The Evaluation of the N-cadherin Promoter’s ability to Block EMT by Specific Expression of Diphtheria Toxin in EMT-induced A549 Cell Lines
-
Zohreh Mehmandoostli
,
Mahmood Dehghani Ashkezari
,
Seyed Morteza Seifati
,
Vida Sadeghi
,
Reza Falak
,
Gholam Ali Kardar
Abstract
During epithelial to mesenchymal transition, the ability of cancer cells to transform and metastasize is primarily determined by N-cadherin-mediated migration and invasion. This study aimed to evaluate whether the N-cadherin promoter can induce diphtheria toxin expression as a suicide gene in epithelial to mesenchymal transition (EMT)-induced cancer cells and whether this can be used as potential gene therapy.
To investigate the expression of diphtheria toxin under the N-cadherin promoter, the promoter was synthesized, and was cloned upstream of diphtheria toxin in a pGL3-Basic vector. The A-549 cells was transfected by electroporation. After induction of EMT by TGF-β and hypoxia treatment, the relative expression of diphtheria toxin, mesenchymal genes such as N-cadherin and Vimentin, and epithelial genes such as E-cadherin and β-catenin were measured by real-time PCR. MTT assay was also performed to measure cytotoxicity. Finally, cell motility was assessed by the Scratch test.
After induction of EMT in transfected cells, the expression of mesenchymal markers such as Vimentin and N-cadherin significantly decreased, and the expression of β-catenin increased. In addition, the MTT assay showed promising toxicity results after induction of EMT with TGF-β in transfected cells, but toxicity was less effective in hypoxia. The scratch test results also showed that cell movement was successfully prevented in EMT-transfected cells and thus confirmed EMT occlusion.
Our findings indicate that by using structures containing diphtheria toxin downstream of a specific EMT promoter such as the N-cadherin promoter, the introduced toxin can kill specifically and block EMT in cancer cells.
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2. Davis AM, Scott TA, Morris KV. Harnessing Rift Valley fever virus NSs gene for cancer gene therapy Cancer Gene Ther. 2022:1-10.
3. Hay ED. An overview of epithelio-mesenchymal transformation. Cells Tissues Organs. 1995;154(1):8-20.
4. Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial–mesenchymal transition. Nat Rev Mol Cell Biol. 2014;15(3):178-96.
5. Thiery JP. Epithelial–mesenchymal transitions in tumour progression. Nat Rev Cancer. 2002;2(6):442-54.
6. Tsai JH, Donaher JL, Murphy DA, Chau S, Yang J. Spatiotemporal regulation of epithelial-mesenchymal transition is essential for squamous cell carcinoma metastasis. Cancer cell. 2012;22(6):725-36.
7. Ocaña OH, Córcoles R, Fabra Á, Moreno-Bueno G, Acloque H, Vega S, et al. Metastatic colonization requires the repression of the epithelial-mesenchymal transition inducer Prrx1. Cancer cell. 2012;22(6):709-24.
8. Gupta S, Shetty DC, Gulati N, Juneja S, Jain A. Potentiated action on the progression of OSMF by hypoxia mediated signaling pathway by the epithelial mesenchymal transition and angiogenic apparatus. J Cancer Res Ther. 2023.
9. Mendik P, Kerestély M, Kamp S, Deritei D, Kunšič N, Vassy Z, et al. Translocating proteins compartment-specifically alter the fate of epithelial-mesenchymal transition in a compartmentalized Boolean network model. NPJ Syst Biol Appl. 2022;9(8):1-19.
10. Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest. 2009;119(6):1420-8.
11. Chui MH. Insights into cancer metastasis from a clinicopathologic perspective: Epithelial‐Mesenchymal Transition is not a necessary step. Int J Cancer. 2013;132(7):1487-95.
12. Bill R, Christofori G. The relevance of EMT in breast cancer metastasis: Correlation or causality? FEBS letters. 2015;589(14):1577-87.
13. Lu X, Kang Y. Hypoxia and Hypoxia-Inducible Factors: Master Regulators of MetastasisHypoxia and HIFs in Cancer Metastasis. Clini Cancer Res. 2010;16(24):5928-35.
14. Yang M-H, Wu M-Z, Chiou S-H, Chen P-M, Chang S-Y, Liu C-J, et al. Direct regulation of TWIST by HIF-1α promotes metastasis. Nat Cell Biol. 2008;10:295.
