Skip to main content

Advertisement

SpringerLink
Log in

The Role of Epithelial Mesenchymal Transition (EMT) in Pathogenesis of Cardiotoxicity: Diagnostic & Prognostic Approach

  • Review Paper
  • Published:
Molecular Biotechnology Aims and scope Submit manuscript

A Correction to this article was published on 30 March 2023

This article has been updated

Abstract

Cancer is one of the diseases, which it is not still completely curable; the existing treatments are associated with many complications, that double its complexity. One of the causes of cancer cell metastasis is Epithelial Mesenchymal Transition (EMT). Recently study demonstrated that EMT cause cardiotoxicity and heart diseases such as heart failure, hypertrophy and fibrosis. This study evaluated molecular and signaling pathway, which lead to cardiotoxicity via EMT. It was demonstrated that the processes of inflammation, oxidative stress and angiogenesis were involved in EMT and cardiotoxicity. The pathways related to these processes act as a double-edged sword. In relation to inflammation and oxidative stress, molecular pathways caused apoptosis of cardiomyocytes and cardiotoxicity induction. While the angiogenesis process inhibits cardiotoxicity despite the progression of EMT. On the other hand, some molecular pathways such as PI3K/mTOR despite causing the progression of EMT lead to the proliferation of cardiomyocytes and prevent cardiotoxicity. Therefore, it was concluded that the identification of molecular pathways can help in designing therapeutic and preventive strategies to increase patients' survival.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Data Availability

This is a review study, and it is not an original. Data availability is corresponding author responsibility.

Change history

References

  1. Darwish, M. M., Riad, A. Y., Salem, D. A., Essa, A. E., Shakweer, M. M., & Sherif, D. E. M. (2021). Prognostic implication of PD-L1 expression and associated tumor infiltrating lymphocytes in metastatic breast cancer. Immunopathologia Persa, 8(1), e18–e18.

    Article  Google Scholar 

  2. van der Valk, M. J. M., Marijnen, C. A. M., van Etten, B., Dijkstra, E. A., Hilling, D. E., Kranenbarg, E. M., Putter, H., Roodvoets, A. G. H., Bahadoer, R. R., Fokstuen, T., Ten Tije, A. J., Capdevila, J., Hendriks, M. P., Edhemovic, I., Cervantes, A. M. R., de Groot, D. J. A., Nilsson, P. J., Glimelius, B., van de Velde, C. J. H., & Hospers, G. A. P. (2020). Compliance and tolerability of short-course radiotherapy followed by preoperative chemotherapy and surgery for high-risk rectal cancer–results of the international randomized RAPIDO-trial. Radiotherapy and Oncology, 147, 75–83.

    Article  PubMed  Google Scholar 

  3. Hao, W., Shi, Y. Y., Qin, Y. N., Sun, C. P., Chen, L. Y., Wu, C. Y., Bao, Y. J., & Liu, S. (2022). Cardioprotective effect of Chinese herbal medicine for anthracycline-induced cardiotoxicity in cancer patients: A meta-analysis of prospective studies. Medicine (Baltimore), 101(30), e29691.

    Article  CAS  PubMed  Google Scholar 

  4. Rottapel, R. E., Hudson, L. B., & Folta, S. C. (2021). Cardiovascular health and African-American women: A qualitative analysis. American Journal of Health Behavior, 45(4), 735–745.

    Article  PubMed  Google Scholar 

  5. Leman, M. A., Claramita, M., & Rahayu, G. R. (2021). Predicting factors on modeling health behavior: A systematic review. American Journal of Health Behavior, 45(2), 268–278. https://doi.org/10.5993/AJHB.45.2.7

    Article  PubMed  Google Scholar 

  6. Alagal, R. I., AlFaris, N. A., Alshammari, G. M., ALTamimi, J. Z., AlMousa, L. A., & Yahya, M. A. (2023). The protection afforded by Berberine against chemotherapy-mediated nephropathy in rats involves regulation of the antioxidant axis. Basic & clinical pharmacology & toxicology, 132(1), 98–110.

    Article  CAS  Google Scholar 

  7. Dadras, F., Sheikh, V., & Khoshjou, F. (2018). Epithelial and endothelial mesenchymal transition and their role in diabetic kidney disease. Journal of Renal Injury Prevention, 7(1), 1–6.

    Article  CAS  Google Scholar 

  8. Seo, J., Ha, J., Kang, E., & Cho, S. (2021). The role of epithelial–mesenchymal transition-regulating transcription factors in anti-cancer drug resistance. Archives of pharmacal research, 44, 281–292.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Zhong, W., & Sun, T. (2023). Epithelial-mesenchymal transition (EMT) as a therapeutic target in cancer. Frontiers in Oncology, 13, 119.

    Google Scholar 

  10. Ashrafizadeh, M., Mirzaei, S., Hashemi, F., Zarrabi, A., Zabolian, A., Saleki, H., Sharifzadeh, S. O., Soleymani, L., Daneshi, S., Hushmandi, K., Khan, H., Kumar, A. P., Aref, A. R., & Samarghandian, S. (2021). New insight towards development of paclitaxel and docetaxel resistance in cancer cells: EMT as a novel molecular mechanism and therapeutic possibilities. Biomedicine & Pharmacotherapy, 141, 111824.

    Article  CAS  Google Scholar 

  11. Sanjaya, A. (2022). microRNA-379 as a Candidate Biomarker for Early Diagnosis of Childhood Active and Latent Tuberculosis.

  12. Efentakis, P., Gavriatopoulou, M., Choustoulaki, E., Georgoulis, A., Tsekenis, G., Chakim, Z., Ntanasis-Stathopoulos, I., Dimopoulos, M. A., Terpos, E., & Andreadou, I. (2022). 33P Immune checkpoint inhibitor-induced cardiotoxicity is driven through inflammation, autophagy and stress. Annals of Oncology, 33, S556.

