Remember Me
Or use your Academic/Social account:


Or use your Academic/Social account:


You have just completed your registration at OpenAire.

Before you can login to the site, you will need to activate your account. An e-mail will be sent to you with the proper instructions.


Please note that this site is currently undergoing Beta testing.
Any new content you create is not guaranteed to be present to the final version of the site upon release.

Thank you for your patience,
OpenAire Dev Team.

Close This Message


Verify Password:
Verify E-mail:
*All Fields Are Required.
Please Verify You Are Human:
fbtwitterlinkedinvimeoflicker grey 14rssslideshare1
Publisher: Public Library of Science
Languages: English
Types: Article
Subjects: Computational Biology, Predictive Biomarkers, Research Article, Molecular Cell Biology, Anatomy, Genome Expression Analysis, Functional Genomics, Carcinoma cells, Genetics, Histology, Genome Analysis, Genomics, Cancer stem cells, Immunology, Biology and Life Sciences, RNA, Health, Medicine, Nucleic Acids, computer-assisted language learning, Q, R, Cell Biology, Autoimmunity, Science, Biochemistry, Cancer, Transcriptome Analysis
PUBLISHED The prognosis of epithelial ovarian cancer is poor in part due to the high frequency of chemoresistance. Recent evidence points to the Toll-like receptor-4 (TLR4), and particularly its adaptor protein MyD88, as one potential mediator of this resistance. This study aims to provide further evidence that MyD88 positive cancer cells are clinically significant, stem-like and reproducibly detectable for the purposes of prognostic stratification. Expression of TLR4 and MyD88 was assessed immunohistochemically in 198 paraffin-embedded ovarian tissues and in an embryonal carcinoma model of cancer stemness. In parallel, expression of TLR4 and MyD88 mRNA and regulatory microRNAs (miR-21 and miR-146a) was assessed, as well as in a series of chemosensitive and resistant cancer cells lines. Functional analysis of the pathway was assessed in chemoresistant SKOV-3 ovarian cancer cells. TLR4 and MyD88 expression can be reproducibly assessed via immunohistochemistry using a semi-quantitative scoring system. TLR4 expression was present in all ovarian epithelium (normal and neoplastic), whereas MyD88 was restricted to neoplastic cells, independent of tumour grade and associated with reduced progression-free and overall survival, in an immunohistological specific subset of serous carcinomas, p<0.05. MiR-21 and miR-146a expression was significantly increased in MyD88 negative cancers (p<0.05), indicating their participation in regulation. Significant alterations in MyD88 mRNA expression were observed between chemosensitive and chemoresistant cells and tissue. Knockdown of TLR4 in SKOV-3 ovarian cells recovered chemosensitivity. Knockdown of MyD88 alone did not. MyD88 expression was down-regulated in differentiated embryonal carcinoma (NTera2) cells, supporting the MyD88+ cancer stem cell hypothesis. Our findings demonstrate that expression of MyD88 is associated with significantly reduced patient survival and altered microRNA levels and suggest an intact/functioning TLR4/MyD88 pathway is required for acquisition of the chemoresistant phenotype. Ex vivo manipulation of ovarian cancer stem cell (CSC) differentiation can decrease MyD88 expression, providing a potentially valuable CSC model for ovarian cancer.
  • The results below are discovered through our pilot algorithms. Let us know how we are doing!