15. Ryan HE, Lo J, Johnson RS. HIF-1 alpha is required for solid tumor formation and embryonic vascularization. EMBO J. 1998;17(11):3005-15.
16. Chen ZF, Behringer RR. twist is required in head mesenchyme for cranial neural tube morphogenesis. Genes Dev. 1995;9(6):686-99.
17. Wu MZ, Tsai YP, Yang MH, Huang CH, Chang SY, Chang CC, et al. Interplay between HDAC3 and WDR5 is essential for hypoxia-induced epithelial-mesenchymal transition. Mol Cell. 2011;43(5):811-22.
18. Kitami K, Yoshihara M, Tamauchi S, Sugiyama M, Koya Y, Yamakita Y, et al. Peritoneal restoration by repurposing vitamin D inhibits ovarian cancer dissemination via blockade of the TGF-β1/thrombospondin-1 axis. Matrix Biol. 2022;109:70-90.
19. Wan CC, Nisar MF, Wu H. Pharmacological Activities of Natural Products through the TGF-β Signalling Pathway. Evid Based Complement Alternat Med. 2022; 2022: 9823258.
20. Seoane J, Gomis RR. TGF-β family signaling in tumor suppression and cancer progression. Cold Spring Harb Perspect Biol. 2017;9(12):a022277.
21. Shafiee F, Aucoin MG, Jahanian-Najafabadi A. Targeted diphtheria toxin-based therapy: a review article. Front Microbiol. 2019;10:2340.
22. Krueger KM, Barbieri JT. The family of bacterial ADP-ribosylating exotoxins. Clin Microbiol Rev. 1995;8(1):34-47.
23. Wolf P, Elsässer-Beile U. Pseudomonas exotoxin A: from virulence factor to anti-cancer agent. Int J Med Microbiol. 2009;299(3):161-76.
24. Mateyak MK, Kinzy TG. ADP-ribosylation of translation elongation factor 2 by diphtheria toxin in yeast inhibits translation and cell separation. J Biol Chemistry. 2013;288(34):24647-55.
25. Gofrit ON, Benjamin S, Halachmi S, Leibovitch I, Dotan Z, Lamm DL, et al. DNA based therapy with diphtheria toxin-A BC-819: a phase 2b marker lesion trial in patients with intermediate risk nonmuscle invasive bladder cancer. J Urol. 2014;191(6):1697-702.
26. Asrorov AM, Muhitdinov B, Tu B, Mirzaakhmedov S, Wang H, Huang Y. Advances on Delivery of Cytotoxic Enzymes as Anticancer Agents. Molecules. 2022;27(12):3836.
27. Markiewicz A, Topa J, Nagel A, Skokowski J, Seroczynska B, Stokowy T, et al. Spectrum of epithelial-mesenchymal transition phenotypes in circulating tumour cells from early breast cancer patients. Cancers. 2019;11(1):59.
28. Brown MS, Muller KE, Pattabiraman DR. Quantifying the epithelial-to-mesenchymal transition (EMT) from bench to bedside. Cancers. 2022;14(5):1138.
29. Falgàs A, Garcia-León A, Núñez Y, Serna N, Sánchez-Garcia L, Unzueta U, et al. A diphtheria toxin-based nanoparticle achieves specific cytotoxic effect on CXCR4+ lymphoma cells without toxicity in immunocompromised and immunocompetent mice. Biomed Pharmacother. 2022;150:112940.
30. Shajari S, Farajollahi MM, Behdani M, Tarighi P. Production and Conjugation of Truncated Recombinant Diphtheria Toxin to VEGFR-2 Specific Nanobody and Evaluation of its Cytotoxic Effect on PC-3 Cell Line. Mol Biotechnol. 2022:1-9.
31. Ohana P, Bibi O, Matouk I, Levy C, Birman T, Ariel I, et al. Use of H19 regulatory sequences for targeted gene therapy in cancer. Int J Cancer. 2002;98(5):645-50.
32. Lavie O, Edelman D, Levy T, Fishman A, Hubert A, Segev Y, et al. A phase 1/2a, dose-escalation, safety, pharmacokinetic, and preliminary efficacy study of intraperitoneal administration of BC-819 (H19-DTA) in subjects with recurrent ovarian/peritoneal cancer. Arch Gynecol Obstet. 2017;295(3):751-61.
