Volume 24, Issue 5 (9-2020)                   IBJ 2020, 24(5): 269-280 | Back to browse issues page


XML Print


Download citation:
BibTeX | RIS | EndNote | Medlars | ProCite | Reference Manager | RefWorks
Send citation to:

Najafi S M A. The Canonical Wnt Signaling (Wnt/β-Catenin Pathway): A Potential Target for Cancer Prevention and Therapy. IBJ 2020; 24 (5) :269-280
URL: http://ibj.pasteur.ac.ir/article-1-3114-en.html
Abstract:  
Precise regulation of signal transduction pathways is crucial for normal animal development and for maintaining cellular and tissue homeostasis in adults. The Wnt/Frizzled-mediated signaling includes canonical and non-canonical signal transduction pathways. Upregulation or downregulation of the canonical Wnt signaling (or the Wnt/β-Catenin signal transduction) leads to a variety of human diseases, including cancers, neurodegenerative disorders, skin and bone diseases, and heart deficiencies. Therefore, Wnt/β-Catenin signal transduction is a potential clinical target for the treatment of not only human cancers but also some other human chronic diseases. Here, some recent results including those from my laboratory highlighting the role of Wnt/β-Catenin signal transduction in human cancers will be reviewed. After a brief overview on canonical Wnt signaling and introducing some critical β-Catenin/T-cell factor-target genes, the interaction of canonical Wnt signaling with some common human cancers will be discussed. In the end, the different segments of the aforesaid signaling pathway, which have been considered as targets for clinical purposes, will be scrutinized.
Type of Study: Review Article | Subject: Related Fields

References
1. Komiya, Habas R. Wnt signal transduction pathways. Organogenesis 2008; 4(2): 68-75. [DOI:10.4161/org.4.2.5851]
2. Rao TP, Kühl M. An updated overview on Wnt signaling pathways: A prelude for more. Circulation research 2010; 106(12):1798-1806. [DOI:10.1161/CIRCRESAHA.110.219840]
3. Peifer M, Rauskolb C, Williams M, Riggleman B, Wieschaus E. The segment polarity gene armadillo interacts with the wingless signaling pathway in both embryonic and adult pattern formation. Development 1991; 111(4):1029-1043.
4. Noordermeer J, Klingensmith J, Perrimon N, Nusse R. Dishevelled and Armadillo act in the wingless signalling pathway in Drosophila. Nature 1994; 367(6458): 80-83. [DOI:10.1038/367080a0]
5. Clevers H, Nusse R. Wnt/β-Catenin signaling and disease. Cell 2012; 149(6): 1192-1205. [DOI:10.1016/j.cell.2012.05.012]
6. Nusse R, Clevers H. Wnt/β -Catenin signaling, disease, and emerging therapeutic modalities. Cell 2017; 169(6): 985-999. [DOI:10.1016/j.cell.2017.05.016]
7. Katoh M. Canonical and non-canonical WNT signaling in cancer stem cells and their niches: Cellular heterogeneity, omics reprogramming, targeted therapy and tumor plasticity. International journal of oncology 2017; 51(5): 1357-1369. [DOI:10.3892/ijo.2017.4129]
8. Zhan T, Rindtorff N, Boutros M. Wnt signaling in cancer. Oncogene 2017; 36(11):1461-1473. [DOI:10.1038/onc.2016.304]
9. Staal FJT, Famili F, Perez LG, Pike-Overzet K. Aberrant Wnt signaling in leukemia. Cancer 2016; 8(9): 78. [DOI:10.3390/cancers8090078]
10. Nusse R, Varmus HE. Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome. Cell 1982; 31(1): 99-109. [DOI:10.1016/0092-8674(82)90409-3]
11. Nusse R, van Ooyen A, Cox D, Fung YK, Varmus HE. Mode of proviral activation of a putative mammary oncogene (int-1) on mouse chromosome 15. Nature 1984; 307 (5947): 131-136. [DOI:10.1038/307131a0]