    Article  Google Scholar 

  13. Quagliariello, V., Paccone, A., Iovine, M., Cavalcanti, E., Berretta, M., Maurea, C., Canale, M. L., & Maurea, N. (2021). Interleukin-1 blocking agents as promising strategy for prevention of anticancer drug-induced cardiotoxicities: Possible implications in cancer patients with COVID-19. European Review for Medical and Pharmacological Sciences, 25(21), 6797–6812.

    CAS  PubMed  Google Scholar 

  14. Ichikawa, M. K., Endo, K., Itoh, Y., Osada, A. H., Kimura, Y., Ueki, K., Yoshizawa, K., Miyazawa, K., & Saitoh, M. (2022). Ets family proteins regulate the EMT transcription factors Snail and ZEB in cancer cells. FEBS Open Bio, 12(7), 1353–1364.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Al-Obaidi, Z. M. J., Abdul-Rasheed, O. F., Mahdi, M. F., & Raauf, A. M. (2019). Biological evaluation of newly synthesized spebrutinib analogues: Potential candidates with enhanced activity and reduced toxicity profiles. International Journal of Drug Delivery Technology, 9(03), 339–346.

    Google Scholar 

  16. Liu, J., Wu, Z., Han, D., Wei, C., Liang, Y., Jiang, T., Chen, L., Sha, M., Cao, Y., Huang, F., Geng, X., Yu, J., Shen, Y., Wang, H., Feng, L., Wang, D., Fang, S., Wang, S., & Shen, Y. (2020). Mesencephalic astrocyte-derived neurotrophic factor inhibits liver cancer through small ubiquitin-related modifier (SUMO)ylation-related suppression of NF-kappaB/snail signaling pathway and epithelial-mesenchymal transition. Hepatology, 71(4), 1262–1278. https://doi.org/10.1002/hep.30917

    Article  CAS  PubMed  Google Scholar 

  17. Jafari, M., Dadras, F., Ghadimipour, H. R., Rabiei, M. A. S., & Khoshjou, F. (2017). Tempol effect on epithelial-mesenchymal transition induced by hyperglycemia. Journal of Nephropathology, 6(1), 1.

    Article  PubMed  Google Scholar 

  18. Suarez-Carmona, M., Lesage, J., Cataldo, D., & Gilles, C. (2017). EMT and inflammation: Inseparable actors of cancer progression. Molecular Oncology, 11(7), 805–823. https://doi.org/10.1002/1878-0261.12095

    Article  PubMed  PubMed Central  Google Scholar 

  19. Grande, M. T., Sanchez-Laorden, B., Lopez-Blau, C., De Frutos, C. A., Boutet, A., Arevalo, M., & Nieto, M. A. (2015). Snail1-induced partial epithelial-to-mesenchymal transition drives renal fibrosis in mice and can be targeted to reverse established disease. Nature Medicine, 21(9), 989–997. https://doi.org/10.1038/nm.3901

    Article  CAS  PubMed  Google Scholar 

  20. Sun, Z., Ji, N., Ma, Q., Zhu, R., Chen, Z., Wang, Z., Qian, Y., Wu, C., Hu, F., Huang, M., & Zhang, M. (2020). Epithelial-Mesenchymal transition in asthma airway remodeling is regulated by the IL-33/CD146 Axis. Frontiers in Immunology, 11, 1598. https://doi.org/10.3389/fimmu.2020.01598

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Liu, J., Mao, W., Ding, B., & Liang, C. S. (2008). ERKs/p53 signal transduction pathway is involved in doxorubicin-induced apoptosis in H9c2 cells and cardiomyocytes. American Journal of Physiology. Heart and Circulatory Physiology, 295(5), H1956-1965. https://doi.org/10.1152/ajpheart.00407.2008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Zhang, D. X., Ma, D. Y., Yao, Z. Q., Fu, C. Y., Shi, Y. X., Wang, Q. L., & Tang, Q. Q. (2016). ERK1/2/p53 and NF-kappaB dependent-PUMA activation involves in doxorubicin-induced cardiomyocyte apoptosis. Eur Rev Med Pharmacol Sci, 20(11), 2435–2442.

    PubMed  Google Scholar 

  23. El-Agamy, D. S., El-Harbi, K. M., Khoshhal, S., Ahmed, N., Elkablawy, M. A., Shaaban, A. A., & Abo-Haded, H. M. (2019). Pristimerin protects against doxorubicin-induced cardiotoxicity and fibrosis through modulation of Nrf2 and MAPK/NF-kB signaling pathways. Cancer Manag Res, 11, 47–61. https://doi.org/10.2147/CMAR.S186696

    Article  CAS  PubMed  Google Scholar 

  24. Imam, F., Al-Harbi, N. O., Khan, M. R., Qamar, W., Alharbi, M., Alshamrani, A. A., Alhamami, H. N., Alsaleh, N. B., & Alharbi, K. S. (2020). Protective effect of RIVA against Sunitinib-induced cardiotoxicity by inhibiting oxidative stress-mediated inflammation: probable role of TGF-beta and smad signaling. Cardiovascular Toxicology, 20(3), 281–290. https://doi.org/10.1007/s12012-019-09551-8

    Article  CAS  PubMed  Google Scholar 

  25. Kabel, A. M., & Elkhoely, A. A. (2017). Targeting proinflammatory cytokines, oxidative stress, TGF-beta1 and STAT-3 by rosuvastatin and ubiquinone to ameliorate trastuzumab cardiotoxicity. Biomedicine & Pharmacotherapy, 93, 17–26. https://doi.org/10.1016/j.biopha.2017.06.033

    Article  CAS  Google Scholar 

  26. Fuxe, J., & Karlsson, M. C. (2012). TGF-beta-induced epithelial-mesenchymal transition: A link between cancer and inflammation. Seminars in Cancer Biology, 22(5–6), 455–461. https://doi.org/10.1016/j.semcancer.2012.05.004

    Article  CAS  PubMed  Google Scholar 

  27. Alaaeldin, R., Ali, F. E., Bekhit, A. A., Zhao, Q.-L., & Fathy, M. (2022). Inhibition of NF-kB/IL-6/JAK2/STAT3 pathway and epithelial-mesenchymal transition in breast cancer cells by azilsartan. Molecules, 27(22), 7825.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Poursani, E. M., Mercatelli, D., Raninga, P., Bell, J. L., Saletta, F., Kohane, F. V., Zheng, Y., Rouaen, J., Jue, T. R., Michniewicz, F. T., & Kasiou, E. (2022). Copper chelation inhibits TGF-β pathways and suppresses epithelial-mesenchymal transition in cancer. biorxiv, 9(2), 112.

