Overcoming Chemotherapy Resistance by Targeting Hyaluronan/ CD44-Mediated Stem Cell Marker (Nanog) Signaling and MicroRNA-21 in Breast, Ovarian, and Head and Neck Cancer

Chapter
Part of the Stem Cells and Cancer Stem Cells book series (STEM, volume 9)

Abstract

Multidrug resistance frequently contributes to the failure of chemotherapeutic drug treatments in patients diagnosed with solid tumors such as breast, ovarian and head and neck cancers. It is now certain that oncogenic signaling is directly involved in chemotherapeutic drug resistance and tumor progression. A number of studies have aimed at identifying those molecules which are expressed specifically by epithelial tumor cells and correlate with metastatic behavior and chemotherapy resistance. Among such candidate molecules is hyaluronan (HA), the major glycosaminoglycan component of extracellular matrix (ECM). HA serves not only as a primary constituent of connective tissue extracellular matrices but also functions as a bio-regulatory molecule. Pertinently, HA is enriched in many types of tumors. HA is capable of binding to CD44 which is a ubiquitous, abundant and functionally important receptor expressed on the surface of many normal cells and tumor cells.

Recent evidence indicates that HA-CD44 interaction with the stem cell marker, Nanog promotes downstream, intracellular signaling pathways that influence multiple cellular functions. In particular, certain microRNAs such as miR-21 (small RNA molecules with ∼20–25 nucleotides) have been shown to play roles in regulating tumor cell survival and chemotherapy resistance. In this article, a special focus is placed on the role of Nanog overexpression in activating oncogenic signaling molecule(s) and miRNA-21 function leading to the concomitant onset of HA/CD44-mediated tumor cell activities (e.g., survival and chemoresistance) and tumor progression. Conversely, donwregulation of Nanog not only inhibits miR-21 expression/function and HA/CD44-mediated tumor cell behaviors but also enhances chemosensitivity. This new knowledge could serve as groundwork for the future development of new drug targets to inhibit the stem cell marker (Nanog) signaling and miR-21 function in order to overcome chemotherapy resistance in the progression of HA/CD44-induced solid tumor cancers such as breast, ovarian and head and neck cancer.