12. Zeng G, Awan F, Otruba W, Muller P, Apte U, Tan X, Gandhi C, Demetris AJ, Monga SP. Wnt'er in liver: Expression of Wnt and Frizzled genes in mouse. Hepatology 2007; 45(1): 195-204. [DOI:10.1002/hep.21473]
13. Okamoto M, Udagawa N, Uehara S, Maeda K, Yamashita T, Nakamichi Y, Kato H, Saito N, Minami Y, Takahashi N, Kobayashi Y. Noncanonical Wnt5a enhances Wnt/β-catenin signaling during osteo-blastogenesis. Scientific reports 2014; 4: 4493. [DOI:10.1038/srep04493]
14. Ji TH, Grossman M, Ji I. G Protein-coupled receptors: Diversity of receptor-ligand interactions. Journal of biological chemistry 1998; 273(28): 17299-17302. [DOI:10.1074/jbc.273.28.17299]
15. Najafi SM. Activators of G proteins inhibit GSK-3beta and stabilize beta-catenin in xenopus oocytes. Biochemical and biophysical research communications 2009; 382(2): 365-369. [DOI:10.1016/j.bbrc.2009.03.027]
16. Salmanian S, Najafi SM, Rafipour M, Arjomand MR, Shahheydari H, Ansari S, Kashkooli L, Rasouli SJ, Saghaeian Jazi M, Minaei T. Regulation of GSK-3beta and beta-Catenin by Galphaq in HEK293T cells. Biochemical and biophysical research communications 2010; 395(4): 577-582. [DOI:10.1016/j.bbrc.2010.04.087]
17. Slusarski DC, Yang-Snyder J, Busa WB, Moon RT. Modulation of embryonic intracellular Ca2/signaling by Wnt-5A. Developmental biology 1997; 182 (1): 114-120. [DOI:10.1006/dbio.1996.8463]
18. Katanaev VL, Ponzielli R, Sémériva M, Tomlinson A. Trimeric G protein-dependent frizzled signaling in Drosophila. Cell 2005; 120(1): 111-122. [DOI:10.1016/j.cell.2004.11.014]
19. Koval A, Purvanov V, Egger-Adam D, Katanaev VL. Yellow submarine of the Wnt/Frizzled signaling: Submerging from the G protein harbor to the targets. Biochemical Pharmacology 2011; 82(10): 1311-1319. [DOI:10.1016/j.bcp.2011.06.005]
20. Egger-Adam D, Katanaev VL. Trimeric G protein-dependent signaling by frizzled receptors in animal development. Frontiers in bioscience 2008; 13: 4740-4755. [DOI:10.2741/3036]
21. Nichols AS, Floyd DH, Bruinsma SP, Narzinski K, Baranski TJ. Frizzled receptors signal through G-proteins. Cellular signalling 2013; 25(6): 1468-1475. [DOI:10.1016/j.cellsig.2013.03.009]
22. Turm H, Grisaru-Granvosky S, Maoz M, Offermanns S, Bar-Shavit R. DVL as a scaffold protein capturing classical GPCRs. Communicative and integrative biology 2010; 3(6): 495-498. [DOI:10.4161/cib.3.6.12979]
23. Feng Q, Gao N. Keeping Wnt signalosome in check by vesicular traffic. Journal of cellular physiology 2015; 230(6): 1170-1180. [DOI:10.1002/jcp.24853]
24. Rahmani M, Carthy JM, McManus BM. Mapping of the Wnt/β-catenin/TCF response elements in the human versican promoter. Methods in molecular biology 2012; 836: 35-52. [DOI:10.1007/978-1-61779-498-8_3]
25. Kang Y, Massague J. Epithelial-mesenchymal transitions: Twist in development and metastasis. Cell 2004; 118(3): 277-279. [DOI:10.1016/j.cell.2004.07.011]
26. Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nature reviews cancer 2002; 2(6): 442-454. [DOI:10.1038/nrc822]
27. Malumbres M, Barbacid M. To cycle or not to cycle: a critical decision in cancer. Nature reviews cancer 2001; 1(3): 222-231. [DOI:10.1038/35106065]
28. Silvia Lapenna S, Giordano A. Cell cycle kinases as therapeutic targets for cancer. Nature reviews drug discovery 2009; 8(7): 547-566. [DOI:10.1038/nrd2907]
29. Blagosklonny MV, Pardee AB. The restriction point of the cell cycle. Cell cycle 2002; 1(2): 103-110. [DOI:10.4161/cc.1.2.108]
