Oxymatrine suppresses oral squamous cell carcinoma progression by suppressing CXC chemokine receptor 4 in an m<sup>6</sup>A modification decrease dependent manner

Luo,Renhui; Xie,Lili; Lin,Yingmei; Shao,Jun; Lin,Zhejing

doi:10.3892/or.2022.8392

Oxymatrine suppresses oral squamous cell carcinoma progression by suppressing CXC chemokine receptor 4 in an m⁶A modification decrease dependent manner

Authors:
- Renhui Luo
- Lili Xie
- Yingmei Lin
- Jun Shao
- Zhejing Lin
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Affiliations: Department of Stomatology, Guangzhou Hospital of Integrated Traditional and West Medicine, Guangzhou, Guangdong 510800, P.R. China, Department of Stomatology, Hainan General Hospital, Haikou, Hainan 570102, P.R. China, Department of Stomatology, Shenzhen Hospital of Guangzhou University of Chinese Medicine (Futian), Shenzhen, Guangdong 518034, P.R. China
Published online on: August 23, 2022 https://doi.org/10.3892/or.2022.8392
Article Number: 177

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Abstract

Oxymatrine has been revealed to exert antitumor activity; however, its role in oral squamous cell carcinoma (OSCC) remains unclear. In the present study, the effects and underlying molecular mechanisms of oxymatrine in OSCC were explored. The antineoplastic effects of oxymatrine were measured using Cell Counting Kit‑8, apoptosis and Transwell assays. The inhibitory effect of oxymatrine on tumor growth was evaluated in vivo. The regulation of oxymatrine on the CXC chemokine receptor 4 (CXCR4) was analyzed using western blotting, reverse transcription‑quantitative PCR, RNA stability and methylated RNA immunoprecipitation assays. The present results revealed that oxymatrine inhibited the proliferation and migration of OSCC cells and promoted cell apoptosis. Furthermore, oxymatrine reduced CXCR4 mRNA and protein expression levels by promoting CXCR4 mRNA degradation. Mechanistically, oxymatrine inhibited the methylation at the N6‑position of adenosine (m⁶A modification) of CXCR4 mRNA by decreasing the expression of the methyltransferase‑like 3 (METTL3) gene. In addition, oxymatrine inhibited tumor growth in vivo. Taken together, our findings demonstrated the antitumor effect of oxymatrine on OSCC. Mechanistically, oxymatrine inhibited the progression of OSCC by downregulating METTL3 and degrading CXCR4 mRNA by decreasing the level of m⁶A modification.