Keywords

Ovarian Cancer Stem Cell Marker Breast Tumor Cell Epithelial Tumor Cell Ovarian Tumor Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A 100:3983–3988PubMedCrossRefGoogle Scholar
  2. Asangani IA, Rasheed SA, Nikolova DA, Leupold JH, Colburn NH, Post S, Allgayer H (2008) MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer. Oncogene 27:2128–2136PubMedCrossRefGoogle Scholar
  3. Baker EK, El-Osta A (2004) MDR1, chemotherapy and chromatin remodeling. Cancer Biol Ther 3:819–824PubMedCrossRefGoogle Scholar
  4. Bhalla KN (2003) Microtubule-targeted anticancer agents and apoptosis. Oncogene 22:9075–9086PubMedCrossRefGoogle Scholar
  5. Bourguignon LY (2008) Hyaluronan-mediated CD44 activation of RhoGTPase signaling and cytoskeleton function promotes tumor progression. Semin Cancer Biol 18:251–259PubMedCrossRefGoogle Scholar
  6. Bourguignon LY, Peyrollier K, Xia W, Gilad E (2008) Hyaluronan-CD44 interaction activates stem cell marker Nanog, Stat-3-mediated MDR1 gene expression, and ankyrin-regulated multidrug efflux in breast and ovarian tumor cells. J Biol Chem 283:17635–17651PubMedCrossRefGoogle Scholar
  7. Bourguignon LY, Spevak CC, Wong G, Xia W, Gilad E (2009a) Hyaluronan-CD44 interaction with PKCε promotes oncogenic signaling by the stem cell marker, Nanog and the production of microRNA-21 leading to downregulation of the tumor suppressor protein, PDCD4, anti-apoptosis and chemotherapy resistance in breast tumor cells. J Biol Chem 284:26533–26546PubMedCrossRefGoogle Scholar
  8. Bourguignon LY, Xia W, Wong G (2009b) Hyaluronan-mediated CD44 interaction with p300 and SIRT1 regulates beta-catenin signaling and NFkappaB-specific transcription activity leading to MDR1 and Bcl-xL gene expression and chemoresistance in breast tumor cells. J Biol Chem 284:2657–2671PubMedCrossRefGoogle Scholar
  9. Bourguignon LY, Earle C, Wong G, Spevak CC, Krueger K (2012) Stem cell marker (Nanog) and Stat-3 signaling promote MicroRNA-21 expression and chemoresistance in hyaluronan/CD44-activated head and neck squamous cell carcinoma cells. Oncogene 31:149–160PubMedCrossRefGoogle Scholar
  10. Cai X, Hagedorn CH, Cullen BR (2004) Human microRNAs are processed from capped, polyadenylated transcripts that can also function as mRNAs. RNA 10:1957–1966PubMedCrossRefGoogle Scholar
  11. Chang SS, Jiang WW, Smith I, Poeta LM, Begum S, Glazer C, Shan S, Westra W, Sidransky D, Califano JA (2008) MicroRNA alterations in head and neck squamous cell carcinoma. Int J Cancer 123:2791–2797PubMedCrossRefGoogle Scholar
  12. Cowland JB, Hother C, Grønbaek K (2007) MicroRNAs and cancer. APMIS 115:1090–1106PubMedCrossRefGoogle Scholar
  13. Darnell JE Jr (1997) STATs and gene regulation. Science 277:1630–1635PubMedCrossRefGoogle Scholar
  14. Davis BN, Hilyard AC, Lagna G, Hata A (2008) SMAD proteins control DROSHA-mediated microRNA maturation. Nature 454:56–61PubMedCrossRefGoogle Scholar
  15. de la Cruz J, Kressler D, Linder P (1999) Unwinding RNA in Saccharomyces cerevisiae:DEAD-box proteins and related families. Trends Biochem Sci 24:192–198PubMedCrossRefGoogle Scholar
  16. Gewirtz DA (1999) A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin. Biochem Pharmacol 57:727–741PubMedCrossRefGoogle Scholar
  17. Giraldez AJ, Cinalli RM, Glasner ME, Enright AJ, Thomson JM, Baskerville S, Hammond SM, Bartel DP, Schier AF (2005) MicroRNAs regulate brain morphogenesis in zebrafish. Science 308:833–838PubMedCrossRefGoogle Scholar
  18. Harnett PR, Kirsten F, Tattersall MH (1986) Drug resistance in clinical practice: patterns of treatment failure in advanced breast and ovarian cancer. J Clin Oncol 4:952–957PubMedGoogle Scholar
  19. Higgins CF (1992) ABC transporters: from microorganisms to man. Annu Rev Cell Biol 8:67–113PubMedCrossRefGoogle Scholar
  20. Hunter AM (2007) The inhibitors of apoptosis (IAPs) as cancer targets. Apoptosis 12:1543–1568PubMedCrossRefGoogle Scholar
  21. Lee JY, Spicer AP (2000) Hyaluronan: a multifunctional, megadalton, stealth molecule. Curr Opin Cell Biol 12:581–586PubMedCrossRefGoogle Scholar
  22. Lee Y, Kim M, Han J, Yeom KH, Lee S, Baek SH, Kim VN (2004) MicroRNA genes are transcribed by RNA polymerase II. EMBO J 23:4051–4060PubMedCrossRefGoogle Scholar
  23. Mitsui K, Tokuzawa Y, Itoh H, Segawa K, Murakami M, Takahashi K, Maruyama M, Maeda M, Yamanaka S (2003) The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells. Cell 113:631–642PubMedCrossRefGoogle Scholar
  24. Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer statistics 2002. CA Cancer J Clin 55:74–108PubMedCrossRefGoogle Scholar
  25. Salzman DW, Shubert-Coleman J, Furneaux H (2007) P68 RNA helicase unwinds the human let-7 microRNA precursor duplex and is required for let-7-directed silencing of gene expression. J Biol Chem 282:32773–32779PubMedCrossRefGoogle Scholar
  26. Screaton GR, Bell MV, Jackson DG, Cornelis FB, Gerth U, Bell JI (1992) Genomic structure of DNA coding the lymphocyte homing receptor CD44 reveals 12 alternatively spliced exons. Proc Natl Acad Sci USA 89:12160–12164PubMedCrossRefGoogle Scholar
  27. Toole BP, Wight T, Tammi M (2002) Hyaluronan-cell interactions in cancer and vascular disease. J Biol Chem 277:4593–4596PubMedCrossRefGoogle Scholar
  28. Valencia-Sanchez MA, Liu J, Hannon GJ, Parker R (2006) Control of translation and mRNA degradation by miRNAs and siRNAs. Genes Dev 20:515–524PubMedCrossRefGoogle Scholar
  29. Wang S, Bourguignon LY (2011) Role of hyaluronan-mediated CD44 signaling in head and neck squamous cell carcinoma progression and chemoresistance. Am J Pathol 178:956–963PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  1. 1.University of California, San Francisco, VA Medical CenterSan FranciscoUSA

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