Huaier promotes sensitivity of colorectal cancer to oxaliplatin by inhibiting METTL3 to regulate the Wnt/&beta;‑catenin signaling pathway

Huo,Mingyi; Gao,Zhixu; Wang,Guizhen; Hou,Zhiping; Zheng,Jining

doi:10.3892/or.2024.8840

Huaier promotes sensitivity of colorectal cancer to oxaliplatin by inhibiting METTL3 to regulate the Wnt/β‑catenin signaling pathway

Authors:
- Mingyi Huo
- Zhixu Gao
- Guizhen Wang
- Zhiping Hou
- Jining Zheng
View Affiliations

Affiliations: Department of Pathophysiology, Chengde Medical University, Chengde, Hebei 067000, P.R. China, Department of Traditional Chinese Medicine, Chengde Medical University, Chengde, Hebei 067000, P.R. China
Published online on: November 8, 2024 https://doi.org/10.3892/or.2024.8840
Article Number: 7
Copyright: © Huo et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Colorectal cancer (CRC) ranks fifth in terms of incidence rate and mortality among malignant tumors in China. Oxaliplatin (OXA) is a first‑line drug for the clinical treatment of CRC, but its antitumor effect is limited because of the development of drug resistance. The present study aimed to investigate whether the traditional Chinese medicine Huaier can regulate the Wnt/β‑catenin signaling pathway by affecting the expression of METTL3, thereby promoting the sensitivity of HCT‑8/L cells to OXA. The expression of METTL3 was analyzed based on the UCSC Xena and Gene Expression Omnibus databases. Silent METTL3 and overexpression METTL3 models were constructed, and Cell Counting Kit‑8 and flow cytometry were used to detect the effects of Huaier on the viability and apoptosis of HCT‑8/L cells. Western blotting, reverse transcription‑quantitative PCR, nuclear cytoplasmic separation and immunofluorescence were used to detect the effects of Huaier on the expression of METTL3, Pgp, Wnt/β‑catenin signaling pathway‑related proteins, apoptosis‑related proteins and related mRNA. The results demonstrated that patients with high expression levels of METTL3 had a shorter overall survival period. The expression level of METTL3 significantly increased in drug‑resistant CRC cells. Silencing METTL3 promoted apoptosis of CRC cells and increased their sensitivity to OXA by inhibiting the Wnt/β‑catenin signaling pathway. Huaier downregulated the expression of METTL3, thereby promoting apoptosis of drug‑resistant CRC cells and increasing their sensitivity to OXA by inhibiting the Wnt/β‑catenin signaling pathway.