33. Hine CM, Seluanov A, Gorbunova V. Rad51 promoter-targeted gene therapy is effective for in vivo visualization and treatment of cancer. Mol Ther. 2012;20(2):347-55.
34. Chen C, Yue D, Lei L, Wang H, Lu J, Zhou Y, et al. Promoter-operating targeted expression of gene therapy in cancer: current stage and prospect. Mol Ther Nucleic Acids. 2018;11:508-14.
35. Cao Y, Xu Y, Zhang L, Li Z, Jiang Y, Tian X, et al. Utilization of Rad51C promoter for transcriptional targeting of cancer cells. Oncotarget. 2014;5(7):1805.
36. Lin B, Gao A, Zhang R, Ma H, Shen H, Hu Q, et al. Use of a novel integrase-deficient lentivirus for targeted anti-cancer therapy with survivin promoter-driven diphtheria toxin A. Medicine. 2015;94(31).
37. Alkharabsheh O, Frankel AE. Clinical activity and tolerability of SL-401 (Tagraxofusp): recombinant diphtheria toxin and interleukin-3 in hematologic malignancies. Biomedicines. 2019;7(1):6.
38. Aruna G. Immunotoxins: a review of their use in cancer treatment . J Stem Cells Regen Med. 2006;1(1):31.
39. Donaghy H, editor Effects of antibody, drug and linker on the preclinical and clinical toxicities of antibody-drug conjugates. MAbs. 2016;8(4):659-71.
40. Gholami MD, Falak R, Heidari S, Khoshmirsafa M, Kazemi MH, Zarnani A-H, et al. A truncated snail1 transcription factor alters the expression of essential EMT markers and suppresses tumor cell migration in a human lung cancer cell line. Recent Pat Anticancer Drug Discov. 2019;14(2):158-69.
41. Steeg PS, Theodorescu D. Metastasis: a therapeutic target for cancer. Nat Clin Practice Oncol. 2008;5(4):206-19.
42. Sidi AA, Ohana P, Benjamin S, Shalev M, Ransom JH, Lamm D, et al. Phase I/II marker lesion study of intravesical BC-819 DNA plasmid in H19 over expressing superficial bladder cancer refractory to bacillus Calmette-Guerin. J Urol. 2008;180(6):2379-83.
43. Zhang D-M, Lin Z-Y, Yang Z-H, Wang Y-Y, Wan D, Zhong J-L, et al. IncRNA H19 promotes tongue squamous cell carcinoma progression through β-catenin/GSK3β/EMT signaling via association with EZH2. Am J Translat Res. 2017;9(7):3474.
44. Mizrahi A, Czerniak A, Ohana P, Amiur S, Gallula J, Matouk I, et al. Treatment of ovarian cancer ascites by intra-peritoneal injection of diphtheria toxin A chain-H19 vector: a case report. Journal of Med Case Rep. 2010;4(1):1-5.
45. Watson-Hurst K, Becker D. The role of N-Cadherin, MCAM, and β3 integrin in melanoma progression, proliferation, migration and invasion. Cancer Biol Ther. 2006;5(10):1375-82.
46. Fu J, Qin L, He T, Qin J, Hong J, Wong J, et al. The TWIST/Mi2/NuRD protein complex and its essential role in cancer metastasis. Cell Res. 2011;21(2):275-89.
47. Kim Y-N, Koo KH, Sung JY, Yun U-J, Kim H. Anoikis Resistance: An Essential Prerequisite for Tumor Metastasis. Int J Cell Biol. 2012;2012:306879.
48. Matouk IJ, Raveh E, Abu-lail R, Mezan S, Gilon M, Gershtain E, et al. Oncofetal H19 RNA promotes tumor metastasis. Biochim Biophys Acta. 2014;1843(7):1414-26.
49. Singh A, Settleman J. EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene. 2010;29(34):4741-51.
50. Caja L, Bertran E, Campbell J, Fausto N, Fabregat I. The transforming growth factor‐beta (TGF‐β) mediates acquisition of a mesenchymal stem cell‐like phenotype in human liver cells. J Cell Physiol. 2011;226(5):1214-23.
