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Modulatory Effect of Indoles on the Expression of miRNAs Regulating G1/S Cell Cycle Phase in Breast Cancer Cells

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Abstract

Indole-3-carbinol (I3C) is a naturally occurring glucosinolate found in Brassica vegetables that is usually converted in gastric acidic environment to the efficient metabolite 3,3′-diindolylmethane (DIM). Both indoles (I3C and DIM) are known chemopreventive agents for various cancers including breast cancer. This study aimed to investigate the influence of both indoles on the tumor suppressor miRNAs (let-7a-e, miR-15a, miR-16, miR-17-5p, miR-19a, and miR-20a) and oncomiRs (miR-181a, miR-181b, miR-210, miR-221, and miR-106a), which are controlling the cell cycle key regulators: cyclin-dependent kinases (CDKs), CDK inhibitor p27Kip1, and cyclin D1. Our results indicated that both indoles generally elevated the expression of the tumor suppressor miRNAs let-7a-e, miR-19a, miR-17-5p, and miR-20a and decreased the expression of the oncomiR list. Both indoles were able to significantly suppress the expression of CDK4 and CDK6 as well as the apoptotic markers Bcl-2 and survivin. Both indoles decreased cyclin-D1 protein, where I3C decreased cytoplasmic and nuclear cyclin-D1 significantly. Cytoplasmic and nuclear P27Kip1 showed overexpression following treatment with I3C higher than that detected following DIM treatment. This study provides a mechanistic elucidation of the previously reported cell cycle arrest by I3C and DIM in breast cancer cells suggesting that this effect could be through modulation of miRNAs expression that, in turn, regulates the genetic network controlling the G1/S phase in cell cycle progression.

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References

  1. Verhoeven, D. T. H., Goldbohm, R. A., Van Poppel, G., Verhagen, H., & Van Den Brandt, P. A. (1996). Epidemiological studies on Brassica vegetables and cancer risk. Cancer Epidemiology, Biomarkers and Prevention, 5(9), 733–748.

    CAS  Google Scholar 

  2. Cartea, M. E., & Velasco, P. (2008). Glucosinolates in Brassica foods: bioavailability in food and significance for human health. Phytochemistry Reviews, 7(2), 213–229.

    CAS  Google Scholar 

  3. Verhoeven, D. T. H., Verhagen, H., Goldbohm, R. A., Van Den Brandt, P. A., & Van Poppel, G. (1997). A review of mechanisms underlying anticarcinogenicity by brassica vegetables. Chemico-Biological Interactions, 103(2), 79–129.

    CAS  Google Scholar 

  4. Weng, J. R., Tsai, C. H., Kulp, S. K., & Chen, C. S. (2008). Indole-3-carbinol as a chemopreventive and anti-cancer agent. Cancer Letters, 262(2), 153–163.

    CAS  Google Scholar 

  5. Bradlow, H. L. (2008). Indole-3-carbinol as a chemoprotective agent in breast and prostate cancer. In Vivo, 22(4):441–5.

  6. Thomson, C. A., Ho, E., & Strom, M. B. (2016). Chemopreventive properties of 3,30-diindolylmethane in breast cancer: evidence from experimental and human studies. Nutrition Reviews, 74(7), 432–443.

    Google Scholar 

  7. Rahman, K. M. W., Li, Y., Wang, Z., Sarkar, S. H., & Sarkar, F. H. (2006). Gene expression profiling revealed survivin as a target of 3,3′-diindolylmethane-induced cell growth inhibition and apoptosis in breast cancer cells. Cancer Research, 66(9), 4952–4960.

    CAS  Google Scholar 

  8. Wang, T. T. Y., Schoene, N. W., Milner, J. A., & Kim, Y. S. (2012). Broccoli-derived phytochemicals indole-3-carbinol and 3,3′-diindolylmethane exerts concentration-dependent pleiotropic effects on prostate cancer cells: comparison with other cancer preventive phytochemicals. Molecular Carcinogenesis, 51(3), 244–256.

    Google Scholar 

  9. Ge, X., Yannai, S., Rennert, G., Gruener, N., & Fares, F. A. (1996). 3,3′-Diindolylmethane induces apoptosis in human cancer cells. Biochemical and Biophysical Research Communications, 228(1), 153–158.