    • 1. Schwartz PE (2002) Current diagnosis and treatment modalities for ovarian cancer. Cancer Treat Res 107: 99-118.
    • 2. O'Lorcain P, Walsh PM, Comber H (2007) Cumulative cancer mortality risk and potential years of life lost to 64 years of age in Ireland, 1953-2002. Eur J Cancer Prev 16: 167-77.
    • 3. O'Lorcain P, Comber H (2006) Morality predictions for Ireland, 2001-2015: cancers of the breast, ovary, and cervix and Corpus uteri. Int J Gynecol Cancer 16 Suppl 1: 1-10.
    • 4. Lee KR, Tavassoli FA, Prat J, Dietel M, Gersell DJ, et al. (2003) Surface Epithelial-Stromal Tumours. In: Tavassoli FA and Devilee P, editors. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Breast and Female Genital Organs. Lyon: IARC Press. pp. 117- 145.
    • 5. Bell DA (2005) Origins and molecular pathology of ovarian cancer. Mod Pathol 18 Suppl 2: S19-32.
    • 6. Marsden DE, Friedlander M, Hacker NF (2000) Current management of epithelial ovarian carcinoma: a review. Semin Surg Oncol 19: 11-9.
    • 7. Armstrong D (2008) Ovaries and fallopian tubes. In: Abeloff MD, Armitage JO, Niederhuber JE, Kastan MB, McKenna WG, editors. Abeloff's Clinical Oncology. 4th ed. Philadelphia: Churcill Livingstone Elsevier. pp. 1827-1850.
    • 8. Piver MS, Wong C (1998) Role of prophylactic surgery for women with genetic predisposition to cancer. Clin Obstet Gynecol 41: 215-24.
    • 9. Stewart JJ, White JT, Yan X, Collins S, Drescher CW, et al. (2006) Proteins associated with Cisplatin resistance in ovarian cancer cells identified by quantitative proteomic technology and integrated with mRNA expression levels. Mol Cell Proteomics 5: 433-43.
    • 10. Beachy PA, Karhadkar SS, Berman DM (2004) Mending and malignancy. Nature 431: 402.
    • 11. Tsan MF (2006) Toll-like receptors, inflammation and cancer. Semin Cancer Biol 16(1): 32-7.
    • 12. Alvero AB, Chen R, Fu HH, Montagna M, Schwartz PE, et al. (2009) Molecular phenotyping of human ovarian cancer stem cells unravels the mechanisms for repair and chemoresistance. Cell Cycle 8: 158-66.
    • 13. O'Neill LA, Bryant CE, Doyle SL (2009) Therapeutic targeting of toll-like receptors for infectious and inflammatory diseases and cancer. Pharmacol Rev 61: 177-97.
    • 14. Conroy H, Marshall NA, Mills KH (2008) TLR ligand suppression or enhancement of Treg cells? A double-edged sword in immunity to tumours. Oncogene 27: 168-80.
    • 15. Zeromski J, Mozer-Lisewska I, Kaczmarek M (2008) Significance of Toll-like Receptors Expression in Tumor Growth and Spreading: A Short Review. Cancer Microenviron 1: 37-42.
    • 16. Baldwin AS Jr (2001) Series introduction: the transcription factor NF-kappaB and human disease. J Clin Invest 107: 3-6.
    • 17. Liew FY, Xu D, Brint EK, O'Neill LA (2005) Negative regulation of toll-like receptor-mediated immune responses. Nat Rev Immunol 5: 446-58.
    • 18. Liston A, Linterman M, Lu MF (2010) MicroRNA in the adaptive immune system, in sickness and in health. J Clin Immunol 30: 339-46.
    • 19. Sheedy FJ, Palsson-McDermott E, Hennessy EJ, Martin C, O'Leary JJ, et al. (2009) Negative regulation of TLR4 via targeting of the proinflammatory tumor suppressor PDCD4 by the microRNA miR-21. Nat Immunol 11: 141-7.
    • 20. Kelly MG, Alvero AB, Chen R, Silasi DA, Abrahams VM, et al. (2006) TLR4 signaling promotes tumor growth and paclitaxel chemoresistance in ovarian cancer. Cancer Res 66: 3859-68.
    • 21. Chen R, Alvero AB, Silasi DA, Steffensen KD, Mor G (2008) Cancers take their Toll-the function and regulation of Toll-like receptors in cancer cells. Oncogene 27: 225-33.
    • 22. Alvero AB, Mor G (2006) MyD88-positive ovarian cancer cells regulate monocyte migration and differentiation. Am J Reprod Immunol 55: 399-400.
    • 23. Szajnik M, Szczepanski MJ, Czystowska M, Elishaev E, Mandapathil M, et al. (2009) TLR4 signaling induced by lipopolysaccharide or paclitaxel regulates tumor survival and chemoresistance in ovarian cancer. Oncogene 28: 4353-63.
