miR-141 and miR-200a act on ovarian tumorigenesis by controlling oxidative stress response


Although there is evidence that redox regulation has an essential role in malignancies, its impact on tumor prognosis remains unclear. Here we show crosstalk between oxidative stress and the miR-200 family of microRNAs that affects tumorigenesis and chemosensitivity. miR-141 and miR-200a target p38α and modulate the oxidative stress response. Enhanced expression of these microRNAs mimics p38α deficiency and increases tumor growth in mouse models, but it also improves the response to chemotherapeutic agents. High-grade human ovarian adenocarcinomas that accumulate miR-200a have low concentrations of p38α and an associated oxidative stress signature. The miR200a-dependent stress signature correlates with improved survival of patients in response to treatment. Therefore, the role of miR-200a in stress could be a predictive marker for clinical outcome in ovarian cancer. In addition, although oxidative stress promotes tumor growth, it also sensitizes tumors to treatment, which could account for the limited success of antioxidants in clinical trials.

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Figure 1: Expression of the miR-200s is stimulated by oxidative stress.
Figure 2: Balance of the p38 and JNK pathways by miR-141 and miR-200a.
Figure 3: miR-141 and miR-200a enhance tumorigenesis in mouse models.
Figure 4: miR-200a and oxidative stress response predict good prognosis in patients with ovarian cancer.
Figure 5: miR-141 and miR-200a enhance the response to chemotherapeutic reagents.

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  1. 1

    Hennessy, B.T., Coleman, R.L. & Markman, M. Ovarian cancer. Lancet 374, 1371–1382 (2009).

    CAS  Article  Google Scholar 

  2. 2

    The Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature 474, 609–615 (2011).

  3. 3

    Allen, R.G. & Tresini, M. Oxidative stress and gene regulation. Free Radic. Biol. Med. 28, 463–499 (2000).

    CAS  Article  Google Scholar 

  4. 4

    Gerald, D. et al. JunD reduces tumor angiogenesis by protecting cells from oxidative stress. Cell 118, 781–794 (2004).

    CAS  Article  Google Scholar 

  5. 5

    Pouysségur, J. & Mechta-Grigoriou, F. Redox regulation of the hypoxia-inducible factor. Biol. Chem. 387, 1337–1346 (2006).

    Article  Google Scholar 

  6. 6

    Laurent, G. et al. Oxidative stress contributes to aging by enhancing pancreatic angiogenesis and insulin signaling. Cell Metab. 7, 113–124 (2008).

    CAS  Article  Google Scholar 

  7. 7

    Weinberg, F. & Chandel, N.S. Reactive oxygen species–dependent signaling regulates cancer. Cell. Mol. Life Sci. 66, 3663–3673 (2009).

    CAS  Article  Google Scholar 

  8. 8

    Pani, G., Galeotti, T. & Chiarugi, P. Metastasis: cancer cell′s escape from oxidative stress. Cancer Metastasis Rev. 29, 351–378 (2010).

    CAS  Article  Google Scholar 

  9. 9

    Toullec, A. et al. Oxidative stress promotes myofibroblast differentiation and tumour spreading. EMBO Mol. Med. 2, 211–230 (2010).

    CAS  Article  Google Scholar 

  10. 10

    Dolado, I. et al. p38α MAP kinase as a sensor of reactive oxygen species in tumorigenesis. Cancer Cell 11, 191–205 (2007).

    CAS  Article  Google Scholar 

  11. 11

    Kennedy, N.J., Cellurale, C. & Davis, R.J. A radical role for p38 MAPK in tumor initiation. Cancer Cell 11, 101–103 (2007).

    CAS  Article  Google Scholar 

  12. 12

    Hui, L. et al. p38α suppresses normal and cancer cell proliferation by antagonizing the JNK-c-Jun pathway. Nat. Genet. 39, 741–749 (2007).

    CAS  Article  Google Scholar 

  13. 13

    Wada, T. et al. Antagonistic control of cell fates by JNK and p38-MAPK signaling. Cell Death Differ. 15, 89–93 (2008).

    CAS  Article  Google Scholar 

  14. 14

    Wagner, E.F. & Nebreda, A.R. Signal integration by JNK and p38 MAPK pathways in cancer development. Nat. Rev. Cancer 9, 537–549 (2009).