    CAS  Google Scholar 

  10. Hong, C., Kim, H. A., Firestone, G. L., & Bjeldanes, L. F. (2002). 3,3′-Diindolymethane (DIM) induces a G1 cell cycle arrest in human breast cancer cells that is accompanied by Sp1-mediated activation of p21WAF1/CIP1 expression. Carcinogenesis, 23(8), 1297–1305.

    CAS  Google Scholar 

  11. Cover, C. M., Hsieh, S. J., Tran, S. H., Hallden, G., Kim, G. S., Bjeldanes, L. F., & Firestone, G. L. (1998). Indole-3-carbinol inhibits the expression of cyclin-dependent kinase-6 and induces a G1 cell cycle arrest of human breast cancer cells independent of estrogen receptor signaling. Journal of Biological Chemistry, 273(7), 3838–3847.

    CAS  Google Scholar 

  12. He, L., & Hannon, G. J. (2004). MicroRNAs: small RNAs with a big role in gene regulation. Nature Reviews Genetics, 5(7), 522–531.

    CAS  Google Scholar 

  13. Lu, J., & Clark, A. G. (2012). Impact of microRNA regulation on variation in human gene expression. Genome Research, 22(7), 1243–1254.

    CAS  Google Scholar 

  14. Muljo, S. A., Kanellopoulou, C., & Aravind, L. (2010). MicroRNA targeting in mammalian genomes: genes and mechanisms. Wiley Interdisciplinary Reviews: Systems Biology and Medicine, 2(2), 148–161.

    CAS  Google Scholar 

  15. El-Daly, S. M., Omara, E. A., Hussein, J., Youness, E. R., & El-Khayat, Z. (2019). Differential expression of miRNAs regulating NF-κB and STAT3 crosstalk during colitis-associated tumorigenesis. Molecular and Cellular Probes, 47, 101442.

    CAS  Google Scholar 

  16. El-Daly, S. M., Morsy, S. M., Medhat, D., El-Bana, M. A., Latif, Y. A., Omara, E. A., & Gamal-Eldeen, A. M. (2019). The diagnostic efficacy of circulating miRNAs in monitoring the early development of colitis-induced colorectal cancer. Journal of Cellular Biochemistry, 120(10), 16668–16680.

    CAS  Google Scholar 

  17. Hata, A., & Kashima, R. (2016). Dysregulation of microRNA biogenesis machinery in cancer. Critical Reviews in Biochemistry and Molecular Biology, 51(3), 121–134.

    CAS  Google Scholar 

  18. Hosseinahli, N., Aghapour, M., Duijf, P. H. G., & Baradaran, B. (2018). Treating cancer with microRNA replacement therapy: a literature review. Journal of Cellular Physiology, 233(8), 5574–5588.

    CAS  Google Scholar 

  19. El-Daly, S. M., Abba, M. L., & Gamal-Eldeen, A. M. (2017). The role of microRNAs in photodynamic therapy of cancer. European Journal of Medicinal Chemistry, 142, 550–555.

    CAS  Google Scholar 

  20. Chen, D., Farwell, M. A., & Zhang, B. (2010). MicroRNA as a new player in the cell cycle. Journal of Cellular Physiology, 225(2), 296–301.

    CAS  Google Scholar 

  21. Bueno, M. J., & Malumbres, M. (2011). MicroRNAs and the cell cycle. Biochimica et Biophysica Acta - Molecular Basis of Disease, 1812(5), 592–601.

    CAS  Google Scholar 

  22. Bandi, N., Zbinden, S., Gugger, M., Arnold, M., Kocher, V., Hasan, L., & Vassella, E. (2009). miR-15a and miR-16 are implicated in cell cycle regulation in a Rb-dependent manner and are frequently deleted or down-regulated in non-small cell lung cancer. Cancer Research, 69(13), 5553–5559.

    CAS  Google Scholar 

  23. Luo, Q., Li, X., Li, J., Kong, X., Zhang, J., Chen, L., & Fang, L. (2013). MiR-15a is underexpressed and inhibits the cell cycle by targeting CCNE1 in breast cancer. International Journal of Oncology, 43(4), 1212–1218.

