https://doi.org/10.4081/ejh.2024.4145

High WTAP expression level as a promising biomarker for poor prognosis in colorectal cancer: a pilot study

Vol. 68 No. 4 (2024)
Submitted: 17 September 2024
Accepted: 18 October 2024
Published: 16 December 2024
Colorectal cancer, METTL3, WTAP, FTO, biomarkers
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Authors

Michela Relucenti
michela.relucenti@uniroma1.it
https://orcid.org/0000-0002-3805-9505
Department of Anatomical, Histological, Forensic, and Orthopaedic Sciences, Section of Anatomy, Sapienza University of Rome, Italy.
Claudia Tito
https://orcid.org/0009-0001-1350-3024
Department of Anatomical, Histological, Forensic, and Orthopaedic Sciences, Section of Histology and Medical Embryology, Sapienza University of Rome, Italy.
Paolo Mercantini
Surgery Unit, Department of Medical Surgical Sciences and Translational Medicine, Sapienza University of Rome, Sant’Andrea University Hospital, Rome, Italy.
Emanuela Pilozzi
Pathology Unit, Department of Clinical and Molecular Medicine, Sapienza University of Rome, Sant’Andrea University Hospital, Rome, Italy.
Claudio Barbaranelli
Psychology Department, Sapienza University, Rome, Italy.
Loredana Cristiano
https://orcid.org/0000-0002-0539-0736
Department of Anatomical, Histological, Forensic, and Orthopaedic Sciences, Section of Anatomy, Sapienza University of Rome, Italy.
Daniela Savarese
Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Pathology Unit ICOT, Latina, Italy.
Daniela Bastianelli
Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Pathology Unit ICOT, Latina, Italy.
Francesco Fazi
https://orcid.org/0000-0003-2910-7912
Department of Anatomical, Histological, Forensic, and Orthopaedic Sciences, Section of Histology and Medical Embryology, Sapienza University of Rome, Italy.
Vincenzo Petrozza
https://orcid.org/0000-0001-9837-8690
Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Pathology Unit ICOT, Latina, Italy, Italy.
Xiaobo Li
Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, China.
Rui Chen
Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, China.
Selenia Miglietta
Department of Anatomical, Histological, Forensic, and Orthopaedic Sciences, Section of Anatomy, Sapienza University of Rome , Italy.
Giuseppe Familiari
https://orcid.org/0000-0002-3456-1434
Department of Anatomical, Histological, Forensic, and Orthopaedic Sciences, Section of Anatomy, Sapienza University of Rome , Italy.

Colorectal cancer (CRC) is a major public health concern and identifying prognostic molecular biomarkers can help stratify patients based on risk profiles, thus enabling personalized medicine. Epitranscriptomic modifications play a relevant role in controlling gene expression, N6-methyladenosine (m6A) regulators play crucial roles in cancer progression, but their clinical significance in CRC cancer has thus far not been elucidated. Thus, we aimed to examine by immunohistochemical techniques and RT-qPCR, protein levels and RNAs expression of m6A writers (METTL3, WTAP) and eraser (FTO) in a cohort of 10 patients affected by CRC. The patients were followed for 5 years and values of METTL3, WTAP and FTO RNAs in alive vs dead patients were compared. Proteins expression and RNAs expression had a different trend, METTL3, WTAP and FTO proteins’ expression showed an increasing trend from non-cancerous adjacent (N) tissue vs carcinoma (CA) tissue G1 stage, and then a decreasing trend from G1 to G2 and G3 stages. The most marked increase was observed in WTAP that, from a 40% of protein expression positivity in N tissue raised to the 81% of positivity in G1 stage K tissue. RNAs expression of METTL3, WTAP and FTO genes in N tissue vs G1 stage CA tissue was significantly different, the analysis and comparison of RNAs values in patient alive after 5 years (0.58±0.04) vs patients dead after 5 years (1.69±0.29) showed that only WTAP values resulted significantly high in dead patients. The fact that WTAP protein expression levels lower while WTAP RNA expression remains high, lets us hypothesize a sort of inhibition of protein expression, but further studies are needed to clarify the mechanism. Although the results suggest a relationship between biological meaning and prognostic utility of WTAP, this prognostic utility must be confirmed by further studies on a larger sample.