    CAS  Article  Google Scholar 

  15. 15

    Kim, E.K. & Choi, E.J. Pathological roles of MAPK signaling pathways in human diseases. Biochim. Biophys. Acta 1802, 396–405 (2010).

    CAS  Article  Google Scholar 

  16. 16

    Marsit, C.J., Eddy, K. & Kelsey, K.T. MicroRNA responses to cellular stress. Cancer Res. 66, 10843–10848 (2006).

    CAS  Article  Google Scholar 

  17. 17

    Ivan, M., Harris, A.L., Martelli, F. & Kulshreshtha, R. Hypoxia response and microRNAs: no longer two separate worlds. J. Cell Mol. Med. 12, 1426–1431 (2008).

    CAS  Article  Google Scholar 

  18. 18

    Lin, Y. et al. Involvement of microRNAs in hydrogen peroxide–mediated gene regulation and cellular injury response in vascular smooth muscle cells. J. Biol. Chem. 284, 7903–7913 (2009).

    CAS  Article  Google Scholar 

  19. 19

    Simone, N.L. et al. Ionizing radiation–induced oxidative stress alters miRNA expression. PLoS ONE 4, e6377 (2009).

    Article  Google Scholar 

  20. 20

    Wang, Z. et al. Profiles of oxidative stress–related microRNA and mRNA expression in auditory cells. Brain Res. 1346, 14–25 (2010).

    CAS  Article  Google Scholar 

  21. 21

    Magenta, A. et al. miR-200c is up-regulated by oxidative stress and induces endothelial cell apoptosis and senescence via ZEB1 inhibition. Cell Death Differ. 18, 1628–1639 (2011).

    CAS  Article  Google Scholar 

  22. 22

    Hurteau, G.J., Carlson, J.A., Spivack, S.D. & Brock, G.J. Overexpression of the microRNA hsa-miR-200c leads to reduced expression of transcription factor 8 and increased expression of E-cadherin. Cancer Res. 67, 7972–7976 (2007).

    CAS  Article  Google Scholar 

  23. 23

    Bracken, C.P. et al. A double-negative feedback loop between ZEB1–SIP1 and the microRNA-200 family regulates epithelial-mesenchymal transition. Cancer Res. 68, 7846–7854 (2008).

    CAS  Article  Google Scholar 

  24. 24

    Burk, U. et al. A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells. EMBO Rep. 9, 582–589 (2008).

    CAS  Article  Google Scholar 

  25. 25

    Gregory, P.A. et al. The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat. Cell Biol. 10, 593–601 (2008).

    CAS  Article  Google Scholar 

  26. 26

    Korpal, M., Lee, E.S., Hu, G. & Kang, Y. The miR-200 family inhibits epithelial-mesenchymal transition and cancer cell migration by direct targeting of E-cadherin transcriptional repressors ZEB1 and ZEB2. J. Biol. Chem. 283, 14910–14914 (2008).

    CAS  Article  Google Scholar 

  27. 27

    Park, S.M., Gaur, A.B., Lengyel, E. & Peter, M.E. The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2. Genes Dev. 22, 894–907 (2008).

    CAS  Article  Google Scholar 

  28. 28

    Shimono, Y. et al. Downregulation of miRNA-200c links breast cancer stem cells with normal stem cells. Cell 138, 592–603 (2009).

    CAS  Article  Google Scholar 

  29. 29

    Wellner, U. et al. The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs. Nat. Cell Biol. 11, 1487–1495 (2009).

    CAS  Article  Google Scholar 

  30. 30

    Iliopoulos, D. et al. Loss of miR-200 inhibition of Suz12 leads to polycomb-mediated repression required for the formation and maintenance of cancer stem cells. Mol. Cell 39, 761–772 (2010).

    CAS  Article  Google Scholar 

  31. 31

    Schickel, R., Park, S.M., Murmann, A.E. & Peter, M.E. miR-200c regulates induction of apoptosis through CD95 by targeting FAP-1. Mol. Cell 38, 908–915 (2010).

    CAS  Article  Google Scholar 

  32. 32

    Chang, C.J. et al. p53 regulates epithelial-mesenchymal transition and stem cell properties through modulating miRNAs. Nat. Cell Biol. 13, 317–323 (2011).

    CAS  Article  Google Scholar 

  33. 33

    Kim, T. et al. p53 regulates epithelial-mesenchymal transition through microRNAs targeting ZEB1 and ZEB2. J. Exp. Med. 208, 875–883 (2011).

