METTL3‑mediated N6‑methyladenosine modification of MMP9 mRNA promotes colorectal cancer proliferation and migration

Chen,Jie; Wu,Henglan; Zuo,Ting; Wu,Jianming; Chen,Zhiheng

doi:10.3892/or.2024.8842

METTL3‑mediated N6‑methyladenosine modification of MMP9 mRNA promotes colorectal cancer proliferation and migration

Authors:
- Jie Chen
- Henglan Wu
- Ting Zuo
- Jianming Wu
- Zhiheng Chen
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Affiliations: Department of Central Laboratory, The First Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang 314000, P.R. China, Department of Nephrology, The First Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang 314000, P.R. China, Department of Anesthesia Surgery, The First Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang 314000, P.R. China, Department of Gastrointestinal Surgery, The First Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang 314000, P.R. China
Published online on: November 12, 2024 https://doi.org/10.3892/or.2024.8842
Article Number: 9
Copyright: © Chen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

N6‑methyladenosine (m⁶A) is the predominant chemical modification of eukaryotic mRNA, dynamically mediated by the RNA methyltransferase, methyltransferase-like 3 (METTL3). m⁶A modification plays a critical role in cancer progression through post‑transcriptional regulation in various types of cancer. However, the role of METTL3 and its associated m⁶A modification in colorectal tumorigenesis remains to be fully elucidated. In the present study, it was demonstrated that METTL3 expression and the m⁶A levels were both upregulated in colorectal cancer (CRC) and positively associated with clinical progression, based on the bioinformatics analysis of cancer databases. Furthermore, knockdown and overexpression of METTL3 notably affected CRC cell viability, apoptosis and migration in vitro. Similarly, xenograft animal models confirmed that METTL3 promoted CRC tumorigenicity in vivo. Mechanistically, it was revealed that the m⁶A modification of matrix metallopeptidase 9 (MMP9) mRNA mediated by METTL3 promoted its expression in CRC by decreasing its degradation. Collectively, the findings of the present study suggested that the METTL3/MMP9 axis could serve as a novel promising therapeutic candidate for CRC.