30. Miller DM, Thomas SD, Islam A, Muench D, Sedoris K. c-Myc and cancer metabolism. Clinical cancer research 2012; 18(20): 5546-5553. [DOI:10.1158/1078-0432.CCR-12-0977]
31. Dang CV, Resar LM, Emison E, Kim S, Li Q, Prescott JE, Wonsey D, Zeller K. Function of the c-Myc oncogenic transcription factor. Experimental cell research 1999; 253(1): 63-77. [DOI:10.1006/excr.1999.4686]
32. Kumari A, Folk WP, Sakamuro D. The dual roles of MYC in genomic instability and cancer chemoresistance. Genes 2017; 8(6): E158. [DOI:10.3390/genes8060158]
33. Kawasaki Y, Komiya M, Matsumura K, Negishi L, Suda S, Okuno M, Yokota N, Osada T, Nagashima T, Hiyoshi M, OkadaHatakeyama M, Kitayama J, Shirahige K, Akiyama T. MYU, a target lncRNA for Wnt/c-Myc signaling, mediates induction of CDK6 to promote cell cycle progression. Cell reports 2016; 16(10): 2554-2564. [DOI:10.1016/j.celrep.2016.08.015]
34. Wisdom R, Johnson RS, Moore C. c-Jun regulates cell cycle progression and apoptosis by distinct mechanisms. EMBO journal 1999; 18: 188-197. [DOI:10.1093/emboj/18.1.188]
35. Gustems M, Woellmer A, Rothbauer U. Eck SH, Wieland T, Lutter D, Hammerschmidt W. c-Jun/c-Fos heterodimers regulate cellular genes via a newly identified class of methylated DNA sequence motifs. Nucleic acids research 2014; 42(5): 3059-3072. [DOI:10.1093/nar/gkt1323]
36. Schreiber M, Kolbus A, Piu F, Szabowski A, Möhle-Steinlein U, Tian J, Karin M, Angel P, Wagner EF. Control of cell cycle progression by c-Jun is p53 dependent. Genes and development 1999; 13(5): 607-619. [DOI:10.1101/gad.13.5.607]
37. Polistena A, Cucina A, Dinicola S, Stene C, Cavallaro G, Ciardi A, Gennaro O, Rossella A, Giuseppe D, Antonino C, Louis Banka J, Giorgio DT. MMP7 expression in colorectal tumours of different stages. In vivo 2014; 28(1): 105-110.
38. Slusarz A, Nichols LA, Grunz-Borgmann EA, Chen G, Akintola AD, Catania JM, Burghardt RC, Trzeciakowski JP, Parrish AR. Overexpression of MMP-7 increases collagen 1A2 in the aging kidney. Physiological reports. 2013; 1(5): pii e00090. [DOI:10.1002/phy2.90]
39. Basu S, Thorat R, Dalal SN. MMP7 is required to mediate cell invasion and tumor formation upon Plakophilin3 loss. PLoS one 2015; 10(4): e0123979. [DOI:10.1371/journal.pone.0123979]
40. Pryczynicz A, Gryko M, Niewiarowska K, Dymicka-Piekarska V, Ustymowicz M, Hawryluk M. CEpowicz D,Borsuk A,Lemona A,Fa,ulski W,Guzinska- Ustymowicz.Immunohistochemical expression of MMP-7 protein and its serum level in colorectal cancer. Folia histochemistry cytobiologica 2013; 51(3): 206-212. [DOI:10.5603/FHC.2013.0029]
41. Senger DR, Gallil SJ, Dvorak AM, Perruzzi CA, Harvey VS, Dvorak HF. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 1983; 219 (4587): 983-985. [DOI:10.1126/science.6823562]
42. Lee SH, Jeong D, Han YS, Baek MJ. Pivotal role of vascular endothelial growth factor pathway in tumor angiogenesis. Annals of surgical treatment and research 2015; 89(1): 1-8. [DOI:10.4174/astr.2015.89.1.1]
43. Bendardaf R, Buhmeida A, Hilska M, Laato M, Syrjänen S, Syrjänen K, Collan Y, Pyrhönen S. VEGF-1 expression in colorectal cancer is associated with disease localization, stage, and long-term disease-specific survival. Anticancer research 2008; 28(6B): 3865-3870. [DOI:10.3109/07357900802672761]
44. Haque T, Nakada S, Hamdy RC. A review of FGF18: its expression, signaling pathways and possible functions during embryogenesis and post-natal development. Histology and histopathology 2007; 22(1): 97-105.