    CAS  Google Scholar 

  24. Liu, Q., Fu, H., Sun, F., Zhang, H., Tie, Y., Zhu, J., & Zheng, X. (2008). miR-16 family induces cell cycle arrest by regulating multiple cell cycle genes. Nucleic Acids Research, 36(16), 5391–5404.

    CAS  Google Scholar 

  25. Le Sage, C., Nagel, R., Egan, D. A., Schrier, M., Mesman, E., Mangiola, A., & Agami, R. (2007). Regulation of the p27Kip1 tumor suppressor by miR-221 and miR-222 promotes cancer cell proliferation. EMBO Journal, 26(15), 3699–3708.

    Google Scholar 

  26. Zhang, C., Kang, C., You, Y., Pu, P., Yang, W., Zhao, P., & Jiang, H. (2009). Co-suppression of miR-221/222 cluster suppresses human glioma cell growth by targeting p27kip1 in vitro and in vivo. International Journal of Oncology, 34(6), 1653–1660.

    CAS  Google Scholar 

  27. Wang, X., Gocek, E., Liu, C. G., & Studzinski, G. P. (2009). MicroRNAs181 regulate the expression of p27Kip1 in human myeloid leukemia cells induced to differentiate by 1,25-dihydroxyvitamin D3. Cell Cycle, 8(5), 736–741.

    CAS  Google Scholar 

  28. Carleton, M., Cleary, M. A., & Linsley, P. S. (2007). MicroRNAs and cell cycle regulation. Cell Cycle, 6(17), 2127–2132.

    CAS  Google Scholar 

  29. El-Daly, S. M., Gouhar, S. A., Gamal-Eldeen, A. M., Abdel Hamid, F. F., Ashour, M. N., & Hassan, N. S. (2019). Synergistic effect of α-solanine and cisplatin induces apoptosis and enhances cell cycle arrest in human hepatocellular carcinoma cells. Anti-Cancer Agents in Medicinal Chemistry, 19(18), 2197–2210.

    CAS  Google Scholar 

  30. Zhang, J., Hsu, J. C., Kinseth, M. A., Bjeldanes, L. F., & Firestone, G. L. (2003). Indole-3-carbinol induces a G1 cell cycle arrest and inhibits prostate-specific antigen production in human LNCaP prostate carcinoma cells. Cancer, 98(11), 2511–2520.

    CAS  Google Scholar 

  31. Cover, C. M., Hsieh, S. J., Cram, E. J., Hong, C., Riby, J. E., Bjeldanes, L. F., & Firestone, G. L. (1999). Indole-3-carbinol and tamoxifen cooperate to arrest the cell cycle of MCF-7 human breast cancer cells. Cancer Research, 59(6), 1244–1251.

    CAS  Google Scholar 

  32. Gamal-Eldeen, A. M., Abdel-Hameed, S. A. M., El-Daly, S. M., Abo-Zeid, M. A. M., & Swellam, M. M. (2017). Cytotoxic effect of ferrimagnetic glass-ceramic nanocomposites on bone osteosarcoma cells. Biomedicine and Pharmacotherapy, 88, 689–697.

    CAS  Google Scholar 

  33. Abo-Zeid, M. A. M., Liehr, T., El-Daly, S. M., Gamal-Eldeen, A. M., Glei, M., Shabaka, A., & Hamid, A. (2013). Molecular cytogenetic evaluation of the efficacy of photodynamic therapy by indocyanine green in breast adenocarcinoma MCF-7 cells. Photodiagnosis and Photodynamic Therapy, 10(2), 194–202.

    CAS  Google Scholar 

  34. Sutherland, R. L., & Musgrove, E. A. (2004). Cyclins and breast cancer. Journal of Mammary Gland Biology and Neoplasia, 9(1), 95–104.

    Google Scholar 

  35. Ortega, S., Malumbres, M., & Barbacid, M. (2002). Cyclin D-dependent kinases, INK4 inhibitors and cancer. Biochimica et Biophysica Acta, 1602(1), 73–87.

    CAS  Google Scholar 

  36. Musgrove, E. A., Caldon, C. E., Barraclough, J., Stone, A., & Sutherland, R. L. (2011). Cyclin D as a therapeutic target in cancer. Nature Reviews Cancer, 11(8), 558–572.