51. Yang M-H, Wu M-Z, Chiou S-H, Chen P-M, Chang S-Y, Liu C-J, et al. Direct regulation of TWIST by HIF-1α promotes metastasis. Nat Cell Biolo. 2008;10(3):295-305.
52. Thiery JP, Boyer B. The junction between cytokines and cell adhesion. Curr Opin Cell Biol. 1992;4(5):782-92.
53. Alexander NR, Tran NL, Rekapally H, Summers CE, Glackin C, Heimark RL. N-cadherin gene expression in prostate carcinoma is modulated by integrin-dependent nuclear translocation of Twist1. Cancer Res. 2006;66(7):3365-9.
54. Gholami MD, Falak R, Heidari S, Khoshmirsafa M, Kazemi MH, Zarnani A-H, et al. A truncated snail1 transcription factor alters the expression of essential EMT markers and suppresses tumor cell migration in a human lung cancer cell line. Recent Pat Anticancer Drug Discov. 2019;14(2):158-69
55. Kurnit KC, Draisey A, Kazen RC, Chung C, Phan LH, Harvey JB, et al. Loss of CD73 shifts transforming growth factor-β1 (TGF-β1) from tumor suppressor to promoter in endometrial cancer. Cancer Lett. 2021;505:75-86.
56. Sadeghi F, Kardar GA, Bolouri MR, Nasri F, Sadri M, Falak R. Overexpression of bHLH domain of HIF-1 failed to inhibit the HIF-1 transcriptional activity in hypoxia. Biol Res. 2020;53(1):1-11.
57. Sullivan LB, Chandel NS. Mitochondrial reactive oxygen species and cancer. Cancer Meta. 2014;2(1):1-12.
58. Gupta R, Chetty C, Bhoopathi P, Lakka S, Mohanam S, Rao JS, et al. Downregulation of uPA/uPAR inhibits intermittent hypoxia-induced epithelial-mesenchymal transition (EMT) in DAOY and D283 medulloblastoma cells. Int J Oncol. 2011;38(3):733-44.
59. Ko H, So Y, Jeon H, Jeong M-H, Choi H-K, Ryu S-H, et al. TGF-β1-induced epithelial–mesenchymal transition and acetylation of Smad2 and Smad3 are negatively regulated by EGCG in human A549 lung cancer cells. Cancer lett. 2013;335(1):205-13.
60. Sheppard D. Transforming growth factor β: a central modulator of pulmonary and airway inflammation and fibrosis. Proc Am Thorac Soc. 2006;3(5):413-7.
61. Li C, Song L, Zhang Z, Bai X-X, Cui M-F, Ma L-J. MicroRNA-21 promotes TGF-β1-induced epithelial-mesenchymal transition in gastric cancer through up-regulating PTEN expression. Oncotarget. 2016;7(41):66989.
2. Davis AM, Scott TA, Morris KV. Harnessing Rift Valley fever virus NSs gene for cancer gene therapy Cancer Gene Ther. 2022:1-10.
3. Hay ED. An overview of epithelio-mesenchymal transformation. Cells Tissues Organs. 1995;154(1):8-20.
4. Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial–mesenchymal transition. Nat Rev Mol Cell Biol. 2014;15(3):178-96.
5. Thiery JP. Epithelial–mesenchymal transitions in tumour progression. Nat Rev Cancer. 2002;2(6):442-54.
6. Tsai JH, Donaher JL, Murphy DA, Chau S, Yang J. Spatiotemporal regulation of epithelial-mesenchymal transition is essential for squamous cell carcinoma metastasis. Cancer cell. 2012;22(6):725-36.
7. Ocaña OH, Córcoles R, Fabra Á, Moreno-Bueno G, Acloque H, Vega S, et al. Metastatic colonization requires the repression of the epithelial-mesenchymal transition inducer Prrx1. Cancer cell. 2012;22(6):709-24.
8. Gupta S, Shetty DC, Gulati N, Juneja S, Jain A. Potentiated action on the progression of OSMF by hypoxia mediated signaling pathway by the epithelial mesenchymal transition and angiogenic apparatus. J Cancer Res Ther. 2023.
9. Mendik P, Kerestély M, Kamp S, Deritei D, Kunšič N, Vassy Z, et al. Translocating proteins compartment-specifically alter the fate of epithelial-mesenchymal transition in a compartmentalized Boolean network model. NPJ Syst Biol Appl. 2022;9(8):1-19.
10. Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest. 2009;119(6):1420-8.
11. Chui MH. Insights into cancer metastasis from a clinicopathologic perspective: Epithelial‐Mesenchymal Transition is not a necessary step. Int J Cancer. 2013;132(7):1487-95.
12. Bill R, Christofori G. The relevance of EMT in breast cancer metastasis: Correlation or causality? FEBS letters. 2015;589(14):1577-87.
13. Lu X, Kang Y. Hypoxia and Hypoxia-Inducible Factors: Master Regulators of MetastasisHypoxia and HIFs in Cancer Metastasis. Clini Cancer Res. 2010;16(24):5928-35.
14. Yang M-H, Wu M-Z, Chiou S-H, Chen P-M, Chang S-Y, Liu C-J, et al. Direct regulation of TWIST by HIF-1α promotes metastasis. Nat Cell Biol. 2008;10:295.
15. Ryan HE, Lo J, Johnson RS. HIF-1 alpha is required for solid tumor formation and embryonic vascularization. EMBO J. 1998;17(11):3005-15.
16. Chen ZF, Behringer RR. twist is required in head mesenchyme for cranial neural tube morphogenesis. Genes Dev. 1995;9(6):686-99.
17. Wu MZ, Tsai YP, Yang MH, Huang CH, Chang SY, Chang CC, et al. Interplay between HDAC3 and WDR5 is essential for hypoxia-induced epithelial-mesenchymal transition. Mol Cell. 2011;43(5):811-22.
18. Kitami K, Yoshihara M, Tamauchi S, Sugiyama M, Koya Y, Yamakita Y, et al. Peritoneal restoration by repurposing vitamin D inhibits ovarian cancer dissemination via blockade of the TGF-β1/thrombospondin-1 axis. Matrix Biol. 2022;109:70-90.
19. Wan CC, Nisar MF, Wu H. Pharmacological Activities of Natural Products through the TGF-β Signalling Pathway. Evid Based Complement Alternat Med. 2022; 2022: 9823258.
20. Seoane J, Gomis RR. TGF-β family signaling in tumor suppression and cancer progression. Cold Spring Harb Perspect Biol. 2017;9(12):a022277.
21. Shafiee F, Aucoin MG, Jahanian-Najafabadi A. Targeted diphtheria toxin-based therapy: a review article. Front Microbiol. 2019;10:2340.
22. Krueger KM, Barbieri JT. The family of bacterial ADP-ribosylating exotoxins. Clin Microbiol Rev. 1995;8(1):34-47.
23. Wolf P, Elsässer-Beile U. Pseudomonas exotoxin A: from virulence factor to anti-cancer agent. Int J Med Microbiol. 2009;299(3):161-76.
24. Mateyak MK, Kinzy TG. ADP-ribosylation of translation elongation factor 2 by diphtheria toxin in yeast inhibits translation and cell separation. J Biol Chemistry. 2013;288(34):24647-55.
25. Gofrit ON, Benjamin S, Halachmi S, Leibovitch I, Dotan Z, Lamm DL, et al. DNA based therapy with diphtheria toxin-A BC-819: a phase 2b marker lesion trial in patients with intermediate risk nonmuscle invasive bladder cancer. J Urol. 2014;191(6):1697-702.
26. Asrorov AM, Muhitdinov B, Tu B, Mirzaakhmedov S, Wang H, Huang Y. Advances on Delivery of Cytotoxic Enzymes as Anticancer Agents. Molecules. 2022;27(12):3836.
27. Markiewicz A, Topa J, Nagel A, Skokowski J, Seroczynska B, Stokowy T, et al. Spectrum of epithelial-mesenchymal transition phenotypes in circulating tumour cells from early breast cancer patients. Cancers. 2019;11(1):59.
28. Brown MS, Muller KE, Pattabiraman DR. Quantifying the epithelial-to-mesenchymal transition (EMT) from bench to bedside. Cancers. 2022;14(5):1138.
29. Falgàs A, Garcia-León A, Núñez Y, Serna N, Sánchez-Garcia L, Unzueta U, et al. A diphtheria toxin-based nanoparticle achieves specific cytotoxic effect on CXCR4+ lymphoma cells without toxicity in immunocompromised and immunocompetent mice. Biomed Pharmacother. 2022;150:112940.