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Scopus
Google Scholar
Europe PMC
1. International Agency for Research on Cancer, WHO. Global cancer observatory. Accessed 2024. Available from: https://gco.iarc.fr
2. Zheng S, Schrijvers JJA, Greuter MJW, Kats-Ugurlu G, Lu W, de Bock GH. Effectiveness of colorectal cancer (CRC) screening on all-cause and CRC-specific mortality reduction: A systematic review and meta-analysis. Cancers (Basel) 2023;15:1-17. DOI: https://doi.org/10.3390/cancers15071948
3. Sun H, Meng Q, Shi C, Yang H, Li X, Wu S, et al. Hypoxia-inducible exosomes facilitate liver-tropic premetastatic niche in colorectal cancer. Hepatology 2021;74:2633–51. DOI: https://doi.org/10.1002/hep.32009
4. Shinagawa T, Tanaka T, Nozawa H, Emoto S, Murono K, Kaneko M, et al. Comparison of the guidelines for colorectal cancer in Japan, the USA, and Europe. Ann Gastroenterol Surg 2018;2:6-12. DOI: https://doi.org/10.1002/ags3.12047
5. Chen K, Collins G, Wang H, Toh JWT. Pathological features and prognostication in colorectal cancer. Curr Oncol 2021;28:5356-83. DOI: https://doi.org/10.3390/curroncol28060447
6. Ashouri K, Wong A, Mittal P, Torres-Gonzalez L, Lo JH, et al. Exploring predictive and prognostic biomarkers in colorectal cancer: A comprehensive review. Cancers (Basel) 2024;16:2796. DOI: https://doi.org/10.3390/cancers16162796
7. Alnakli AAA, Mohamedali A, Heng B, Chan C, Shin J-S, Solomon M, et al. Protein prognostic biomarkers in stage II colorectal cancer: Implications for post-operative management. BJC Rep 2024;2:13. DOI: https://doi.org/10.1038/s44276-024-00043-z
8. Liu N, Pan T. RNA epigenetics. Transl Res 2015;165:28-35. DOI: https://doi.org/10.1016/j.trsl.2014.04.003
9. Helm M, Motorin Y. Detecting RNA modifications in the epitranscriptome: Predict and validate. Nat Rev Genet 2017;18:275-91. DOI: https://doi.org/10.1038/nrg.2016.169
10. Gilbert WV, Bell TA, Schaening C. Messenger RNA modifications: Form, distribution, and function. Science 2016;352:1408-12. DOI: https://doi.org/10.1126/science.aad8711
11. Davalos V, Blanco S, Esteller M. SnapShot: Messenger RNA modifications. Cell 2018;174:498-498.e1. DOI: https://doi.org/10.1016/j.cell.2018.06.046
12. Boccaletto P, Stefaniak F, Ray A, Cappannini A, Mukherjee S, Purta E, et al. MODOMICS: A database of RNA modification pathways. Nucleic Acids Res 2022;50:D231-5. DOI: https://doi.org/10.1093/nar/gkab1083
13. Dai D, Wang H, Zhu L, Jin H, Wang X. N6-methyladenosine links RNA metabolism to cancer progression. Cell Death Dis 2018;9:124. DOI: https://doi.org/10.1038/s41419-017-0129-x
14. Zhao BS, Roundtree IA, He C. Post-transcriptional gene regulation by mRNA modifications. Nat Rev Mol Cell 2017;18:31-42. DOI: https://doi.org/10.1038/nrm.2016.132
15. Wang S, Sun C, Li J, Zhang E, Ma Z, Xu W, et al. Roles of RNA methylation by means of N (6)-methyladenosine (m6A) in human cancers. Cancer Lett 2017;408:112-20. DOI: https://doi.org/10.1016/j.canlet.2017.08.030
16. Nombela P, Miguel-López B, Blanco S. The role of m6A, m5C and ΨRNA modifications in cancer: Novel therapeutic opportunities. Mol Cancer 2021;20:1-30. DOI: https://doi.org/10.1186/s12943-020-01263-w
17. Wu F, Cheng W, Zhao F, Tang M, Diao Y, Xu R. Association of N6-methyladenosine with viruses and related diseases. Virol J 2019;16:133. DOI: https://doi.org/10.1186/s12985-019-1236-3