    Google Scholar 

  29. Wang, F., Wang, L., Jiao, Y., & Wang, Z. (2020). Qishen Huanwu capsule reduces pirarubicin-induced cardiotoxicity in rats by activating the PI3K/Akt/mTOR pathway. Annals of Palliative Medicine, 9(5), 3453–3461. https://doi.org/10.21037/apm-20-1746

    Article  PubMed  Google Scholar 

  30. Wang, X., Wang, Q., Li, W., Zhang, Q., Jiang, Y., Guo, D., Sun, X., Lu, W., Li, C., & Wang, Y. (2020). TFEB-NF-kappaB inflammatory signaling axis: A novel therapeutic pathway of Dihydrotanshinone I in doxorubicin-induced cardiotoxicity. Journal of Experimental & Clinical Cancer Research, 39(1), 93. https://doi.org/10.1186/s13046-020-01595-x

    Article  CAS  Google Scholar 

  31. Amiri, M. (2018). Oxidative stress and free radicals in liver and kidney diseases; an updated short-review. Journal of Nephropathology, 7, 3.

    Google Scholar 

  32. Phan, T. H. G., Paliogiannis, P., Nasrallah, G. K., Giordo, R., Eid, A. H., Fois, A. G., Zinellu, A., Mangoni, A. A., & Pintus, G. (2021). Emerging cellular and molecular determinants of idiopathic pulmonary fibrosis. Cellular and Molecular Life Sciences, 78(5), 2031–2057. https://doi.org/10.1007/s00018-020-03693-7

    Article  CAS  PubMed  Google Scholar 

  33. Kartini, D., Taher, A., Panigoro, S. S., Setiabudy, R., Jusman, S. W., Haryana, S. M., Murdani, A., Rustamadji, P., Karisyah, A., & Rasyid, S. H. (2021). Melatonin effect on hypoxia inducible factor-1α and clinical response in patients with oral squamous cell carcinoma receiving neoadjuvant chemotherapy: A randomized controlled trial. Journal of Carcinogenesis. https://doi.org/10.4103/jcar.JCar_19_20

    Article  PubMed  PubMed Central  Google Scholar 

  34. Lage, R., Cebro-Marquez, M., Rodriguez-Manero, M., Gonzalez-Juanatey, J. R., & Moscoso, I. (2019). Omentin protects H9c2 cells against docetaxel cardiotoxicity. PLoS One, 14(2), e0212782. https://doi.org/10.1371/journal.pone.0212782

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Giannoni, E., Parri, M., & Chiarugi, P. (2012). EMT and oxidative stress: A bidirectional interplay affecting tumor malignancy. Antioxidants & Redox Signaling, 16(11), 1248–1263. https://doi.org/10.1089/ars.2011.4280

    Article  CAS  Google Scholar 

  36. Shete, M. V., Deshmukh, R. S., Kulkarni, T., Shete, A. V., Karande, P., & Hande, P. (2020). Myofibroblasts as important diagnostic and prognostic indicators of oral squamous cell carcinoma: An immunohistochemical study in normal oral mucosa, epithelial dysplasia, and oral squamous cell carcinoma. Journal of Carcinogenesis. https://doi.org/10.4103/jcar.JCar_3_20

    Article  PubMed  PubMed Central  Google Scholar 

  37. Chatterjee, R., & Chatterjee, J. (2020). ROS and oncogenesis with special reference to EMT and stemness. Eur J Cell Biol, 99(2–3), 151073. https://doi.org/10.1016/j.ejcb.2020.151073

    Article  CAS  PubMed  Google Scholar 

  38. Kong, D., Zhang, Z., Chen, L., Huang, W., Zhang, F., Wang, L., Wang, Y., Cao, P., & Zheng, S. (2020). Curcumin blunts epithelial-mesenchymal transition of hepatocytes to alleviate hepatic fibrosis through regulating oxidative stress and autophagy. Redox Biol, 36, 101600. https://doi.org/10.1016/j.redox.2020.101600

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Arjuna, S., Chakraborty, G., Venkataram, R., Dechamma, P. N., & Chakraborty, A. (2020). Detection of epidermal growth factor receptor T790M mutation by allele-specific loop mediated isothermal amplification. Journal of Carcinogenesis, 19.

  40. Huang, G., Yang, L., Zhou, W., Tang, X., Wang, Y., Ma, Z., Gao, S., & Gao, Y. (2018). Study on cardiotoxicity and mechanism of “Fuzi” extracts based on metabonomics. International Journal of Molecular Sciences. https://doi.org/10.3390/ijms19113506

    Article  PubMed  PubMed Central  Google Scholar 

  41. Gondo, H. K. (2021). The effect of spirulina on apoptosis through the caspase-3 pathway in a Preeclamptic Wistar rat model. Journal of Natural Science, Biology and Medicine, 12(3), 280–284.