30. Shajari S, Farajollahi MM, Behdani M, Tarighi P. Production and Conjugation of Truncated Recombinant Diphtheria Toxin to VEGFR-2 Specific Nanobody and Evaluation of its Cytotoxic Effect on PC-3 Cell Line. Mol Biotechnol. 2022:1-9.
31. Ohana P, Bibi O, Matouk I, Levy C, Birman T, Ariel I, et al. Use of H19 regulatory sequences for targeted gene therapy in cancer. Int J Cancer. 2002;98(5):645-50.
32. Lavie O, Edelman D, Levy T, Fishman A, Hubert A, Segev Y, et al. A phase 1/2a, dose-escalation, safety, pharmacokinetic, and preliminary efficacy study of intraperitoneal administration of BC-819 (H19-DTA) in subjects with recurrent ovarian/peritoneal cancer. Arch Gynecol Obstet. 2017;295(3):751-61.
33. Hine CM, Seluanov A, Gorbunova V. Rad51 promoter-targeted gene therapy is effective for in vivo visualization and treatment of cancer. Mol Ther. 2012;20(2):347-55.
34. Chen C, Yue D, Lei L, Wang H, Lu J, Zhou Y, et al. Promoter-operating targeted expression of gene therapy in cancer: current stage and prospect. Mol Ther Nucleic Acids. 2018;11:508-14.
35. Cao Y, Xu Y, Zhang L, Li Z, Jiang Y, Tian X, et al. Utilization of Rad51C promoter for transcriptional targeting of cancer cells. Oncotarget. 2014;5(7):1805.
36. Lin B, Gao A, Zhang R, Ma H, Shen H, Hu Q, et al. Use of a novel integrase-deficient lentivirus for targeted anti-cancer therapy with survivin promoter-driven diphtheria toxin A. Medicine. 2015;94(31).
37. Alkharabsheh O, Frankel AE. Clinical activity and tolerability of SL-401 (Tagraxofusp): recombinant diphtheria toxin and interleukin-3 in hematologic malignancies. Biomedicines. 2019;7(1):6.
38. Aruna G. Immunotoxins: a review of their use in cancer treatment . J Stem Cells Regen Med. 2006;1(1):31.
39. Donaghy H, editor Effects of antibody, drug and linker on the preclinical and clinical toxicities of antibody-drug conjugates. MAbs. 2016;8(4):659-71.
40. Gholami MD, Falak R, Heidari S, Khoshmirsafa M, Kazemi MH, Zarnani A-H, et al. A truncated snail1 transcription factor alters the expression of essential EMT markers and suppresses tumor cell migration in a human lung cancer cell line. Recent Pat Anticancer Drug Discov. 2019;14(2):158-69.
41. Steeg PS, Theodorescu D. Metastasis: a therapeutic target for cancer. Nat Clin Practice Oncol. 2008;5(4):206-19.
42. Sidi AA, Ohana P, Benjamin S, Shalev M, Ransom JH, Lamm D, et al. Phase I/II marker lesion study of intravesical BC-819 DNA plasmid in H19 over expressing superficial bladder cancer refractory to bacillus Calmette-Guerin. J Urol. 2008;180(6):2379-83.
43. Zhang D-M, Lin Z-Y, Yang Z-H, Wang Y-Y, Wan D, Zhong J-L, et al. IncRNA H19 promotes tongue squamous cell carcinoma progression through β-catenin/GSK3β/EMT signaling via association with EZH2. Am J Translat Res. 2017;9(7):3474.
44. Mizrahi A, Czerniak A, Ohana P, Amiur S, Gallula J, Matouk I, et al. Treatment of ovarian cancer ascites by intra-peritoneal injection of diphtheria toxin A chain-H19 vector: a case report. Journal of Med Case Rep. 2010;4(1):1-5.
45. Watson-Hurst K, Becker D. The role of N-Cadherin, MCAM, and β3 integrin in melanoma progression, proliferation, migration and invasion. Cancer Biol Ther. 2006;5(10):1375-82.
46. Fu J, Qin L, He T, Qin J, Hong J, Wong J, et al. The TWIST/Mi2/NuRD protein complex and its essential role in cancer metastasis. Cell Res. 2011;21(2):275-89.