    CAS  Article  Google Scholar 

  34. 34

    Ramanathan, B. et al. Resistance to paclitaxel is proportional to cellular total antioxidant capacity. Cancer Res. 65, 8455–8460 (2005).

    CAS  Article  Google Scholar 

  35. 35

    Alexandre, J., Hu, Y., Lu, W., Pelicano, H. & Huang, P. Novel action of paclitaxel against cancer cells: bystander effect mediated by reactive oxygen species. Cancer Res. 67, 3512–3517 (2007).

    CAS  Article  Google Scholar 

  36. 36

    Konstantinopoulos, P.A. et al. Carboplatin-induced gene expression changes in vitro are prognostic of survival in epithelial ovarian cancer. BMC Med. Genomics 1, 59 (2008).

    Article  Google Scholar 

  37. 37

    Liu, H. et al. mRNA and microRNA expression profiles of the NCI-60 integrated with drug activities. Mol. Cancer Ther. 9, 1080–1091 (2010).

    CAS  Article  Google Scholar 

  38. 38

    Iorio, M.V. et al. MicroRNA signatures in human ovarian cancer. Cancer Res. 67, 8699–8707 (2007).

    CAS  Article  Google Scholar 

  39. 39

    Nam, E.J. et al. MicroRNA expression profiles in serous ovarian carcinoma. Clin. Cancer Res. 14, 2690–2695 (2008).

    CAS  Article  Google Scholar 

  40. 40

    Hu, X. et al. A miR-200 microRNA cluster as prognostic marker in advanced ovarian cancer. Gynecol. Oncol. 114, 457–464 (2009).

    CAS  Article  Google Scholar 

  41. 41

    Bendoraite, A. et al. Regulation of miR-200 family microRNAs and ZEB transcription factors in ovarian cancer: evidence supporting a mesothelial-to-epithelial transition. Gynecol. Oncol. 116, 117–125 (2010).

    CAS  Article  Google Scholar 

  42. 42

    Cochrane, D.R., Howe, E.N., Spoelstra, N.S. & Richer, J.K. Loss of miR-200c: a marker of aggressiveness and chemoresistance in female reproductive cancers. J. Oncol. 2010, 821717 (2010).

    Article  Google Scholar 

  43. 43

    Mezzanzanica, D., Bagnoli, M., De Cecco, L., Valeri, B. & Canevari, S. Role of microRNAs in ovarian cancer pathogenesis and potential clinical implications. Int. J. Biochem. Cell Biol. 42, 1262–1272 (2010).

    CAS  Article  Google Scholar 

  44. 44

    van Jaarsveld, M.T., Helleman, J., Berns, E.M. & Wiemer, E.A. MicroRNAs in ovarian cancer biology and therapy resistance. Int. J. Biochem. Cell Biol. 42, 1282–1290 (2010).

    CAS  Article  Google Scholar 

  45. 45

    Tothill, R.W. et al. Novel molecular subtypes of serous and endometrioid ovarian cancer linked to clinical outcome. Clin. Cancer Res. 14, 5198–5208 (2008).

    CAS  Article  Google Scholar 

  46. 46

    Yang, H. et al. MicroRNA expression profiling in human ovarian cancer: miR-214 induces cell survival and cisplatin resistance by targeting PTEN. Cancer Res. 68, 425–433 (2008).

    CAS  Article  Google Scholar 

  47. 47

    Wyman, S.K. et al. Repertoire of microRNAs in epithelial ovarian cancer as determined by next generation sequencing of small RNA cDNA libraries. PLoS ONE 4, e5311 (2009).

    Article  Google Scholar 

  48. 48

    Olson, P. et al. MicroRNA dynamics in the stages of tumorigenesis correlate with hallmark capabilities of cancer. Genes Dev. 23, 2152–2165 (2009).

    CAS  Article  Google Scholar 

  49. 49

    Gibbons, D.L. et al. Contextual extracellular cues promote tumor cell EMT and metastasis by regulating miR-200 family expression. Genes Dev. 23, 2140–2151 (2009).

    CAS  Article  Google Scholar 

  50. 50

    Wiklund, E.D. et al. Coordinated epigenetic repression of the miR-200 family and miR-205 in invasive bladder cancer. Int. J. Cancer 128, 1327–1334 (2011).