    CAS  Google Scholar 

  42. Yarmohammadi, F., Hayes, A. W., & Karimi, G. (2021). Natural compounds against cytotoxic drug-induced cardiotoxicity: A review on the involvement of PI3K/Akt signaling pathway. J Biochem Mol Toxicol, 35(3), e22683. https://doi.org/10.1002/jbt.22683

    Article  CAS  PubMed  Google Scholar 

  43. Zhao, D., Yang, J., & Yang, L. (2017). Insights for oxidative stress and mTOR signaling in myocardial ischemia/reperfusion injury under diabetes. Oxidative Medicine and Cellular Longevity, 2017, 6437467. https://doi.org/10.1155/2017/6437467

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Song, Y., Zhang, W., Zhang, J., You, Z., Hu, T., Shao, G., Zhang, Z., Xu, Z., & Yu, X. (2021). TWIST2 inhibits EMT and induces oxidative stress in lung cancer cells by regulating the FGF21-mediated AMPK/mTOR pathway. Experimental cell research, 405(1), 112661. https://doi.org/10.1016/j.yexcr.2021.112661

    Article  CAS  PubMed  Google Scholar 

  45. Chan, B. Y. H., Roczkowsky, A., Cho, W. J., Poirier, M., Sergi, C., Keschrumrus, V., Churko, J. M., Granzier, H., & Schulz, R. (2021). MMP inhibitors attenuate doxorubicin cardiotoxicity by preventing intracellular and extracellular matrix remodelling. Cardiovascular Research, 117(1), 188–200. https://doi.org/10.1093/cvr/cvaa017

    Article  CAS  PubMed  Google Scholar 

  46. Rabinovich-Nikitin, I., Love, M., & Kirshenbaum, L. A. (2021). Inhibition of MMP prevents doxorubicin-induced cardiotoxicity by attenuating cardiac intracellular and extracellular matrix remodelling. Cardiovascular Research, 117(1), 11–12. https://doi.org/10.1093/cvr/cvaa198

    Article  CAS  PubMed  Google Scholar 

  47. Baroroh, H. N., Nugroho, A. E., Lukitaningsih, E., & Nurrochmad, A. (2021). Immune-enhancing effect of bengkoang (Pachyrhizus erosus (L.) Urban) fiber fractions on mouse peritoneal macrophages, lymphocytes, and cytokines. Journal of Natural Science, Biology and Medicine, 12(1), 84–92.

    Article  CAS  Google Scholar 

  48. Kang, M. K., Kim, S. I., Oh, S. Y., Na, W., & Kang, Y. H. (2020). Tangeretin ameliorates glucose-induced podocyte injury through blocking epithelial to mesenchymal transition caused by oxidative stress and hypoxia. International Journal of Molecular Sciences. https://doi.org/10.3390/ijms21228577

    Article  PubMed  PubMed Central  Google Scholar 

  49. Das, N. A., Carpenter, A. J., Belenchia, A., Aroor, A. R., Noda, M., Siebenlist, U., Chandrasekar, B., & DeMarco, V. G. (2020). Empagliflozin reduces high glucose-induced oxidative stress and miR-21-dependent TRAF3IP2 induction and RECK suppression, and inhibits human renal proximal tubular epithelial cell migration and epithelial-to-mesenchymal transition. Cell Signal, 68, 109506. https://doi.org/10.1016/j.cellsig.2019.109506

    Article  CAS  PubMed  Google Scholar 

  50. Chen, Q. M., & Maltagliati, A. J. (2018). Nrf2 at the heart of oxidative stress and cardiac protection. Physiological Genomics, 50(2), 77–97. https://doi.org/10.1152/physiolgenomics.00041.2017

    Article  CAS  PubMed  Google Scholar 

  51. Tonelli, C., Chio, I. I. C., & Tuveson, D. A. (2018). Transcriptional regulation by Nrf2. Antioxidants & Redox Signaling, 29(17), 1727–1745. https://doi.org/10.1089/ars.2017.7342

    Article  CAS  Google Scholar 

  52. Wang, J., Zhu, H., Huang, L., Zhu, X., Sha, J., Li, G., Ma, G., Zhang, W., Gu, M., & Guo, Y. (2019). Nrf2 signaling attenuates epithelial-to-mesenchymal transition and renal interstitial fibrosis via PI3K/Akt signaling pathways. Experimental and Molecular Pathology, 111, 104296. https://doi.org/10.1016/j.yexmp.2019.104296

    Article  CAS  PubMed  Google Scholar 

  53. Jin, M., Wang, J., Ji, X., Cao, H., Zhu, J., Chen, Y., Yang, J., Zhao, Z., Ren, T., & Xing, J. (2019). MCUR1 facilitates epithelial-mesenchymal transition and metastasis via the mitochondrial calcium dependent ROS/Nrf2/Notch pathway in hepatocellular carcinoma. Journal of Experimental & Clinical Cancer Research, 38(1), 136. https://doi.org/10.1186/s13046-019-1135-x

    Article  Google Scholar 

  54. Feng, R., Morine, Y., Ikemoto, T., Imura, S., Iwahashi, S., Saito, Y., & Shimada, M. (2018). Nrf2 activation drive macrophages polarization and cancer cell epithelial-mesenchymal transition during interaction. Cell Communication and Signaling: CCS, 16(1), 54. https://doi.org/10.1186/s12964-018-0262-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Zhao, L., Qi, Y., Xu, L., Tao, X., Han, X., Yin, L., & Peng, J. (2018). MicroRNA-140-5p aggravates doxorubicin-induced cardiotoxicity by promoting myocardial oxidative stress via targeting Nrf2 and Sirt2. Redox Biology, 15, 284–296. https://doi.org/10.1016/j.redox.2017.12.013

    Article  CAS  PubMed  Google Scholar 

  56. Jiang, B. H., & Liu, L. Z. (2008). PI3K/PTEN signaling in tumorigenesis and angiogenesis. Biochimica et Biophysica Acta, 1784(1), 150–158. https://doi.org/10.1016/j.bbapap.2007.09.008

    Article  CAS  PubMed  Google Scholar 

  57. Mashouri, L., Yousefi, H., Aref, A. R., Ahadi, A. M., Molaei, F., & Alahari, S. K. (2019). Exosomes: Composition, biogenesis, and mechanisms in cancer metastasis and drug resistance. Molecular Cancer, 18(1), 75. https://doi.org/10.1186/s12943-019-0991-5