45. Sonvilla G, Allerstorfer S, Stättner S, Karner J, Klimpfinger M, Fischer H, Grasl-Kraupp B, Holzmann K, Berger W, Friedrich Wrba F, Marian B, Grusch M. FGF18 in colorectal tumour cells: autocrine and paracrine effects. Carcinogenesis 2008; 29(1): 15-24. [DOI:10.1093/carcin/bgm202]
46. Beenken A, Mohammadi M. The FGF family: biology, pathophysiology and therapy. Nature reviews drug discovery 2009; 8(3): 235-253. [DOI:10.1038/nrd2792]
47. Moore EE, Bendele AM, Thompson DL, Littau A, Waggie KS, Reardon B, Ellsworth JL. Fibroblast growth factor-18 stimulates chondrogenesis and cartilage repair in a rat model of injury-induced osteoarthritis. Osteoarthritis cartilage 2005; 13(7): 623-631. [DOI:10.1016/j.joca.2005.03.003]
48. Organ SL, Tsao MS. An overview of the c-MET signaling pathway. Therapeutic advances in medical oncology 2011; 3(1 Suppl): S7-S19. [DOI:10.1177/1758834011422556]
49. Sagi Z, Hieronymus T. The impact of the epithelial-mesenchymal transition regulator hepatocyte growth factor receptor/Met on skin immunity by modulating langerhans cell migration. Frontiers in immunology 2018; 9: 517. [DOI:10.3389/fimmu.2018.00517]
50. Kermorgant S, Aparicio T, Dessirier V, Lewin MJ, Lehy T. Hepatocyte growth factor induces colonic cancer cell invasiveness via enhanced motility and protease overproduction. Evidence for PI3 kinase and PKC involvement. Carcinogenesis 2001; 22(7): 1035-1042. [DOI:10.1093/carcin/22.7.1035]
51. Yin X, Zhang T, Su X, Ji Y, Ye P, Fu H, Fan S, Shen Y, Gavine PR, Gu Y. Relationships between Chromosome 7 gain, MET gene copy number increase and MET protein overexpression in chinese papillary renal cell carcinoma patients. PLoS one 2015; 10 (12): e0143468. [DOI:10.1371/journal.pone.0143468]
52. Safaie Qamsari E, Safaei Ghaderi S, Zarei B, Dorostkar R, Bagheri S, Jadidi-Niaragh F Somi MH, Yousefi M. The c-Met receptor: Implication for targeted therapies in colorectal cancer. Tumor biology 2017; 39(5): 1-13. [DOI:10.1177/1010428317699118]
53. Sharpless NE, DePinho RA. Telomeres, stem cells, senescence, and cancer. Journal of clinical investigation 2004; 113(2): 160-168. [DOI:10.1172/JCI20761]
54. Morgan G. Telomerase regulation and the intimate relationship with aging. Research and reports in biochemistry 2013; 3: 71-78. [DOI:10.2147/RRBC.S28603]
55. Mathon NF, Lloyd AC. Cell senescense and cancer. Nature reviews cancer 2001; 1(3): 203-213. [DOI:10.1038/35106045]
56. Nakamura Y, de Paiva Alves E, Veenstra GJ, Hoppler S. Tissue- and stage-specific Wnt target gene expression is controlled subsequent to β-catenin recruitment to cis-regulatory modules. Development 2016; 143(11): 1914-1925. [DOI:10.1242/dev.131664]
57. Kam Y, Quaranta V. Cadherin-bound β-Catenin feeds into the Wnt pathway upon adherens junctions dissociation: evidence for an intersection between β-Catenin pools. PLoS one 2009; 4(2): e4580. [DOI:10.1371/journal.pone.0004580]
58. Peinado H, Portillo F, Cano A. Transcriptional regulation of cadherins during development and Carcinogenesis. The international journal of developmental biology 2004; 48(5-6): 365-375. [DOI:10.1387/ijdb.041794hp]