    CAS  Article  Google Scholar 

  51. 51

    Eitan, R. et al. Tumor microRNA expression patterns associated with resistance to platinum based chemotherapy and survival in ovarian cancer patients. Gynecol. Oncol. 114, 253–259 (2009).

    CAS  Article  Google Scholar 

  52. 52

    Marchini, S. et al. Association between miR-200c and the survival of patients with stage I epithelial ovarian cancer: a retrospective study of two independent tumour tissue collections. Lancet Oncol. 12, 273–285 (2011).

    CAS  Article  Google Scholar 

  53. 53

    Karres, J.S., Hilgers, V., Carrera, I., Treisman, J. & Cohen, S.M. The conserved microRNA miR-8 tunes atrophin levels to prevent neurodegeneration in Drosophila. Cell 131, 136–145 (2007).

    CAS  Article  Google Scholar 

  54. 54

    Hyun, S. et al. Conserved MicroRNA miR-8/miR-200 and its target USH/FOG2 control growth by regulating PI3K. Cell 139, 1096–1108 (2009).

    CAS  Article  Google Scholar 

  55. 55

    Flynt, A.S. et al. miR-8 microRNAs regulate the response to osmotic stress in zebrafish embryos. J. Cell Biol. 185, 115–127 (2009).

    CAS  Article  Google Scholar 

  56. 56

    Naidu, S., Vijayan, V., Santoso, S., Kietzmann, T. & Immenschuh, S. Inhibition and genetic deficiency of p38 MAPK up-regulates heme oxygenase-1 gene expression via Nrf2. J. Immunol. 182, 7048–7057 (2009).

    CAS  Article  Google Scholar 

  57. 57

    Helleman, J., Smid, M., Jansen, M.P., van der Burg, M.E. & Berns, E.M. Pathway analysis of gene lists associated with platinum-based chemotherapy resistance in ovarian cancer: the big picture. Gynecol. Oncol. 117, 170–176 (2010).

    CAS  Article  Google Scholar 

  58. 58

    Leskelä, S. et al. The miR-200 family controls β-tubulin III expression and is associated with paclitaxel-based treatment response and progression-free survival in ovarian cancer patients. Endocr. Relat. Cancer 18, 85–95 (2011).

    Article  Google Scholar 

  59. 59

    Raj, L. et al. Selective killing of cancer cells by a small molecule targeting the stress response to ROS. Nature 475, 231–234 (2011).

    CAS  Article  Google Scholar 

  60. 60

    Meyniel, J.P. et al. A genomic and transcriptomic approach for a differential diagnosis between primary and secondary ovarian carcinomas in patients with a previous history of breast cancer. BMC Cancer 10, 222 (2010).

    Article  Google Scholar 

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We thank O. Delattre and S. Chanock for fruitful discussions and comments on the manuscript. We acknowledge S. Alran and B. Baranger (Surgery Department of Institut Curie) and the Biological Resource Center of Institut Curie for providing human ovarian tumors and B. Hasselain and D. Hajage for advice regarding our statistical analyses. We thank the members of the animal facility and the flow-cytometry platform of Institut Curie for their expertise. The experimental work was supported by grants from Institut National de la Santé et de la Recherche Médicale, the Institut Curie, the Ligue Nationale Contre le Cancer, the Institut National du Cancer and the Association pour la Recherche Contre le Cancer. B.M. was supported by a post-doctoral fellowship from the INSERM Avenir program and the Association pour la Recherche Contre le Cancer.

Author information




B.M. and F.M.-G. participated in the conception and design of the experiments. B.M., L.B., M.C., T.G. and Y.d.F. performed the experiments. X.S.-G. selected the human ovarian cancers after adapted characterization, and J.-P.M. provided transcriptome data. P.C. provided the associated clinical data from the subjects. O.M. and A.N. provided technical assistance and expertise in the ovarian tumor sample preparation. J.-P.M., B.M., L.B. and M.C. contributed to the statistical analyses of the data. F.M.-G. wrote the paper with suggestions and comments from all authors.

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Correspondence to Fatima Mechta-Grigoriou.

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The authors declare no competing financial interests.

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Mateescu, B., Batista, L., Cardon, M. et al. miR-141 and miR-200a act on ovarian tumorigenesis by controlling oxidative stress response. Nat Med 17, 1627–1635 (2011). https://doi.org/10.1038/nm.2512

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