    • 24. Zhu Y, Huang JM, Zhang GN, Zha X, Deng BF (2012) Prognostic significance of MyD88 expression by human epithelial ovarian carcinoma cells. J Transl Med 10: 77.
    • 25. Kamsteeg M, Rutherford T, Sapi E, Hanczaruk B, Shahabi S, et al. (2003) Phenoxodiol-an isoflavone analog-induces apoptosis in chemoresistant ovarian cancer cells. Oncogene 22: 2611-20.
    • 26. Pommier Y, Sordet O, Antony S, Hayward RL, Kohn KW (2004) Apoptosis defects and chemotherapy resistance: molecular interaction maps and networks. Oncogene 23: 2934-49.
    • 27. Silasi DA, Alvero AB, Illuzzi J, Kelly M, Chen R, et al. (2006) MyD88 predicts chemoresistance to paclitaxel in epithelial ovarian cancer. Yale J Biol Med 79: 153-63.
    • 28. Szajnik M, Szczepanski M, Czystowska M, Elishaev E, Mandapathil M, et al. (2009) Expression and signaling of Toll-like receptor 4 (TLR4) and MyD88 in ovarian carcinoma cells. J Clin Oncol 27(15S): e16508.
    • 29. Gallagher MF, Flavin RJ, Elbaruni SA, McInerney JK, Smyth PC, et al. (2009) Regulation of microRNA biosynthesis and expression in 2102Ep embryonal carcinoma stem cells is mirrored in ovarian serous adenocarcinoma patients. J Ovarian Res 2: 19.
    • 30. Andrews PW, Damjanov I, Simon D, Banting GS, Carlin C, et al. (1984) Pluripotent embryonal carcinoma clones derived from the human teratocarcinoma cell line Tera-2. Differentiation in vivo and in vitro. Lab Invest 50: 147- 62.
    • 31. Andrews PW, Fenderson B, Hakomori S (1987) Human embryonal carcinoma cells and their differentiation in culture. Int J Androl 10: 95-104.
    • 32. Andrews PW (2002) From teratocarcinomas to embryonic stem cells. Philos Trans R Soc Lond B Biol Sci 357: 405-17.
    • 33. Andrews PW, Matin MM, Bahrami AR, Damjanov I, Gokhale P, et al. (2005) Embryonic stem (ES) cells and embryonal carcinoma (EC) cells: opposite sides of the same coin. Biochem Soc Trans 33: 1526-30.
    • 34. Taganov KD, Boldin MP, Baltimore D (2006) NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci U S A 103: 12481-6.
    • 35. Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116: 281-97.
    • 36. Nisolle M, Gillerot S, Casanas-Roux F, Squifflet J, Berliere M, et al. (1999) Immunohistochemical study of the proliferation index, oestrogen receptors and progesterone receptors A and B in leiomyomata and normal myometrium during the menstrual cycle and under gonadotrophin-releasing hormone agonist therapy. Hum Reprod 14: 2844-50.
    • 37. Geisler S, L√łnning PE, Aas T, Johnsen H, Fluge O, et al. (2001) Influence of TP53 gene alterations and c-erbB-2 expression on the response to treatment with doxorubicin in locally advanced breast cancer. Cancer Res 61: 2505-12.
    • 38. Mohsin SK, Weiss H, Havighurst T, Clark GM, Berardo M, et al. (2004) Progesterone receptor by immunohistochemistry and clinical outcome in breast cancer: a validation study. Mod Pathol 17: 1545-54.
    • 39. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25: 402-8.
    • 40. Ma J, Maliepaard M, Kolker HJ, Verweij J, Schellens JH (1998) Abrogated energy-dependent uptake of cisplatin in a cisplatin-resistant subline of the human ovarian cancer cell line IGROV-1. Cancer Chemotherapy & Pharmacology 41: 186-192.
    • 41. Stordal B, Hamon M, McEneaney V, Roche S, Gillet JP, et al. (2012) Resistance to paclitaxel in a cisplatin-resistant ovarian cancer cell line is mediated by Pglycoprotein. PLoS One 7:e40717.
    • 42. Shen DW, Fojo A, Chin JE, Roninson IB, Richert N, et al. (1986) Human multidrug-resistant cell lines: increased mdr1 expression can precede gene amplification. Science 232: 643-5.
  • Inferred research data

    The results below are discovered through our pilot algorithms. Let us know how we are doing!

    Title Trust
  • Discovered through pilot similarity algorithms. Send us your feedback.

Share - Bookmark

Funded by projects

  • SFI | CSET BDI: Biomedical Diagno...

Cite this article