59. Krejci P, Aklian A, Kaucka M, Sevcikova E, Prochazkova J, Masek JK, Mikolka P, Pospisilova T, Spoustova T, Weis MA, Paznekas WA, Wolf JH, Gutkind JS, Wilcox WR, Kozubik A, Wang Jabs E, Bryja V, Salazar L, Vesela I, Balek L. Receptor tyrosine kinases activate canonical Wnt/β-Catenin signaling via MAP kinase/LRP6 pathway and direct β-Catenin phosphorylation. PLoS one 2012; 7(4): e35826. [DOI:10.1371/journal.pone.0035826]
60. Ilyas M, Tomlinson IPM, Rowan A, Pignatelli M, Bodmer WF. Beta-Catenin mutations in cell lines established from human colorectal cancers. Proceedings of the national academy of sciences USA 1997; 94(19): 10330-10334. [DOI:10.1073/pnas.94.19.10330]
61. Qi J, Zhu YQ, Luo J, Tao WH. Hypermethylation and expression regulation of secreted Frizzled-related protein genes in colorectal tumor. World journal of gastroenterology 2006; 12(44): 7113-7117. [DOI:10.3748/wjg.v12.i44.7113]
62. Senda T, Iizuka-Kogo A, Onouchi T, Shimomura A. Adenomatous polyposis coli (APC) plays multiple roles in the intestinal and colorectal epithelia. Medical molecular morphology 2007; 40(2): 68-81. [DOI:10.1007/s00795-006-0352-5]
63. Fodde R, Smits R, Clevers H. APC, signal transduction and genetic instability colorectal cancer. Nature reviews cancer 2001; 1(1): 55-67. [DOI:10.1038/35094067]
64. Johnson V, Volikos E, Halford SE, Eftekhar Sadat ET, Popat S, Talbot I, Truninger K, Martin J, Jass J, Houlston R, Atkin W, Tomlinson IP, Silver AR. Exon 3 beta-catenin mutations are specifically associated with colorectal carcinomas in hereditary non-polyposis colorectal cancer syndrome. Gut 2005; 54(2): 264-267. [DOI:10.1136/gut.2004.048132]
65. Kaur A, Webster MR, Weeraratna AT. In the Wnt-er of life: Wnt signalling in melanoma and ageing. British journal of cancer 2016; 115(11): 1273-1279. [DOI:10.1038/bjc.2016.332]
66. Chien AJ, Moore EC, Lonsdorf AS, Kulikauskas RM, Rothberg BG, Berger AJ, Major MB, Hwang ST, Rimm DL, Moon RT. Activated Wnt/beta-catenin signaling in melanoma is associated with decreased proliferation in patient tumors and a murine melanoma model. Proceedings of the national academy of sciences USA 2009; 106(4): 1193-1198. [DOI:10.1073/pnas.0811902106]
67. Kovacs D, Migliano E, Muscardin L, Silipo V, Catricalà C, Picardo M, Bellei B. The role of WNT/β-catenin signaling pathway in melanoma epithelial-to-mesenchyma-like switching: evidences from patients-derived cell lines. Oncotarget 2016; 7(28): 43295-43314. [DOI:10.18632/oncotarget.9232]
68. O'Connell MP, Fiori JL, Baugher KM, Indig FE, French AD, Camilli TC, Frank BP, Earley R, Hoek KS, Hasskamp JH, George Elias E, Taub DD, Bernier M, Weeraratna AT. Wnt5A activates the calpain-mediated cleavage of filamin A. Journal of investigative dermatology 2009; 129(7): 1782-1789. [DOI:10.1038/jid.2008.433]
69. Liu LJ, Xie SX, Chen YT, Xue JL, Zhang CJ, Zhu F. Aberrant regulation of Wnt signaling in hepatocellular carcinoma. World journal of gastroenterology 2016; 22(33): 7486-7499. [DOI:10.3748/wjg.v22.i33.7486]
70. Waisberg J, Saba GT. Wnt-/-β-catenin pathway signaling in human hepatocellular carcinoma. World journal of hepatology 2015; 7(26): 2631-2635. [DOI:10.4254/wjh.v7.i26.2631]
71. Pez F, Lopez A, Kim M, Wands JR, Caron de Fromentel C, Merle P. Wnt signaling and hepatocarcinogenesis: Molecular targets for the development of innovative anticancer drugs. Journal of hepatology 2013; 59(5): 1107-1117. [DOI:10.1016/j.jhep.2013.07.001]