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1	Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A and Bray F: Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 71:209–249. 2021. View Article : Google Scholar : PubMed/NCBI
2	Sun S, Wang J, Liu J, Yin F, Xin C, Zeng X, Li J and Chen Q: MiR-302b suppresses tumor metastasis by targeting frizzled 6 in OSCC. J Dent Res. 100:739–745. 2021. View Article : Google Scholar : PubMed/NCBI
3	Hartner L: Chemotherapy for oral cancer. Dent Clin North Am. 62:87–97. 2018. View Article : Google Scholar : PubMed/NCBI
4	Rabea EI, Nasr HM and Badawy ME: Toxic effect and biochemical study of chlorfluazuron, oxymatrine, and spinosad on honey bees (Apis mellifera). Arch Environ Contam Toxicol. 58:722–732. 2010. View Article : Google Scholar : PubMed/NCBI
5	Wu XN and Wang GJ: Experimental studies of oxymatrine and its mechanisms of action in hepatitis B and C viral infections. Chin J Dig Dis. 5:12–16. 2004. View Article : Google Scholar : PubMed/NCBI
6	Shen XC, Yang YP, Xiao TT, Peng J and Liu XD: Protective effect of oxymatrine on myocardial fibrosis induced by acute myocardial infarction in rats involved in TGF-β1-Smads signal pathway. J Asian Nat Prod Res. 13:215–224. 2011. View Article : Google Scholar : PubMed/NCBI
7	Wang Y, Yuan J, Yuan X, Wang W, Pei X, Zhao Q, Cao H, Xu M and Liu Z: Observation of antinociceptive effects of oxymatrine and its effect on delayed rectifier K+ currents (Ik) in PC12 cells. Neurochem Res. 37:2143–2149. 2012. View Article : Google Scholar : PubMed/NCBI
8	He X, Fang J, Huang L, Wang J and Huang X: Sophora flavescens Ait.: Traditional usage, phytochemistry and pharmacology of an important traditional Chinese medicine. J Ethnopharmacol. 172:10–29. 2015. View Article : Google Scholar : PubMed/NCBI
9	Guo B, Zhang T, Su J, Wang K and Li X: Oxymatrine targets EGFR(p-Tyr845) and inhibits EGFR-related signaling pathways to suppress the proliferation and invasion of gastric cancer cells. Cancer Chemother Pharmacol. 75:353–363. 2015. View Article : Google Scholar : PubMed/NCBI
10	Wang X, Liu C, Wang J, Fan Y, Wang Z and Wang Y: Oxymatrine inhibits the migration of human colorectal carcinoma RKO cells via inhibition of PAI-1 and the TGF-β1/Smad signaling pathway. Oncol Rep. 37:747–753. 2017. View Article : Google Scholar : PubMed/NCBI
11	Wu C, Huang W, Guo Y, Xia P, Sun X, Pan X and Hu W: Oxymatrine inhibits the proliferation of prostate cancer cells in vitro and in vivo. Mol Med Rep. 11:4129–4134. 2015. View Article : Google Scholar : PubMed/NCBI
12	Li M, Su BS, Chang LH, Gao Q, Chen KL, An P, Huang C, Yang J and Li ZF: Oxymatrine induces apoptosis in human cervical cancer cells through guanine nucleotide depletion. Anticancer Drugs. 25:161–173. 2014. View Article : Google Scholar : PubMed/NCBI
13	Barbieri F, Bajetto A, Stumm R, Pattarozzi A, Porcile C, Zona G, Dorcaratto A, Ravetti JL, Minuto F, Spaziante R, et al: Overexpression of stromal cell-derived factor 1 and its receptor CXCR4 induces autocrine/paracrine cell proliferation in human pituitary adenomas. Clin Cancer Res. 14:5022–5032. 2008. View Article : Google Scholar : PubMed/NCBI
14	Zhou Y, Cao HB, Li WJ and Zhao L: The CXCL12 (SDF-1)/CXCR4 chemokine axis: Oncogenic properties, molecular targeting, and synthetic and natural product CXCR4 inhibitors for cancer therapy. Chin J Nat Med. 16:801–810. 2018.PubMed/NCBI
15	Yu T, Wu Y, Huang Y, Yan C, Liu Y, Wang Z, Wang X, Wen Y, Wang C and Li L: RNAi targeting CXCR4 inhibits tumor growth through inducing cell cycle arrest and apoptosis. Mol Ther. 20:398–407. 2012. View Article : Google Scholar : PubMed/NCBI
16	Duan Y, Zhang S, Wang L, Zhou X, He Q, Liu S, Yue K and Wang X: Targeted silencing of CXCR4 inhibits epithelial-mesenchymal transition in oral squamous cell carcinoma. Oncol Lett. 12:2055–2061. 2016. View Article : Google Scholar : PubMed/NCBI
17	Wang X, Li F and Zhou X: miR-204-5p regulates cell proliferation and metastasis through inhibiting CXCR4 expression in OSCC. Biomed Pharmacother. 82:202–207. 2016. View Article : Google Scholar : PubMed/NCBI
18	Xia J, Chen N, Hong Y, Chen X, Tao X, Cheng B and Huang Y: Expressions of CXCL12/CXCR4 in oral premalignant and malignant lesions. Mediators Inflamm. 2012:5163952012. View Article : Google Scholar : PubMed/NCBI
19	Barbieri I and Kouzarides T: Role of RNA modifications in cancer. Nat Rev Cancer. 20:303–322. 2020. View Article : Google Scholar : PubMed/NCBI