18. Liu ZX, Li LM, Sun HL, Liu SM. Link between m6A modification and cancers. Front Bioeng Biotechnol 2018;6:89. DOI: https://doi.org/10.3389/fbioe.2018.00089
19. Zaccara S, Ries RJ, Jaffrey SR. Reading, writing and erasing mRNA methylation. Nat Rev Mol Cell Biol 2019;20:608-24. DOI: https://doi.org/10.1038/s41580-019-0168-5
20. Frye M, Harada BT, Behm M, He C. RNA modifications modulate gene expression during development. Science 2018;361:1346-9. DOI: https://doi.org/10.1126/science.aau1646
21. Shi H, Wei J, He C. Where, when, and how: Context-dependent functions of RNA methylation writers, readers, and erasers. Mol Cell 2019;74:640-50. DOI: https://doi.org/10.1016/j.molcel.2019.04.025
22. Hamilton SR, Bosman FT, Boffetta P, Theise ND. Carcinoma of the colon and rectum. In: Bosman FT, Carneiro F, Hruban RH, Theise ND, Editors, WHO Classification of tumours of the digestive system. Lyon, IARC Press; 2010. pp. 134-46.
23. Compton C, Fenoglio-Preiser CM, Pettigrew N, Fielding LP. American joint committee on cancer prognostic factors consensus conference: Colorectal working group. Cancer 2000;88:1739-57. DOI: https://doi.org/10.1002/(SICI)1097-0142(20000401)88:7<1739::AID-CNCR30>3.0.CO;2-T
24. Compton CC. Key issues in reporting common cancer specimens: Problems in pathologic staging of colon cancer. Arch Pathol Lab Med 2006;130:318-24. DOI: https://doi.org/10.5858/2006-130-318-KIIRCC
25. Di Emidio G, Placidi M, Rea F, Rossi G, Falone S, Cristiano L, et al. Methylglyoxal-dependent glycative stress and deregulation of SIRT1 functional network in the ovary of PCOS mice. Cells 2020;14:209. DOI: https://doi.org/10.3390/cells9010209
26. Bossù M, Matassa R, Relucenti M, Iaculli F, Salucci A, Di Giorgio G, et al. Morpho-chemical observations of human deciduous teeth enamel in response to biomimetic toothpastes treatment. Materials (Basel) 2020;13:1803. DOI: https://doi.org/10.3390/ma13081803
27. Relucenti M, Heyn R, Petruzziello L, Pugliese G, Taurino M, Familiari G. Detecting microcalcifications in atherosclerotic plaques by a simple trichromic staining method for epoxy-embedded carotid endarterectomies. Eur J Histochem 2010;54:e33. DOI: https://doi.org/10.4081/ejh.2010.e33
28. Relucenti M, Heyn R, Correr S, Familiari G. Cumulus oophorus extracellular matrix in the human oocyte: A role for adhesive proteins. It J Anat Embryol 2005;110:219-24.
29. Relucenti M, Francescangeli F, De Angelis ML, D'Andrea V, Miglietta S, Pilozzi E, et al. The ultrastructural analysis of human colorectal cancer stem cell-derived spheroids and their mouse xenograft shows that the same cell types have different ratios. Biology (Basel) 2021;10:929. DOI: https://doi.org/10.3390/biology10090929
30. Relucenti M, Francescangeli F, De Angelis ML, D'Andrea V, Miglietta S, Donfrancesco O, et al. A different exosome secretion pattern characterizes patient-derived colorectal cancer multicellular spheroids and their mouse xenografts. Biology (Basel) 2022;11:1427. DOI: https://doi.org/10.3390/biology11101427
31. Sawilowsky SS. New effect size rules of thumb. J Mod Appl Stat Methods 2009;8:597-9. DOI: https://doi.org/10.22237/jmasm/1257035100