    Article  PubMed  PubMed Central  Google Scholar 

  58. Mohammadi, H., & Ashari, S. (2021). Mechanistic insight into toxicity of phthalates, the involved receptors, and the role of Nrf2, NF-kappaB, and PI3K/AKT signaling pathways. Environmental Science and Pollution Research International, 28(27), 35488–35527. https://doi.org/10.1007/s11356-021-14466-5

    Article  CAS  PubMed  Google Scholar 

  59. Cheng, S., Zhang, X., Feng, Q., Chen, J., Shen, L., Yu, P., Yang, L., Chen, D., Zhang, H., Sun, W., & Chen, X. (2019). Astragaloside IV exerts angiogenesis and cardioprotection after myocardial infarction via regulating PTEN/PI3K/Akt signaling pathway. Life Sciences, 227, 82–93. https://doi.org/10.1016/j.lfs.2019.04.040

    Article  CAS  PubMed  Google Scholar 

  60. Chung, C. (2020). From oxygen sensing to angiogenesis: Targeting the hypoxia signaling pathway in metastatic kidney cancer. American Journal of Health System Pharmacy, 77(24), 2064–2073. https://doi.org/10.1093/ajhp/zxaa308

    Article  PubMed  Google Scholar 

  61. Soni, H., Pandya, G., Patel, P., Acharya, A., Jain, M., & Mehta, A. A. (2011). Beneficial effects of carbon monoxide-releasing molecule-2 (CORM-2) on acute doxorubicin cardiotoxicity in mice: Role of oxidative stress and apoptosis. Toxicology and Applied Pharmacology, 253(1), 70–80. https://doi.org/10.1016/j.taap.2011.03.013

    Article  CAS  PubMed  Google Scholar 

  62. Ma, W., Zhang, X., & Liu, Y. (2021). miR-124 promotes apoptosis and inhibits the proliferation of vessel endothelial cells through P38/MAPK and PI3K/AKT pathways, making it a potential mechanism of vessel endothelial injury in acute myocardial infarction. Experimental and Therapeutic Medicine, 22(6), 1383. https://doi.org/10.3892/etm.2021.10819

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Bi, Q. R., Hou, J. J., Qi, P., Ma, C. H., Feng, R. H., Yan, B. P., Wang, J. W., Shi, X. J., Zheng, Y. Y., Wu, W. Y., & Guo, D. A. (2016). TXNIP/TRX/NF-kappaB and MAPK/NF-kappaB pathways involved in the cardiotoxicity induced by Venenum Bufonis in rats. Science and Reports, 6, 22759. https://doi.org/10.1038/srep22759

    Article  CAS  Google Scholar 

  64. Cao, Y., Ruan, Y., Shen, T., Huang, X., Li, M., Yu, W., Zhu, Y., Man, Y., Wang, S., & Li, J. (2014). Astragalus polysaccharide suppresses doxorubicin-induced cardiotoxicity by regulating the PI3k/Akt and p38MAPK pathways. Oxid Med Cell Longev. https://doi.org/10.1155/2014/674219

    Article  PubMed  PubMed Central  Google Scholar 

  65. Gallego, I., Beaumont, J., López, B., Ravassa, S., Gómez-Doblas, J. J., Moreno, M. U., Valencia, F., de Teresa, E., Díez, J., & González, A. (2016). Potential role of microRNA-10b down-regulation in cardiomyocyte apoptosis in aortic stenosis patients. Clinical Science (London, England), 130(23), 2139–2149. https://doi.org/10.1042/CS20160462

    Article  CAS  Google Scholar 

  66. Kalantary-Charvadeh, A., Sanajou, D., Hemmati-Dinarvand, M., Marandi, Y., Khojastehfard, M., Hajipour, H., Mehran, M. A., Leila, R., & Ahmad, N. S. (2019). Micheliolide protects against doxorubicin-induced cardiotoxicity in mice by regulating PI3K/Akt/NF-kB signaling pathway. Cardiovascular Toxicology, 19(4), 297–305. https://doi.org/10.1007/s12012-019-09511-2

    Article  CAS  PubMed  Google Scholar 

  67. Hassanein, E. H. M., Abd El-Ghafar, O. A. M., Ahmed, M. A., Sayed, A. M., Gad-Elrab, W. M., Ajarem, J. S., & Mahmoud, A. M. (2020). Edaravone and acetovanillone upregulate Nrf2 and PI3K/Akt/mTOR signaling and prevent cyclophosphamide cardiotoxicity in rats. Drug Design, Development and Therapy, 14, 5275–5288. https://doi.org/10.2147/DDDT.S281854

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Sun, L., Wang, H., Xu, D., Yu, S., Zhang, L., & Li, X. (2022). Lapatinib induces mitochondrial dysfunction to enhance oxidative stress and ferroptosis in doxorubicin-induced cardiomyocytes via inhibition of PI3K/AKT signaling pathway. Bioengineered, 13(1), 48–60. https://doi.org/10.1080/21655979.2021.2004980

    Article  CAS  PubMed  Google Scholar 

  69. Yu, W., Qin, X., Zhang, Y., Qiu, P., Wang, L., Zha, W., & Ren, J. (2020). Curcumin suppresses doxorubicin-induced cardiomyocyte pyroptosis via a PI3K/Akt/mTOR-dependent manner. Cardiovascular Diagnosis and Therapy, 10(4), 752–769. https://doi.org/10.21037/cdt-19-707

    Article  PubMed  PubMed Central  Google Scholar 

  70. Scheau, C., Badarau, I. A., Costache, R., Caruntu, C., Mihai, G. L., Didilescu, A. C., Constantin, C., & Neagu, M. (2019). The role of matrix metalloproteinases in the epithelial-mesenchymal transition of hepatocellular carcinoma. Analytical Cellular Pathology (Amsterdam), 2019, 9423907. https://doi.org/10.1155/2019/9423907