47. Kim Y-N, Koo KH, Sung JY, Yun U-J, Kim H. Anoikis Resistance: An Essential Prerequisite for Tumor Metastasis. Int J Cell Biol. 2012;2012:306879.
48. Matouk IJ, Raveh E, Abu-lail R, Mezan S, Gilon M, Gershtain E, et al. Oncofetal H19 RNA promotes tumor metastasis. Biochim Biophys Acta. 2014;1843(7):1414-26.
49. Singh A, Settleman J. EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene. 2010;29(34):4741-51.
50. Caja L, Bertran E, Campbell J, Fausto N, Fabregat I. The transforming growth factor‐beta (TGF‐β) mediates acquisition of a mesenchymal stem cell‐like phenotype in human liver cells. J Cell Physiol. 2011;226(5):1214-23.
51. Yang M-H, Wu M-Z, Chiou S-H, Chen P-M, Chang S-Y, Liu C-J, et al. Direct regulation of TWIST by HIF-1α promotes metastasis. Nat Cell Biolo. 2008;10(3):295-305.
52. Thiery JP, Boyer B. The junction between cytokines and cell adhesion. Curr Opin Cell Biol. 1992;4(5):782-92.
53. Alexander NR, Tran NL, Rekapally H, Summers CE, Glackin C, Heimark RL. N-cadherin gene expression in prostate carcinoma is modulated by integrin-dependent nuclear translocation of Twist1. Cancer Res. 2006;66(7):3365-9.
54. Gholami MD, Falak R, Heidari S, Khoshmirsafa M, Kazemi MH, Zarnani A-H, et al. A truncated snail1 transcription factor alters the expression of essential EMT markers and suppresses tumor cell migration in a human lung cancer cell line. Recent Pat Anticancer Drug Discov. 2019;14(2):158-69
55. Kurnit KC, Draisey A, Kazen RC, Chung C, Phan LH, Harvey JB, et al. Loss of CD73 shifts transforming growth factor-β1 (TGF-β1) from tumor suppressor to promoter in endometrial cancer. Cancer Lett. 2021;505:75-86.
56. Sadeghi F, Kardar GA, Bolouri MR, Nasri F, Sadri M, Falak R. Overexpression of bHLH domain of HIF-1 failed to inhibit the HIF-1 transcriptional activity in hypoxia. Biol Res. 2020;53(1):1-11.
57. Sullivan LB, Chandel NS. Mitochondrial reactive oxygen species and cancer. Cancer Meta. 2014;2(1):1-12.
58. Gupta R, Chetty C, Bhoopathi P, Lakka S, Mohanam S, Rao JS, et al. Downregulation of uPA/uPAR inhibits intermittent hypoxia-induced epithelial-mesenchymal transition (EMT) in DAOY and D283 medulloblastoma cells. Int J Oncol. 2011;38(3):733-44.
59. Ko H, So Y, Jeon H, Jeong M-H, Choi H-K, Ryu S-H, et al. TGF-β1-induced epithelial–mesenchymal transition and acetylation of Smad2 and Smad3 are negatively regulated by EGCG in human A549 lung cancer cells. Cancer lett. 2013;335(1):205-13.
60. Sheppard D. Transforming growth factor β: a central modulator of pulmonary and airway inflammation and fibrosis. Proc Am Thorac Soc. 2006;3(5):413-7.
61. Li C, Song L, Zhang Z, Bai X-X, Cui M-F, Ma L-J. MicroRNA-21 promotes TGF-β1-induced epithelial-mesenchymal transition in gastric cancer through up-regulating PTEN expression. Oncotarget. 2016;7(41):66989.
| Files | ||
| Issue | Vol 23 No 2 (2024) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijaai.v23i2.15327 | |
| Keywords | ||
| Cancer Diphtheria toxin Epithelial-mesenchymal transition N-cadherin Promoter | ||
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How to Cite
1.
Mehmandoostli Z, Dehghani Ashkezari M, Seifati SM, Sadeghi V, Falak R, Kardar GA. The Evaluation of the N-cadherin Promoter’s ability to Block EMT by Specific Expression of Diphtheria Toxin in EMT-induced A549 Cell Lines. Iran J Allergy Asthma Immunol. 2024;23(2):220-230.
