kumar, 2008, Oxidative stress is inherent in prostate cancer cells and is required for aggressive phenotype, Cancer Res, 68, 1777, 10.1158/0008-5472.CAN-07-5259

Nishikawa, 2008, Reactive oxygen species in tumor metastasis, Cancer Lett, 266, 53, 10.1016/j.canlet.2008.02.031

Diehn, 2009, Association of reactive oxygen species levels and radioresistance in cancer stem cells, Nature, 458, 780, 10.1038/nature07733

Lorente, 2011, Free radicals in breast carcinogenesis, breast cancer progression and cancer stem cells. Biological bases to develop oxidative-based therapies, Crit. Rev. Oncol. Hematol, 80, 347, 10.1016/j.critrevonc.2011.01.004

Cannito, 2008, Redox mechanisms switch on hypoxia-dependent epithelial-mesenchymal transition in cancer cells, Carcinogenesis, 29, 2267, 10.1093/carcin/bgn216

Wang, 2010, Signaling mechanism(s) of reactive oxygen species in Epithelial-Mesenchymal Transition reminiscent of cancer stem cells in tumor progression, Curr. Stem. Cell Res. Ther, 5, 74, 10.2174/157488810790442813

Chen, C., Zimmermann, M., Tinhofer, I., Kaufmann, A.M., and Albers, A.E. (2012). Epithelial-to-mesenchymal transition and cancer stem(-like) cells in head and neck squamous cell carcinoma. Cancer Lett.

Kong, 2011, Cancer Stem Cells and Epithelial-to-Mesenchymal Transition (EMT)-Phenotypic Cells: Are They Cousins or Twins?, Cancers, 3, 716, 10.3390/cancers30100716

Luo, 2012, Aberrant expression of nuclear vimentin and related epithelial-mesenchymal transition markers in nasopharyngeal carcinoma, Int. J. Cancer, 131, 1863, 10.1002/ijc.27467

Bensouda, 2011, Treatment for metastatic nasopharyngeal carcinoma, Eur. Ann. Otorhinolaryngol. Head Neck Dis, 128, 79, 10.1016/j.anorl.2010.10.003

Qiu, 2012, Characterization of sphere-forming cells with stem-like properties from the small cell lung cancer cell line H446, Cancer Lett, 323, 161, 10.1016/j.canlet.2012.04.004

Rybak, 2011, Characterization of sphere-propagating cells with stem-like properties from DU145 prostate cancer cells, Biochim. Biophys. Acta, 1813, 683, 10.1016/j.bbamcr.2011.01.018

Arumugam, 2009, Epithelial to mesenchymal transition contributes to drug resistance in pancreatic cancer, Cancer Res, 69, 5820, 10.1158/0008-5472.CAN-08-2819

Marchini, 2013, Resistance to platinum-based chemotherapy is associated with epithelial to mesenchymal transition in epithelial ovarian cancer, Eur. J. Cancer, 49, 520, 10.1016/j.ejca.2012.06.026

Storz, 2005, Reactive oxygen species in tumor progression, Front. Biosci, 10, 1881, 10.2741/1667

Wu, 2006, The signaling mechanism of ROS in tumor progression, Cancer Metastasis Rev, 25, 695, 10.1007/s10555-006-9037-8

2010, CD44, a therapeutic target for metastasising tumours, Eur. J. Cancer, 46, 1271, 10.1016/j.ejca.2010.02.024

Ween, 2011, Role of Versican, hyaluronan and CD44 in ovarian cancer metastasis, Int. J. Mol. Sci, 12, 1009, 10.3390/ijms12021009

Kawakami, 2001, Inhibitory effect of N-acetylcysteine on invasion and MMP-9 production of T24 human bladder cancer cells, Anticancer Res, 21, 213

Zahid, 2011, Resveratrol and N-acetylcysteine block the cancer-initiating step in MCF-10F cells, Free Radic. Biol. Med, 50, 78, 10.1016/j.freeradbiomed.2010.10.662

Lun, 2012, CD44+ cancer stem-like cells in EBV-associated nasopharyngeal carcinoma, PLoS One, 7, e52426, 10.1371/journal.pone.0052426

Shi, 2007, Inhibition of malignant activities of nasopharyngeal carcinoma cells with high expression of CD44 by siRNA, Oncol. Rep., 18, 397

Jin, 2011, An easy method to detect the kinetics of CD44 antibody and its receptors on B16 cells using atomic force microscopy, Mol. Biol. Rep, 38, 4495, 10.1007/s11033-010-0580-6

Geng, 2013, Cancer stem-like cells enriched with CD29 and CD44 markers exhibit molecular characteristics with epithelial-mesenchymal transition in squamous cell carcinoma, Arch. Dermatol. Res, 305, 35, 10.1007/s00403-012-1260-2

Li, 2009, Identification of human pancreatic cancer stem cells, Methods Mol. Biol, 568, 161, 10.1007/978-1-59745-280-9_10

Okamoto, 2009, Expansion and characterization of cancer stem-like cells in squamous cell carcinoma of the head and neck, Oral Oncol, 45, 633, 10.1016/j.oraloncology.2008.10.003

Zhang, 2008, Identification and characterization of ovarian cancer-initiating cells from primary human tumors, Cancer Res, 68, 4311, 10.1158/0008-5472.CAN-08-0364

Liu, 2009, Hyaluronan substratum induces multidrug resistance in human mesenchymal stem cells via CD44 signaling, Cell Tissue Res, 336, 465, 10.1007/s00441-009-0780-3

Ishimoto, 2011, CD44 variant regulates redox status in cancer cells by stabilizing the xCT subunit of system xc(-) and thereby promotes tumor growth, Cancer Cell, 19, 387, 10.1016/j.ccr.2011.01.038

Nagano, O., Okazaki, S., and Saya, H. (2013). Redox regulation in stem-like cancer cells by CD44 variant isoforms. Oncogene.

Tamada, 2012, Modulation of glucose metabolism by CD44 contributes to antioxidant status and drug resistance in cancer cells, Cancer Res, 72, 1438, 10.1158/0008-5472.CAN-11-3024

Wang, 2009, CD44 variant isoforms in head and neck squamous cell carcinoma progression, Laryngoscope, 119, 1518, 10.1002/lary.20506

Wu, G., Zhou, Y., Li, T., Guo, J., and Zhou, Z. (2013). Immunohistochemical levels of matrix metalloproteinase-2 and CD44 variant 6 protein in the diagnosis and lateral cervical lymph node metastasis of papillary thyroid carcinoma. J. Int. Med. Res.