View Figures

View References

1	Xi Y and Xu P: Global colorectal cancer burden in 2020 and projections to 2040. Transl Oncol. 14:1011742021. View Article : Google Scholar : PubMed/NCBI
2	Wang Z, Dan W, Zhang N, Fang J and Yang Y: Colorectal cancer and gut microbiota studies in China. Gut Microbes. 15:22363642023. View Article : Google Scholar : PubMed/NCBI
3	He K, Wang Y, Zhong Y, Pan X, Si L and Lu J: KRAS codon 12 mutation is associated with more aggressive invasiveness in synchronous metastatic colorectal cancer (mCRC): Retrospective research. Onco Targets Ther. 13:12601–12613. 2020. View Article : Google Scholar : PubMed/NCBI
4	Van der Jeught K, Xu HC, Li YJ, Lu XB and Ji G: Drug resistance and new therapies in colorectal cancer. World J Gastroenterol. 24:3834–3848. 2018. View Article : Google Scholar : PubMed/NCBI
5	Douillard JY, Cunningham D, Roth AD, Navarro M, James RD, Karasek P, Jandik P, Iveson T, Carmichael J, Alakl M, et al: Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: A multicentre randomised trial. Lancet. 355:1041–1047. 2000. View Article : Google Scholar : PubMed/NCBI
6	Giacchetti S, Perpoint B, Zidani R, Le Bail N, Faggiuolo R, Focan C, Chollet P, Llory JF, Letourneau Y, Coudert B, et al: Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol. 18:136–147. 2000. View Article : Google Scholar : PubMed/NCBI
7	Lee YT, Tan YJ and Oon CE: Molecular targeted therapy: Treating cancer with specificity. Eur J Pharmacol. 834:188–196. 2018. View Article : Google Scholar : PubMed/NCBI
8	Ohishi T, Kaneko MK, Yoshida Y, Takashima A, Kato Y and Kawada M: Current targeted therapy for metastatic colorectal cancer. Int J Mol Sci. 24:17022023. View Article : Google Scholar : PubMed/NCBI
9	Ganesh K, Stadler ZK, Cercek A, Mendelsohn RB, Shia J, Segal NH and Diaz LA Jr: Immunotherapy in colorectal cancer: Rationale, challenges and potential. Nat Rev Gastroenterol Hepatol. 16:361–375. 2019. View Article : Google Scholar : PubMed/NCBI
10	Overman MJ, Ernstoff MS and Morse MA: Where we stand with immunotherapy in colorectal cancer: Deficient mismatch repair, proficient mismatch repair, and toxicity management. Am Soc Clin Oncol Educ Book. 38:239–247. 2018. View Article : Google Scholar : PubMed/NCBI
11	Szakács G, Paterson JK, Ludwig JA, Booth-Genthe C and Gottesman MM: Targeting multidrug resistance in cancer. Nat Rev Drug Discov. 5:219–234. 2006. View Article : Google Scholar : PubMed/NCBI
12	Dean M, Rzhetsky A and Allikmets R: The human ATP-binding cassette (ABC) transporter superfamily. Genome Res. 11:1156–1166. 2001. View Article : Google Scholar : PubMed/NCBI
13	Ma Y, Guo C, Wang X, Wei X and Ma J: Impact of chemotherapeutic agents on liver microenvironment: Oxaliplatin create a pro-metastatic landscape. J Exp Clin Cancer Res. 42:2372023. View Article : Google Scholar : PubMed/NCBI
14	Wu CP, Calcagno AM and Ambudkar SV: Reversal of ABC drug transporter-mediated multidrug resistance in cancer cells: Evaluation of current strategies. Curr Mol Pharmacol. 1:93–105. 2008. View Article : Google Scholar : PubMed/NCBI
15	Li M, Xia M, Zhang Z, Tan Y, Li E, Guo Z, Fang M, Zhu Y and Hu Z: METTL3 antagonizes 5-FU chemotherapy and confers drug resistance in colorectal carcinoma. Int J Oncol. 61:1062022. View Article : Google Scholar : PubMed/NCBI
16	Liu S, Zhuo L, Wang J, Zhang Q, Li Q, Li G, Yan L, Jin T, Pan T, Sui X, et al: METTL3 plays multiple functions in biological processes. Am J Cancer Res. 10:1631–1646. 2020.PubMed/NCBI
17	El-Shami K, Oeffinger KC, Erb NL, Willis A, Bretsch JK, Pratt-Chapman ML, Cannady RS, Wong SL, Rose J, Barbour AL, et al: American cancer society colorectal cancer survivorship care guidelines. CA Cancer J Clin. 65:428–455. 2015. View Article : Google Scholar : PubMed/NCBI