    Article  CAS  PubMed  Google Scholar 

  71. Schanza, L. M., Seles, M., Stotz, M., Fosselteder, J., Hutterer, G. C., Pichler, M., & Stiegelbauer, V. (2017). MicroRNAs associated with von hippel-lindau pathway in renal cell carcinoma: a comprehensive review. International Journal of Molecular Sciences. https://doi.org/10.3390/ijms18112495

    Article  PubMed  PubMed Central  Google Scholar 

  72. Skala, M., Hanouskova, B., Skalova, L., & Matouskova, P. (2019). MicroRNAs in the diagnosis and prevention of drug-induced cardiotoxicity. Archives of Toxicology, 93(1), 1–9. https://doi.org/10.1007/s00204-018-2356-z

    Article  CAS  PubMed  Google Scholar 

  73. Pan, J. A., Tang, Y., Yu, J. Y., Zhang, H., Zhang, J. F., Wang, C. Q., & Gu, J. (2019). miR-146a attenuates apoptosis and modulates autophagy by targeting TAF9b/P53 pathway in doxorubicin-induced cardiotoxicity. Cell Death & Disease, 10(9), 668. https://doi.org/10.1038/s41419-019-1901-x

    Article  CAS  Google Scholar 

  74. Vosgha, H., Ariana, A., Smith, R. A., & Lam, A. K. (2018). miR-205 targets angiogenesis and EMT concurrently in anaplastic thyroid carcinoma. Endocrine-Related Cancer, 25(3), 323–337. https://doi.org/10.1530/ERC-17-0497

    Article  CAS  PubMed  Google Scholar 

  75. Chakraborti, S., Pramanick, A., Saha, S., Roy, S. S., Chaudhuri, A. R., Das, M., Ghosh, S., Stewart, A., & Maity, B. (2018). Atypical G protein beta5 promotes cardiac oxidative stress, apoptosis, and fibrotic remodeling in response to multiple cancer chemotherapeutics. Cancer Research, 78(2), 528–541. https://doi.org/10.1158/0008-5472.CAN-17-1280

    Article  CAS  PubMed  Google Scholar 

  76. Iqubal, A., Iqubal, M. K., Sharma, S., Ansari, M. A., Najmi, A. K., Ali, S. M., Ali, J., & Haque, S. E. (2019). Molecular mechanism involved in cyclophosphamide-induced cardiotoxicity: Old drug with a new vision. Life Sciences, 218, 112–131. https://doi.org/10.1016/j.lfs.2018.12.018

    Article  CAS  PubMed  Google Scholar 

  77. Ren, X., Zhao, B., Chang, H., Xiao, M., Wu, Y., & Liu, Y. (2018). Paclitaxel suppresses proliferation and induces apoptosis through regulation of ROS and the AKT/MAPK signaling pathway in canine mammary gland tumor cells. Molecular Medicine Reports, 17(6), 8289–8299. https://doi.org/10.3892/mmr.2018.8868

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Oh, E. T., Kim, C. W., Kim, S. J., Lee, J. S., Hong, S. S., & Park, H. J. (2016). Docetaxel induced-JNK2/PHD1 signaling pathway increases degradation of HIF-1α and causes cancer cell death under hypoxia. Science and Reports, 6, 27382. https://doi.org/10.1038/srep27382

    Article  CAS  Google Scholar 

  79. Zhang, X., Shao, J., Li, X., Cui, L., & Tan, Z. (2019). Docetaxel promotes cell apoptosis and decreases SOX2 expression in CD133expressing hepatocellular carcinoma stem cells by suppressing the PI3K/AKT signaling pathway. Oncology Reports, 41(2), 1067–1074. https://doi.org/10.3892/or.2018.6891

    Article  CAS  PubMed  Google Scholar 

  80. Sadek, K. M., Mahmoud, S. F. E., Zeweil, M. F., & Abouzed, T. K. (2021). Proanthocyanidin alleviates doxorubicin-induced cardiac injury by inhibiting NF-kB pathway and modulating oxidative stress, cell cycle, and fibrogenesis. Journal of Biochemical and Molecular Toxicology, 35(4), e22716. https://doi.org/10.1002/jbt.22716

    Article  CAS  PubMed  Google Scholar 

  81. Xu, J., Liu, D., Niu, H., Zhu, G., Xu, Y., Ye, D., Li, J., & Zhang, Q. (2017). Resveratrol reverses Doxorubicin resistance by inhibiting epithelial-mesenchymal transition (EMT) through modulating PTEN/Akt signaling pathway in gastric cancer. Journal of Experimental & Clinical Cancer Research, 36(1), 19. https://doi.org/10.1186/s13046-016-0487-8

    Article  CAS  Google Scholar 

  82. Kitani, T., Ong, S. G., Lam, C. K., Rhee, J. W., Zhang, J. Z., Oikonomopoulos, A., Ma, N., Tian, L., Lee, J., Telli, M. L., Witteles, R. M., Sharma, A., Sayed, N., & Wu, J. C. (2019). Human-induced pluripotent stem cell model of trastuzumab-induced cardiac dysfunction in patients with breast cancer. Circulation, 139(21), 2451–2465. https://doi.org/10.1161/CIRCULATIONAHA.118.037357

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Roukos, D. H. (2011). Trastuzumab and beyond: Sequencing cancer genomes and predicting molecular networks. The Pharmacogenomics Journal, 11(2), 81–92. https://doi.org/10.1038/tpj.2010.81

    Article  CAS  PubMed  Google Scholar 

  84. Huang, Z., Hu, Z., Ouyang, J., & Huang, C. (2019). Electroacupuncture regulates the DREAM/NF-kappaB signalling pathway and ameliorates cyclophosphamide-induced immunosuppression in mice. Acupuncture in Medicine, 37(5), 292–300. https://doi.org/10.1136/acupmed-2017-011593