32. Yi D, Xu F, Wang R, Jiang C, Qin J, Lee Y, Shi X, Sang J. Deciphering the map of METTL14-mediated lncRNA m6A modification at the transcriptome-wide level in breast cancer. J Clin Lab Anal 2022;36:e24754. DOI: https://doi.org/10.1002/jcla.24754
33. Xu X, Huang J, Ocansey DKW, Xia Y, Zhao Z, Xu Z, et al. The emerging clinical application of m6A RNA modification in inflammatory bowel disease and its associated colorectal cancer. J Inflamm Res 2021;14:3289-306. DOI: https://doi.org/10.2147/JIR.S320449
34. Guo W, Zhang C, Feng P, Li M, Wang X, Xia Y, et al. M6A methylation of DEGS2, a key ceramide-synthesizing enzyme, is involved in colorectal cancer progression through ceramide synthesis. Oncogene 2021;40:5913-24. DOI: https://doi.org/10.1038/s41388-021-01987-z
35. Yue Q, Zhang Y, Wang F, Cao F, Bai J, Duan X. Characterization of m6A methylation modification patterns in colorectal cancer determines prognosis and tumor microenvironment infiltration. J Immunol Res 2022;2022:8766735. DOI: https://doi.org/10.1155/2022/8766735
36. Ozato Y, Hara T, Meng S, Sato H, Tatekawa S, Uemura M, et al. RNA methylation in inflammatory bowel disease. Cancer Sci 2024;115:723-33. DOI: https://doi.org/10.1111/cas.16048
37. Zhang Z, Zhang X. Identification of m6A-related biomarkers associated with prognosis of colorectal cancer. Med Sci Monit 2021;27:e932370. DOI: https://doi.org/10.12659/MSM.932370
38. Lan Q, Liu PY, Haase J, Bell JL, Hüttelmaier S, Liu T. The critical role of RNA m6A methylation in cancer. Cancer Res 2019;79:1285-92. DOI: https://doi.org/10.1158/0008-5472.CAN-18-2965
39. Pu J, Wang J, Qin Z, Wang A, Zhang Y, Wu X, et al. IGF2BP2 promotes liver cancer growth through an m6A-FEN1-dependent mechanism. Front Oncol 2020;10:578816. DOI: https://doi.org/10.3389/fonc.2020.578816
40. Li H, Liu Z, Wang H. Expression and clinical significance of METTL3 in colorectal cancer. Medicine (Baltimore) 2023;102:e34658. DOI: https://doi.org/10.1097/MD.0000000000034658
41. Dong X, Wang Y, Tang CH, Huang BF, Du Z, Wang Q, et al. Upregulated WTAP expression in colorectal cancer correlates with tumor site and differentiation. PLoS One 2022;17:e0263749. DOI: https://doi.org/10.1371/journal.pone.0263749
42. Dai X, Chen K, Xie Y. WTAP mediated the N6-methyladenosine modification of PDK4 to regulate the malignant behaviors of colorectal cancer cells in vitro and in vivo. Curr Med Chem 2023;30:3368-81. DOI: https://doi.org/10.2174/0929867329666220922102949
43. Ye M, Chen J, Yu P, Hu C, Wang B, Bao J, et al. WTAP activates MAPK signaling through m6A methylation in VEGFA mRNA mediated by YTHDC1 to promote colorectal cancer development. FASEB J 2023;37:e23090. DOI: https://doi.org/10.1096/fj.202300344RRR
44. Zhou Z, Lv J, Yu H, Han J, Yang X, Feng D, et al. Mechanism of RNA modification N6-methyladenosine in human cancer. Mol Cancer 2020;19:104. DOI: https://doi.org/10.1186/s12943-020-01216-3
45. Fang Z, Hu Y, Hu J, Huang Y, Zheng S, Guo C. The crucial roles of N6-methyladenosine (m6A) modification in the carcinogenesis and progression of colorectal cancer. Cell Biosci 2021;11:72. DOI: https://doi.org/10.1186/s13578-021-00583-8
46. Liu W, Gao X, Chen X, Zhao N, Sun Y, Zou Y, et al. Mir-139-5p loss-mediated WTAP activation contributes to hepatocellular carcinoma progression by promoting the epithelial to mesenchymal transition. Front Oncol 2021;11:611544. DOI: https://doi.org/10.3389/fonc.2021.611544