    CAS  Google Scholar 

  37. Fan, S., Meng, Q., Auborn, K., Carter, T., & Rosen, E. M. (2006). BRCA1 and BRCA2 as molecular targets for phytochemicals indole-3-carbinol and genistein in breast and prostate cancer cells. British Journal of Cancer, 94(3), 407–426.

    CAS  Google Scholar 

  38. Brew, C. T., Aronchik, I., Hsu, J. C., Sheen, J. H., Dickson, R. B., Bjeldanes, L. F., & Firestone, G. L. (2006). Indole-3-carbinol activates the ATM signaling pathway independent of DNA damage to stabilize p53 and induce G1 arrest of human mammary epithelial cells. International Journal of Cancer, 118(4), 857–868.

    CAS  Google Scholar 

  39. Chinnakannu, K., Chen, D., Li, Y., Wang, Z., Dou, Q. P., Reddy, G. P. V., & Sarkar, F. H. (2009). Cell cycle-dependent effects of 3,3′-diindolylmethane on proliferation and apoptosis of prostate cancer cells. Journal of Cellular Physiology, 219(1), 94–99.

    CAS  Google Scholar 

  40. Johnson, C. D., Esquela-Kerscher, A., Stefani, G., Byrom, M., Kelnar, K., Ovcharenko, D., & Slack, F. J. (2007). The let-7 microRNA represses cell proliferation pathways in human cells. Cancer Research, 67(16), 7713–7722.

    CAS  Google Scholar 

  41. Zhu, X., Wu, L., Yao, J., Jiang, H., Wang, Q., Yang, Z., & Wu, F. (2015). MicroRNA let-7c inhibits cell proliferation and induces cell cycle arrest by targeting CDC25A in human hepatocellular carcinoma. Plos One, 10(4), e0124266.

    Google Scholar 

  42. Subramaniam, D., Ponnurangam, S., Ramamoorthy, P., Standing, D., Battafarano, R. J., Anant, S., & Sharma, P. (2012). Curcumin induces cell death in esophageal cancer cells through modulating Notch signaling. Plos One, 7(2), e30590.

    CAS  Google Scholar 

  43. Quan, R., Wei, L., Zhu, S., Wang, J., Cao, Y., Xue, C., & Liu, J. (2016). Involvement of miR-15a in G0/G1 phase cell cycle arrest induced by porcine Circovirus type 2 replication. Scientific Reports, 6(1), 1–10.

    Google Scholar 

  44. Cimmino, A., Calin, G. A., Fabbri, M., Iorio, M. V., Ferracin, M., Shimizu, M., & Croce, C. M. (2005). miR-15 and miR-16 induce apoptosis by targeting BCL2. Proceedings of the National Academy of Sciences, 102(39), 13944–13949.

    CAS  Google Scholar 

  45. Qin, X., Wang, X., Wang, Y., Tang, Z., Cui, Q., Xi, J., & Wang, N. (2010). MicroRNA-19a mediates the suppressive effect of laminar flow on cyclin D1 expression in human umbilical vein endothelial cells. Proceedings of the National Academy of Sciences, 107(7), 3240–3244.

    CAS  Google Scholar 

  46. Pickering, M. T., Stadler, B. M., & Kowalik, T. F. (2009). miR-17 and miR-20a temper an E2F1-induced G1 checkpoint to regulate cell cycle progression. Oncogene, 28(1), 140–145.

    CAS  Google Scholar 

  47. Ottman, R., Levy, J., Grizzle, W. E., & Chakrabarti, R. (2016). The other face of miR-17-92a cluster, exhibiting tumor suppressor effects in prostate cancer. Oncotarget, 7(45), 73739–73753.

    Google Scholar 

  48. Yu, Z., Wang, C., Wang, M., Li, Z., Casimiro, M. C., Liu, M., & Pestell, R. G. (2008). A cyclin D1/microRNA 17/20 regulatory feedback loop in control of breast cancer cell proliferation. Journal of Cell Biology, 182(3), 509–517.

    CAS  Google Scholar 

  49. O’Donnell, K. A., Wentzel, E. A., Zeller, K. I., Dang, C. V., & Mendell, J. T. (2005). c-Myc-regulated microRNAs modulate E2F1 expression. Nature, 435(7043), 839–843.