    Article  CAS  PubMed  Google Scholar 

  85. Chen, X., Wei, W., Li, Y., Huang, J., & Ci, X. (2019). Hesperetin relieves cisplatin-induced acute kidney injury by mitigating oxidative stress, inflammation and apoptosis. Chemico-Biological Interactions, 308, 269–278. https://doi.org/10.1016/j.cbi.2019.05.040

    Article  CAS  PubMed  Google Scholar 

  86. Ma, W., Wei, S., Zhang, B., & Li, W. (2020). Molecular mechanisms of cardiomyocyte death in drug-induced cardiotoxicity. Front Cell Dev Biol, 8, 434. https://doi.org/10.3389/fcell.2020.00434

    Article  PubMed  PubMed Central  Google Scholar 

  87. Zhang, P., Yi, L. H., Meng, G. Y., Zhang, H. Y., Sun, H. H., & Cui, L. Q. (2017). Apelin-13 attenuates cisplatin-induced cardiotoxicity through inhibition of ROS-mediated DNA damage and regulation of MAPKs and AKT pathways. Free Radical Research, 51(5), 449–459. https://doi.org/10.1080/10715762.2017.1313414

    Article  CAS  PubMed  Google Scholar 

  88. Li, J.-P., Liu, Y.-J., Zeng, S.-H., Gao, H.-J., Chen, Y.-G., & Zou, X. (2022). Identification of COX4I2 as a hypoxia-associated gene acting through FGF1 to promote EMT and angiogenesis in CRC. Cellular & Molecular Biology Letters, 27(1), 76. https://doi.org/10.1186/s11658-022-00380-2

    Article  CAS  Google Scholar 

  89. Li, P., Liu, X., Xing, W., Qiu, H., Li, R., Liu, S., & Sun, H. (2022). Exosome-derived miR-200a promotes esophageal cancer cell proliferation and migration via the mediating Keap1 expression. Molecular and Cellular Biochemistry, 477(4), 1295–1308. https://doi.org/10.1007/s11010-022-04353-z

    Article  CAS  PubMed  Google Scholar 

  90. Xia, W., Chen, H., Xie, C., & Hou, M. (2020). Long-noncoding RNA MALAT1 sponges microRNA-92a-3p to inhibit doxorubicin-induced cardiac senescence by targeting ATG4a. Aging (Albany NY), 12(9), 8241–8260. https://doi.org/10.18632/aging.103136

    Article  CAS  PubMed  Google Scholar 

  91. Gallo, S., Sala, V., Gatti, S., & Crepaldi, T. (2015). Cellular and molecular mechanisms of HGF/Met in the cardiovascular system. Clinical Science (London, England), 129(12), 1173–1193. https://doi.org/10.1042/cs20150502

    Article  CAS  Google Scholar 

  92. Jiao, D., Wang, J., Lu, W., Tang, X., Chen, J., Mou, H., & Chen, Q. Y. (2016). Curcumin inhibited HGF-induced EMT and angiogenesis through regulating c-Met dependent PI3K/Akt/mTOR signaling pathways in lung cancer. Mol Ther Oncolytics, 3, 16018. https://doi.org/10.1038/mto.2016.18

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Chen, J., Yuan, W., Wu, L., Tang, Q., Xia, Q., Ji, J., Liu, Z., Ma, Z., Zhou, Z., Cheng, Y., & Shu, X. (2017). PDGF-D promotes cell growth, aggressiveness, angiogenesis and EMT transformation of colorectal cancer by activation of Notch1/Twist1 pathway. Oncotarget., 8(6), 9961–9973. https://doi.org/10.18632/oncotarget.14283

    Article  PubMed  Google Scholar 

  94. Mansour, H. H., El Kiki, S. M., Ibrahim, A. B., & Omran, M. M. (2021). Effect of l-carnitine on cardiotoxicity and apoptosis induced by imatinib through PDGF/ PPARγ /MAPK pathways. Archives of biochemistry and biophysics, 704, 108866. https://doi.org/10.1016/j.abb.2021.108866

    Article  CAS  PubMed  Google Scholar 

  95. Gonzalez-Moreno, O., Lecanda, J., Green, J. E., Segura, V., Catena, R., Serrano, D., & Calvo, A. (2010). VEGF elicits epithelial-mesenchymal transition (EMT) in prostate intraepithelial neoplasia (PIN)-like cells via an autocrine loop. Experimental Cell Research, 316(4), 554–567. https://doi.org/10.1016/j.yexcr.2009.11.020

    Article  CAS  PubMed  Google Scholar 

  96. Räsänen, M., Degerman, J., Nissinen, T. A., Miinalainen, I., Kerkelä, R., Siltanen, A., Backman, J. T., Mervaala, E., Hulmi, J. J., Kivelä, R., & Alitalo, K. (2016). VEGF-B gene therapy inhibits doxorubicin-induced cardiotoxicity by endothelial protection. Proceedings of the National Academy of Sciences, 113(46), 13144–13149. https://doi.org/10.1073/pnas.1616168113

    Article  CAS  Google Scholar 

  97. Shen, X., Hu, X., Mao, J., Wu, Y., Liu, H., Shen, J., Yu, J., & Chen, W. (2020). The long noncoding RNA TUG1 is required for TGF-β/TWIST1/EMT-mediated metastasis in colorectal cancer cells. Cell death & disease, 11(1), 65. https://doi.org/10.1038/s41419-020-2254-1

    Article  CAS  Google Scholar 

  98. Xu, Y., Zhou, J., Lv, G., Liu, Y., Zhao, X., Li, X., Ye, D., Qu, X., & Huang, X. (2020). Effect of Pilose Antler peptide on doxorubicin-induced H9c2 cells Injury via TGF-β/Smad/ERK signaling pathway. Pakistan Journal of Zoology, 52(5), 1787.