47. Heng L, Lin Z, Ye Y, Luo R, Zeng L. ARRB2 promotes colorectal cancer growth through triggering WTAP. Acta Biochim Biophys 2020;53:85-93. DOI: https://doi.org/10.1093/abbs/gmaa151
48. Xie W, Wei L, Guo J, Guo H, Song X, Sheng X. Physiological functions of Wilms’ tumor 1-associating protein and its role in tumorigenesis. J Cell Biochem 2019;120:10884-92. DOI: https://doi.org/10.1002/jcb.28402
49. Lei J, Fan Y, Yan C, Jiamaliding Y, Tang Y, Zhou J, et al. Comprehensive analysis about prognostic and immunological role of WTAP in pan-cancer. Front Genet 2022;13:1007696. DOI: https://doi.org/10.3389/fgene.2022.1007696
50. Muinelo-Romay L, Vázquez-Martín C, Villar-Portela S, Cuevas E, Gil-Martín E, Fernández-Briera A. Expression and enzyme activity of α (1,6) fucosyltransferase in human colorectal cancer. Int J Cancer 2008;123:641-6. DOI: https://doi.org/10.1002/ijc.23521
51. Yue C, Chen J, Li Z, Li L, Chen J, Guo Y. MicroRNA-96 promotes occurrence and progression of colorectal cancer via regulation of the AMPKα2-FTO-m6A/MYC axis. J Exp Clin Cancer Res 2020;39:240. DOI: https://doi.org/10.1186/s13046-020-01731-7
52. Ruan D, Li T, Wang Y, Meng Q, Li Y, Yu K, et al. FTO downregulation mediated by hypoxia facilitates colorectal cancer metastasis. Oncogene 2021;40:5168-81. DOI: https://doi.org/10.1038/s41388-021-01916-0
53. Landskron-Ramos G, Domínguez-Beltrando A, Zambra-Rojas M, Sanguineti A, Vasquez G, Fuente M, et al. Abstract 1251: Novel potential role of m6A-demethylase FTO (fat mass and obesity) protein in colorectal cancer. Cancer Res 2023;83:1251. DOI: https://doi.org/10.1158/1538-7445.AM2023-1251
54. Liu X, Liu L, Dong Z, Li J, Yu Y, Chen X, et al. Expression patterns and prognostic value of m6A-related genes in colorectal cancer. Am J Transl Res 2019;11:3972-91.
55. Li J, Li S, Xing X, Liu N, Lai S, Liao D, Li J. FTO-mediated ZNF687 accelerates tumor growth, metastasis, and angiogenesis in colorectal cancer through the Wnt/β-catenin pathway. Biotechnol Appl Biochem 2024;71:245-55. DOI: https://doi.org/10.1002/bab.2536
56. Relier S, Rivals E, David A. The multifaceted functions of the fat mass and obesity-associated protein (FTO) in normal and cancer cells. RNA Biol 2022;19:132-42. DOI: https://doi.org/10.1080/15476286.2021.2016203
57. Gui S, Wang Q, Bao L, He X, Wang Z, Liu L, et al. Effects of Helicobacter pylori on the expression of the FTO gene and its biological role in gastric cancer. Oncol Lett 2023;25:143. DOI: https://doi.org/10.3892/ol.2023.13729
58. Liu QZ, Zhang N, Chen JY, Zhou MJ, Zhou DH, Chen Z, et al. WTAP-induced N6-methyladenosine of PD-L1 blocked T-cell-mediated antitumor activity under hypoxia in colorectal cancer. Cancer Sci 2024;115:1749-62. DOI: https://doi.org/10.1111/cas.16136

Ethics Approval

this pilot study was approved by the Institutional Review Board of the Sapienza University of Rome, Italy

How to Cite

Relucenti, M., Tito, C., Mercantini, P., Pilozzi, E., Barbaranelli, C., Cristiano, L., … Familiari, G. (2024). High WTAP expression level as a promising biomarker for poor prognosis in colorectal cancer: a pilot study. European Journal of Histochemistry, 68(4). https://doi.org/10.4081/ejh.2024.4145
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