    Google Scholar 

  50. Biyashev, D. (2011). E2F and microRNA regulation of angiogenesis. American Journal of Cardiovascular Disease, 1(2), 110–118.

    CAS  Google Scholar 

  51. Cloonan, N., Brown, M. K., Steptoe, A. L., Wani, S., Forrest, A. R. R., Kolle, G., & Grimmond, S. M. (2008). The miR-17-5p microRNA is a key regulator of the G1/S phase cell cycle transition. Genome Biology, 9(8), R127.

    Google Scholar 

  52. Lee, J., & Kim, S. S. (2009). The function of p27KIP1 during tumor development. Experimental and Molecular Medicine, 41(11), 765–771.

    CAS  Google Scholar 

  53. Cuesta, R., Martinez-Sanchez, A., & Gebauer, F. (2009). miR-181a regulates cap-dependent translation of p27kip1 mRNA in myeloid cells. Molecular and Cellular Biology, 29(10), 2841–2851.

    CAS  Google Scholar 

  54. Visone, R., Russo, L., Pallante, P., De Martino, I., Ferraro, A., Leone, V., & Fusco, A. (2007). MicroRNAs (miR)-221 and miR-222, both overexpressed in human thyroid papillary carcinomas, regulate p27Kip1 protein levels and cell cycle. Endocrine-Related Cancer, 14(3), 791–798.

    CAS  Google Scholar 

  55. Miller, T. E., Ghoshal, K., Ramaswamy, B., Roy, S., Datta, J., Shapiro, C. L., & Majumder, S. (2008). MicroRNA-221/222 confers tamoxifen resistance in breast cancer by targeting p27Kip1. Journal of Biological Chemistry, 283(44), 29897–29903.

    CAS  Google Scholar 

  56. Volinia, S., Calin, G. A., Liu, C.-G., Ambs, S., Cimmino, A., Petrocca, F., & Croce, C. M. (2006). A microRNA expression signature of human solid tumors defines cancer gene targets. Proceedings of the National Academy of Sciences, 103(7), 2257–2261.

    CAS  Google Scholar 

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Funding

This research was financially supported by the National Research Centre, Cairo, Egypt (NRC project grant No# 11010332, Principle Investigator; Sherien M. El-Daly).

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Authors and Affiliations

  1. Medical Biochemistry Department, Medical Research Division, National Research Centre, 33 El Buhouth St. Dokki, Cairo, 12622, Egypt

    Sherien M. El-Daly, Shaimaa A. Gouhar & Gamila El-Saeed

  2. Cancer Biology and Genetics Laboratory, Centre of Excellence for Advanced Sciences, National Research Centre, Cairo, Egypt

    Sherien M. El-Daly, Amira M. Gamal-Eldeen & Mahmoud T. Abo-elfadl

  3. Biochemistry Department, National Research Centre, Cairo, Egypt

    Amira M. Gamal-Eldeen & Mahmoud T. Abo-elfadl

  4. Clinical Laboratory Department, College of Applied Medical Sciences, Taif University, Taif, Kingdom of Saudi Arabia

    Amira M. Gamal-Eldeen

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  1. Sherien M. El-Daly
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  2. Amira M. Gamal-Eldeen
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  3. Shaimaa A. Gouhar
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  4. Mahmoud T. Abo-elfadl
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Contributions

S.M.E. is the principal investigator of the project; S.M.E. and A.M.G. planned for the project; S.M.E., S.A.G., and M.T.A. performed the required experiments; S.M.E. wrote the manuscript in consultation with A.M.G; S.M.E., A.M.G., and G.E. participated in drafting the article and reviewing the manuscript. All authors discussed the results and contributed to the final form of the manuscript.

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Correspondence to Sherien M. El-Daly.

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El-Daly, S.M., Gamal-Eldeen, A.M., Gouhar, S.A. et al. Modulatory Effect of Indoles on the Expression of miRNAs Regulating G1/S Cell Cycle Phase in Breast Cancer Cells. Appl Biochem Biotechnol 192, 1208–1223 (2020). https://doi.org/10.1007/s12010-020-03378-8

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