    Article  CAS  Google Scholar 

  99. Liu, C., Xue, J., Xu, B., Zhang, A., Qin, L., Liu, J., & Yang, Y. (2021). Exosomes derived from miR-146a-5p-enriched mesenchymal stem cells protect the cardiomyocytes and myocardial tissues in the polymicrobial sepsis through regulating MYBL1. Stem Cells Int, 2021, 1530445. https://doi.org/10.1155/2021/1530445

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Meng, Q., Liang, C., Hua, J., Zhang, B., Liu, J., Zhang, Y., Wei, M., Yu, X., Xu, J., & Shi, S. (2020). A miR-146a-5p/TRAF6/NF-kB p65 axis regulates pancreatic cancer chemoresistance: Functional validation and clinical significance. Theranostics, 10(9), 3967–3979. https://doi.org/10.7150/thno.40566

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Hu, X., Liu, H., Wang, Z., Hu, Z., & Li, L. (2019). miR-200a Attenuated doxorubicin-induced cardiotoxicity through upregulation of Nrf2 in mice. Oxidative Medicine and Cellular Longevity, 2019, 1512326. https://doi.org/10.1155/2019/1512326

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Chen, C., Zhou, Y., Ding, P., & He, L. (2021). miR-1 targeted downregulation of Bcl-2 increases chemosensitivity of lung cancer cells. Genetic Testing and Molecular Biomarkers, 25(8), 540–545. https://doi.org/10.1089/gtmb.2021.0009

    Article  CAS  PubMed  Google Scholar 

  103. Wu, J., Sun, C., Wang, R., Li, J., Zhou, M., Yan, M., Xue, X., & Wang, C. (2018). Cardioprotective effect of paeonol against epirubicin-induced heart injury via regulating miR-1 and PI3K/AKT pathway. Chemico-Biological Interactions, 286, 17–25. https://doi.org/10.1016/j.cbi.2018.02.035

    Article  CAS  PubMed  Google Scholar 

  104. Wu, Y., Pu, N., Su, W., Yang, X., & Xing, C. (2020). Downregulation of miR-1 in colorectal cancer promotes radioresistance and aggressive phenotypes. Journal of Cancer, 11(16), 4832–4840. https://doi.org/10.7150/jca.44753

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Lin, F., Yin, H. B., Li, X. Y., Zhu, G. M., He, W. Y., & Gou, X. (2020). Bladder cancer cellsecreted exosomal miR21 activates the PI3K/AKT pathway in macrophages to promote cancer progression. International Journal of Oncology, 56(1), 151–164. https://doi.org/10.3892/ijo.2019.4933

    Article  CAS  PubMed  Google Scholar 

  106. Tong, Z., Jiang, B., Wu, Y., Liu, Y., Li, Y., Gao, M., Jiang, Y., Lv, Q., & Xiao, X. (2015). MiR-21 protected cardiomyocytes against doxorubicin-induced apoptosis by targeting BTG2. International Journal of Molecular Sciences, 16(7), 14511–14525. https://doi.org/10.3390/ijms160714511

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Guo, D., Guo, J., Li, X., & Guan, F. (2018). Enhanced motility and proliferation by miR-10b/FUT8/p-AKT axis in breast cancer cells. Oncology Letters, 16(2), 2097–2104. https://doi.org/10.3892/ol.2018.8891

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Lin, C. C., Yang, T. Y., Lu, H. J., Wan, C. K., Hsu, S. L., & Wu, C. C. (2021). Attenuating role of withaferin A in the proliferation and migration of lung cancer cells via a p53-miR-27a/miR-10b pathway. Oncology Letters, 21(3), 232. https://doi.org/10.3892/ol.2021.12493

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Bian, W. S., Shi, P. X., Mi, X. F., Sun, Y. Y., Yang, D. D., Gao, B. F., Wu, S. X., & Fan, G. C. (2018). MiR-210 protects cardiomyocytes from OGD/R injury by inhibiting E2F3. Eur Rev Med Pharmacol Sci, 22(3), 743–749. https://doi.org/10.26355/eurrev_201802_14305

    Article  PubMed  Google Scholar 

  110. Yang, F., Yan, Y., Yang, Y., Hong, X., Wang, M., Yang, Z., Liu, B., & Ye, L. (2020). MiR-210 in exosomes derived from CAFs promotes non-small cell lung cancer migration and invasion through PTEN/PI3K/AKT pathway. Cell Signal, 73, 109675. https://doi.org/10.1016/j.cellsig.2020.109675

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We wish thank you of all our colleague in IRAN university of medical science.

Author information

Authors and Affiliations

  1. Department of Cardiology, School of Medicine, Atherosclerosis Research Center, Golestan Hospital, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

    Ali Kardooni

  2. Shiraz University of Medical Science, Shiraz, Iran

    Aida Bahrampour

  3. Department of Internal Medicine, School of Medicine, Iran University of Medical Sciences, Tehran, Iran

    Somaye Golmohammadi

  4. Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACER, Tehran, Iran

    Arsalan Jalili

  5. Parvaz Research Ideas Supporter Institute, Tehran, Iran

    Arsalan Jalili

  6. Islamic Azad University, Tehran Medical Branch, Tehran, Iran

    Mohammad Mobin Alishahi

Authors
  1. Ali Kardooni
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Aida Bahrampour
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Somaye Golmohammadi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Arsalan Jalili
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mohammad Mobin Alishahi
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

MMA: has conceived the manuscript and revised it. AB and AJ: wrote the manuscript. AK and AB: revise the manuscript. SG: edited manuscript English language.

Corresponding author

Correspondence to Mohammad Mobin Alishahi.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical Approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kardooni, A., Bahrampour, A., Golmohammadi, S. et al. The Role of Epithelial Mesenchymal Transition (EMT) in Pathogenesis of Cardiotoxicity: Diagnostic & Prognostic Approach. Mol Biotechnol 65, 1403–1413 (2023). https://doi.org/10.1007/s12033-023-00697-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12033-023-00697-z

Keywords

Search

Navigation