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1	Siegel RL, Wagle NS, Cercek A, Smith RA and Jemal A: Colorectal cancer statistics, 2023. CA Cancer J Clin. 73:233–254. 2023. View Article : Google Scholar : PubMed/NCBI
2	Wolf D, Salcher S and Pircher A: The multivisceral landscape of colorectal cancer metastasis: Implications for targeted therapies. J Clin Invest. 134:e1783312024. View Article : Google Scholar : PubMed/NCBI
3	Association NHCOTPROCSOOCM: National Health Commission guidelines for diagnosis and treatment of colorectal cancer 2023 in China (English version). Chin J Cancer Res. 35:197–232. 2023.PubMed/NCBI
4	Bien J and Lin A: A review of the diagnosis and treatment of metastatic colorectal cancer. Jama-J Am Med Assoc. 325:2404–2405. 2021. View Article : Google Scholar : PubMed/NCBI
5	Miranda E, Bianchi P, Destro A, Morenghi E, Malesci A, Santoro A, Laghi L and Roncalli M: Genetic and epigenetic alterations in primary colorectal cancers and related lymph node and liver metastases. Cancer. 119:266–276. 2013. View Article : Google Scholar : PubMed/NCBI
6	Clemens AW, Lin S, Jain S, Su YH and Song W: Detection of colorectal cancer-associated genetic and epigenetic alterations in urine of patients with CRC. Cancer Res. 75:abs. 1561. 2015.https://doi.org/10.1158/1538-7445.AM2015-1561 View Article : Google Scholar
7	Nosho K, Kawasaki T, Ohnishi M, Suemoto Y, Kirkner GJ, Zepf D, Yan L, Longtine JA, Fuchs CS and Ogino S: mutation in colorectal cancer: Relationship with genetic and epigenetic alterations. Neoplasia. 10:534–541. 2008. View Article : Google Scholar : PubMed/NCBI
8	Jiang XL, Liu BY, Nie Z, Duan L, Xiong Q, Jin Z, Yang C and Chen Y: The role of m6A modification in the biological functions and diseases. Signal Transduct Tar. 6:742021. View Article : Google Scholar : PubMed/NCBI
9	Roundtree IA, Luo GZ, Zhang Z, Wang X, Zhou T, Cui Y, Sha J, Huang X, Guerrero L, Xie P, et al: YTHDC1 mediates nuclear export of N⁶ - methyladenosine methylated mRNAs. Elife. 6:e313112017. View Article : Google Scholar : PubMed/NCBI
10	Zhu ZM, Huo FC, Zhang J, Shan HJ and Pei DS: Crosstalk between m6A modification and alternative splicing during cancer progression. Clin Transl Med. 13:e14602023. View Article : Google Scholar : PubMed/NCBI
11	Fang Z, Mei WT, Qu C, Lu J, Shang L, Cao F and Li F: Role of m6A writers, erasers and readers in cancer. Exp Hematol Oncol. 11:452022. View Article : Google Scholar : PubMed/NCBI
12	Liu J, Yue Y, Han D, Wang X, Fu Y, Zhang L, Jia G, Yu M, Lu Z, Deng X, et al: A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation. Nat Chem Biol. 10:93–95. 2014. View Article : Google Scholar : PubMed/NCBI
13	Ping XL, Sun BF, Wang L, Xiao W, Yang X, Wang WJ, Adhikari S, Shi Y, Lv Y, Chen YS, et al: Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase. Cell Res. 24:177–189. 2014. View Article : Google Scholar : PubMed/NCBI
14	Yue Y, Liu J, Cui X, Cao J, Luo G, Zhang Z, Cheng T, Gao M, Shu X, Ma H, et al: VIRMA mediates preferential m⁶A mRNA methylation in 3′UTR and near stop codon and associates with alternative polyadenylation. Cell Discov. 4:102018. View Article : Google Scholar : PubMed/NCBI
15	Patil DP, Chen CK, Pickering BF, Chow A, Jackson C, Guttman M and Jaffrey SR: m(6)A RNA methylation promotes XIST-mediated transcriptional repression. Nature. 537:369–373. 2016. View Article : Google Scholar : PubMed/NCBI
16	Zheng G, Dahl JA, Niu Y, Fedorcsak P, Huang CM, Li CJ, Vågbø CB, Shi Y, Wang WL, Song SH, et al: ALKBH5 Is a Mammalian RNA Demethylase that Impacts RNA Metabolism and Mouse Fertility. Mol Cell. 49:18–29. 2013. View Article : Google Scholar : PubMed/NCBI
17	Jia G, Fu Y, Zhao X, Dai Q, Zheng G, Yang Y, Yi C, Lindahl T, Pan T, Yang YG and He C: 6-Methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat Chem Biol. 7:885–887. 2011. View Article : Google Scholar : PubMed/NCBI
18	Li T, Hu PS, Zuo Z, Lin JF, Li X, Wu QN, Chen ZH, Zeng ZL, Wang F, Zheng J, et al: METTL3 facilitates tumor progression via an mA-IGF2BP2-dependent mechanism in colorectal carcinoma. Mol Cancer. 18:1122019. View Article : Google Scholar : PubMed/NCBI
19	Sun Y, Gong W and Zhang S: METTL3 promotes colorectal cancer progression through activating JAK1/STAT3 signaling pathway. Cell Death Dis. 14:7652023. View Article : Google Scholar : PubMed/NCBI
20	Xiang S, Liang XL, Yin S, Liu J and Xiang Z: N6-methyladenosine methyltransferase METTL3 promotes colorectal cancer cell proliferation through enhancing MYC expression. Am J Transl Res. 12:1789–1806. 2020.PubMed/NCBI