20	Huang H, Weng H and Chen J: m⁶A modification in coding and non-coding RNAs: Roles and therapeutic implications in cancer. Cancer Cell. 37:270–288. 2020. View Article : Google Scholar : PubMed/NCBI
21	Barbieri I, Tzelepis K, Pandolfini L, Shi J, Millan-Zambrano G, Robson SC, Aspris D, Migliori V, Bannister AJ, Han N, et al: Promoter-bound METTL3 maintains myeloid leukaemia by m⁶A-dependent translation control. Nature. 552:126–131. 2017. View Article : Google Scholar : PubMed/NCBI
22	Cai X, Wang X, Cao C, Gao Y, Zhang S, Yang Z, Liu Y, Zhang X, Zhang W and Ye L: HBXIP-elevated methyltransferase METTL3 promotes the progression of breast cancer via inhibiting tumor suppressor let-7g. Cancer Lett. 415:11–19. 2018. View Article : Google Scholar : PubMed/NCBI
23	Xu J, Chen Q, Tian K, Liang R, Chen T, Gong A, Mathy NW, Yu T and Chen X: m6A methyltransferase METTL3 maintains colon cancer tumorigenicity by suppressing SOCS2 to promote cell proliferation. Oncol Rep. 44:973–986. 2020. View Article : Google Scholar : PubMed/NCBI
24	Liu L, Wu Y, Li Q, Liang J, He Q, Zhao L, Chen J, Cheng M, Huang Z, Ren H, et al: METTL3 promotes tumorigenesis and metastasis through BMI1 m⁶A methylation in oral squamous cell carcinoma. Mol Ther. 28:2177–2190. 2020. View Article : Google Scholar : PubMed/NCBI
25	Chen D, Wang H, Chen J, Li Z, Li S, Hu Z, Huang S, Zhao Y and He X: MicroRNA-129-5p regulates glycolysis and cell proliferation by targeting the glucose transporter SLC2A3 in gastric cancer cells. Front Pharmacol. 9:5022018. View Article : Google Scholar : PubMed/NCBI
26	Ling Q, Xu X, Wei X, Wang W, Zhou B, Wang B and Zheng S: Oxymatrine induces human pancreatic cancer PANC-1 cells apoptosis via regulating expression of Bcl-2 and IAP families, and releasing of cytochrome c. J Exp Clin Cancer Res. 30:662011. View Article : Google Scholar : PubMed/NCBI
27	Li S, Zhang Y, Liu Q, Zhao Q, Xu L, Huang S, Huang S and Wei X: Oxymatrine inhibits proliferation of human bladder cancer T24 cells by inducing apoptosis and cell cycle arrest. Oncol Lett. 13:4453–4458. 2017. View Article : Google Scholar : PubMed/NCBI
28	Caruz A, Samsom M, Alonso JM, Alcami J, Baleux F, Virelizier JL, Parmentier M and Arenzana-Seisdedos F: Genomic organization and promoter characterization of human CXCR4 gene. FEBS Lett. 426:271–278. 1998. View Article : Google Scholar : PubMed/NCBI
29	Jiang Q, Cao Y, Qiu Y, Li C, Liu L and Xu G: Progression of squamous cell carcinoma is regulated by miR-139-5p/CXCR4. Front Biosci (Landmark Ed). 25:1732–1745. 2020. View Article : Google Scholar : PubMed/NCBI
30	Zainal NS, Gan CP, Lau BF, Yee PS, Tiong KH, Abdul Rahman ZA, Patel V and Cheong SC: Zerumbone targets the CXCR4-RhoA and PI3K-mTOR signaling axis to reduce motility and proliferation of oral cancer cells. Phytomedicine. 39:33–41. 2018. View Article : Google Scholar : PubMed/NCBI
31	Nombela P, Miguel-López B and Blanco S: The role of m⁶A, m⁵C and Ψ RNA modifications in cancer: Novel therapeutic opportunities. Mol Cancer. 20:182021. View Article : Google Scholar : PubMed/NCBI
32	Pan Y, Ma P, Liu Y, Li W and Shu Y: Multiple functions of m⁶A RNA methylation in cancer. J Hematol Oncol. 11:482018. View Article : Google Scholar : PubMed/NCBI
33	Li F, Yi Y, Miao Y, Long W, Long T, Chen S, Cheng W, Zou C, Zheng Y, Wu X, et al: N⁶-methyladenosine modulates nonsense-mediated mRNA decay in human glioblastoma. Cancer Res. 79:5785–5798. 2019. View Article : Google Scholar : PubMed/NCBI
34	Yao QJ, Sang L, Lin M, Yin X, Dong W, Gong Y and Zhou BO: Mettl3-Mettl14 methyltransferase complex regulates the quiescence of adult hematopoietic stem cells. Cell Res. 28:952–954. 2018. View Article : Google Scholar : PubMed/NCBI
35	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
36	Zhao W, Cui Y, Liu L, Ma X, Qi X, Wang Y, Liu Z, Ma S, Liu J and Wu J: METTL3 facilitates oral squamous cell carcinoma tumorigenesis by enhancing c-Myc stability via YTHDF1-mediated m⁶A modification. Mol Ther Nucleic Acids. 20:1–12. 2020. View Article : Google Scholar : PubMed/NCBI
37	Ban Y, Tan P, Cai J, Li J, Hu M, Zhou Y, Mei Y, Tan Y, Li X, Zeng Z, et al: LNCAROD is stabilized by m6A methylation and promotes cancer progression via forming a ternary complex with HSPA1A and YBX1 in head and neck squamous cell carcinoma. Mol Oncol. 14:1282–1296. 2020. View Article : Google Scholar : PubMed/NCBI