72. Wands JR, Kim M. WNT/β-Catenin signaling and hepatocellular carcinoma. Hepatology 2014; 60(2): 452-454. [DOI:10.1002/hep.27081]
73. Fako V, Yu Z, Henrich CJ, Ransom T, Budhu AS, Wang XW. Inhibition of Wnt/β-catenin signaling in hepatocellular carcinoma by an antipsychotic drug pimozide. International journal of biological sciences 2016; 12(7): 768-775. [DOI:10.7150/ijbs.14718]
74. Sano M, Driscoll DR, Wilfredo E, Quattrochi B, Appleman VA, Ou J, Zhu LJ, Yoshida N, Yamazaki S, Takayama T, Sugitani M, Nemoto N, Klimstra DS, Lewis BC. Activation of Wnt/β-Catenin signaling enhances pancreatic cancer development and the malignant potential via up-regulation of Cyr61. Neoplasia 2016; 18(12): 785-794. [DOI:10.1016/j.neo.2016.11.004]
75. Zhang Y, Morris JP, Yan W, Schofield HK, Gurney A, Simeone DM, Millar SE, Hoey T Hebrok M, Pasca di Maglian M. Canonical Wnt signaling is required for pancreatic carcinogenesis. Cancer research 2013; 73(15): 4909-4922. [DOI:10.1158/0008-5472.CAN-12-4384]
76. Wall I, Schmidt-Wolf IG. Effect of Wnt inhibitors in pancreatic cancer. Anticancer research 2014; 34(10): 5375-5380.
77. Zeng G, Germinaro M, Micsenyi A, Monga NK, Bell A, Sood A, Malhotraz V, Soodz N, Midday V, Monga DK, Kokkinakis DM, Monga SPS. Aberrant Wnt/β-Catenin signaling in pancreatic adenocarcinoma. Neoplasia 2006; 8(4): 279-289. [DOI:10.1593/neo.05607]
78. Nusse R, Varmus H. Three decades of Wnts: a personal perspective on how a scientific field developed. EMBO journal 2012; 31(12): 2670-2684. [DOI:10.1038/emboj.2012.146]
79. Hwang SY, Deng X, Byun S, Lee C, Lee SJ, Suh H, Zhang J, Kang Q, Zhang T, Westover KD, Mandinova A, Lee SW. Direct targeting of β-Catenin by a small molecule stimulates proteasomal degradation and suppresses oncogenic Wnt/ β-Catenin signaling. Cell reports 2016; 16(1): 28-36. [DOI:10.1016/j.celrep.2016.05.071]
80. Shin SH, Lim DY, Reddy K, Malakhova M, Liu F, Wang T, Song M, Chen H, Bae KB, Ryu J, Liu K, Lee M-H, Bode AM, Dong Z. A small molecule inhibitor of the β-Catenin-TCF4 interaction suppresses colorectal cancer growth in vitro and in vivo. EBioMedicine 2017; 25: 22-31. [DOI:10.1016/j.ebiom.2017.09.029]
81. Ashihara E, Takada T, Maekawa T. Targeting the canonical Wnt⁄β-catenin pathway in hematological malignancies. Cancer science 2015; 106(6): 665-671. [DOI:10.1111/cas.12655]
82. Kahn M. Can we safely target the WNT pathway? Nature Reviews Drug discovery 2014; 13(7): 513-532. [DOI:10.1038/nrd4233]
83. Willert K, Nusse R. Wnt proteins. Cold spring harbor perspectives in biology 2012; 4(9): a007864. [DOI:10.1101/cshperspect.a007864]
84. Masuda M, Sawa M, Yamada T. Therapeutic targets in theWnt signaling pathway: feasibility of targeting TNIK in colorectal cancer. Pharmacology and therapeutics 2015; 156: 1-9. [DOI:10.1016/j.pharmthera.2015.10.009]
85. Skorski T. Oncogenic tyrosine kinases and DNA-damage responses. Nature reviews cancer 2002; 2(5): 351-360. [DOI:10.1038/nrc799]

Add your comments about this article : Your username or Email:
CAPTCHA

Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

© 2024 CC BY-NC 4.0 | Iranian Biomedical Journal

Designed & Developed by : Yektaweb