21	Zhou D, Tang W, Xu Y, Xu Y, Xu B, Fu S, Wang Y, Chen F, Chen Y, Han Y and Wang G: METTL3/YTHDF2 m6A axis accelerates colorectal carcinogenesis through epigenetically suppressing YPEL5. Mol Oncol. 15:2172–2184. 2021. View Article : Google Scholar : PubMed/NCBI
22	Zhu W, Si Y, Xu J, Lin Y, Wang JZ, Cao M, Sun S, Ding Q, Zhu L and Wei JF: Methyltransferase like 3 promotes colorectal cancer proliferation by stabilizing CCNE1 mRNA in an m6A-dependent manner. J Cell Mol Med. 24:3521–3533. 2020. View Article : Google Scholar : PubMed/NCBI
23	Mondal S, Adhikari N, Banerjee S, Amin SA and Jha T: Matrix metalloproteinase-9 (MMP-9) and its inhibitors in cancer: A minireview. Eur J Med Chem. 194:1122602020. View Article : Google Scholar : PubMed/NCBI
24	Marshall DC, Lyman SK, McCauley S, Kovalenko M, Spangler R, Liu C, Lee M, O'Sullivan C, Barry-Hamilton V, Ghermazien H, et al: Selective Allosteric Inhibition of MMP9 is efficacious in preclinical models of ulcerative colitis and colorectal cancer. PLoS One. 10:e01270632015. View Article : Google Scholar : PubMed/NCBI
25	Choi SH, Lee HJ, Jin YB, Jang J, Kang GY, Lee M, Kim CH, Kim J, Yoon SS, Lee YS and Lee YJ: MMP9 Processing of HSPB1 Regulates Tumor Progression. PLoS One. 9:e855092014. View Article : Google Scholar : PubMed/NCBI
26	Lee MA, Park JH, Rhyu SY, Oh ST, Kang WK and Kim HN: Wnt3a expression is associated with MMP-9 expression in primary tumor and metastatic site in recurrent or stage IV colorectal cancer. BMC Cancer. 14:1252014. View Article : Google Scholar : PubMed/NCBI
27	Bauer L, Takacs A, Slotta-Huspenina J, Langer R, Becker K, Novotny A, Ott K, Walch A, Hapfelmeier A and Keller G: Clinical significance of NOTCH1 and NOTCH2 expression in gastric carcinomas: An immunohistochemical study. Front Oncol. 5:942015. View Article : Google Scholar : PubMed/NCBI
28	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
29	Boonsongserm P, Angsuwatcharakon P, Puttipanyalears C, Aporntewan C, Kongruttanachok N, Aksornkitti V, Kitkumthorn N and Mutirangura A: Tumor-induced DNA methylation in the white blood cells of patients with colorectal cancer. Oncol Lett. 18:3039–3048. 2019.PubMed/NCBI
30	Barbieri I and Kouzarides T: Role of RNA modifications in cancer. Nat Rev Cancer. 20:303–322. 2020. View Article : Google Scholar : PubMed/NCBI
31	Chen Z, Zhao P, Li FY, Wang Y, Smith AI, Webb GI, Akutsu T, Baggag A, Bensmail H and Song J: Comprehensive review and assessment of computational methods for predicting RNA post-transcriptional modification sites from RNA sequences. Brief Bioinform. 21:1676–1696. 2020. View Article : Google Scholar : PubMed/NCBI
32	Roundtree IA, Evans ME, Pan T and He C: Dynamic RNA Modifications in gene expression regulation. Cell. 169:1187–1200. 2017. View Article : Google Scholar : PubMed/NCBI
33	Zeng C, Huang W, Li Y and Weng H: Roles of METTL3 in cancer: Mechanisms and therapeutic targeting. J Hematol Oncol. 13:1172020. View Article : Google Scholar : PubMed/NCBI
34	Chen H, Pan Y, Zhou Q, Liang C, Wong CC, Zhou Y, Huang D, Liu W, Zhai J, Gou H, et al: METTL3 Inhibits Antitumor Immunity by Targeting m⁶A-BHLHE41-CXCL1/CXCR2 Axis to promote colorectal cancer. Gastroenterology. 163:891–907. 2022. View Article : Google Scholar : PubMed/NCBI
35	Wei X, Huo Y, Pi J, Gao Y, Rao S, He M, Wei Q, Song P, Chen Y, Lu D, et al: METTL3 preferentially enhances non-mA translation of epigenetic factors and promotes tumourigenesis. Nat Cell Biol. 24:1278–1290. 2022. View Article : Google Scholar : PubMed/NCBI
36	Zaccara S, Ries RJ and Jaffrey SR: Reading, writing and erasing mRNA methylation. Nat Rev Mol Cell Biol. 20:608–624. 2019. View Article : Google Scholar : PubMed/NCBI
37	Huang H, Weng H, Sun W, Qin X, Shi H, Wu H, Zhao BS, Mesquita A, Liu C, Yuan CL, et al: Recognition of RNA N⁶-methyladenosine by IGF2BP proteins enhances mRNA stability and translation. Nat Cell Biol. 20:285–295. 2018. View Article : Google Scholar : PubMed/NCBI
38	Mizuno R, Kawada K, Itatani Y, Ogawa R, Kiyasu Y and Sakai Y: The role of tumor-associated neutrophils in colorectal cancer. Int J Mol Sci. 20:5292019. View Article : Google Scholar : PubMed/NCBI
39	Song Z, Yang L, Hu W, Yi J, Feng F and Zhu L: Effects of histone H4 hyperacetylation on inhibiting MMP2 and MMP9 in human amniotic epithelial cells and in premature rupture of fetal membranes. Exp Ther Med. 21:5152021. View Article : Google Scholar : PubMed/NCBI
40	Pirooz HJ, Jafari N, Rastegari M, Fathi-Roudsari M, Tasharrofi N, Shokri G, Tamadon M, Sazegar H and Kouhkan F: Functional SNP in microRNA-491-5p binding site of MMP9 3-UTR affects cancer susceptibility. J Cell Biochem. 119:5126–5134. 2018. View Article : Google Scholar : PubMed/NCBI