18	Pachman DR, Qin R, Seisler DK, Smith EML, Beutler AS, Ta LE, Lafky JM, Wagner-Johnston ND, Ruddy KJ, Dakhil S, et al: Clinical course of oxaliplatin-induced neuropathy: Results from the randomized phase III trial N08CB (alliance). J Clin Oncol. 33:3416–3422. 2015. View Article : Google Scholar : PubMed/NCBI
19	Chen JF, Wu SW, Shi ZM and Hu B: Traditional Chinese medicine for colorectal cancer treatment: Potential targets and mechanisms of action. Chin Med. 18:142023. View Article : Google Scholar : PubMed/NCBI
20	Chen Y, Wu H, Wang X, Wang C, Gan L, Zhu J, Tong J and Li Z: Huaier Granule extract inhibit the proliferation and metastasis of lung cancer cells through down-regulation of MTDH, JAK2/STAT3 and MAPK signaling pathways. Biomed Pharmacother. 101:311–321. 2018. View Article : Google Scholar : PubMed/NCBI
21	Hu B, Yan W, Wang M, Cui X, Hu Y, Chen Q, Zhang Y, Qi X and Jiang J: Huaier polysaccharide inhibits the stem-like characteristics of ERα-36^high triple negative breast cancer cells via inactivation of the ERα-36 signaling pathway. Int J Biol Sci. 15:1358–1367. 2019. View Article : Google Scholar : PubMed/NCBI
22	Liu Z, Liu C, Yan K, Liu J, Fang Z and Fan Y: Huaier extract inhibits prostate cancer growth via targeting AR/AR-V7 pathway. Front Oncol. 11:6155682021. View Article : Google Scholar : PubMed/NCBI
23	Su D, Jiang B, Yang Y, Miao Y, Fu Q and Zhang F: Effect of Huaier on melanoma invasion, metastasis, and angiogenesis. Biomed Res Int. 2020:81638392020. View Article : Google Scholar : PubMed/NCBI
24	Pan J, Yang C, Jiang Z and Huang J: Trametes robiniophila Murr: A traditional Chinese medicine with potent anti-tumor effects. Cancer Manag Res. 11:1541–1549. 2019. View Article : Google Scholar : PubMed/NCBI
25	Xu DQ, Yuan XJ, Toyoda H and Hirayama M: Anti-tumor effect of Huaier extract against neuroblastoma cells in vitro. Int J Med Sci. 18:1015–1023. 2021. View Article : Google Scholar : PubMed/NCBI
26	Ji D, Zheng W, Huang P, Yao Y, Zhong X, Kang P, Wang Z, Shi G, Xu Y and Cui Y: Huaier restrains cholangiocarcinoma progression in vitro and in vivo through modulating lncRNA TP73-AS1 and inducing oxidative stress. Onco Targets Ther. 13:7819–7837. 2020. View Article : Google Scholar : PubMed/NCBI
27	Luo Z, Hu X, Xiong H, Qiu H, Yuan X, Zhu F, Wang Y and Zou Y: A polysaccharide from Huaier induced apoptosis in MCF-7 breast cancer cells via down-regulation of MTDH protein. Carbohydr Polym. 151:1027–1033. 2016. View Article : Google Scholar : PubMed/NCBI
28	Hu Z, Yang A, Fan H, Wang Y, Zhao Y, Zha X, Zhang H and Tu P: Huaier aqueous extract sensitizes cells to rapamycin and cisplatin through activating mTOR signaling. J Ethnopharmacol. 186:143–150. 2016. View Article : Google Scholar : PubMed/NCBI
29	Fang L, Zhang Y, Zang Y, Chai R, Zhong G, Li Z, Duan Z, Ren J and Xu Z: HP-1 inhibits the progression of ccRCC and enhances sunitinib therapeutic effects by suppressing EMT. Carbohydr Polym. 223:1151092019. View Article : Google Scholar : PubMed/NCBI
30	Yan X, Lyu T, Jia N, Yu Y, Hua K and Feng W: Huaier aqueous extract inhibits ovarian cancer cell motility via the AKT/GSK3β/β-catenin pathway. PLoS One. 8:e637312013. View Article : Google Scholar : PubMed/NCBI
31	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
32	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
33	Yang Z, Zhang X, Bai X, Xi X, Liu W and Zhong W: Anti-angiogenesis in colorectal cancer therapy. Cancer Sci. 115:734–751. 2024. View Article : Google Scholar : PubMed/NCBI
34	Yu T, Guo F, Yu Y, Sun T, Ma D, Han J, Qian Y, Kryczek I, Sun D, Nagarsheth N, et al: Fusobacterium nucleatum promotes chemoresistance to colorectal cancer by modulating autophagy. Cell. 170:548–563.e16. 2017. View Article : Google Scholar : PubMed/NCBI
35	Visvanathan A, Patil V, Arora A, Hegde AS, Arivazhagan A, Santosh V and Somasundaram K: Essential role of METTL3-mediated m⁶A modification in glioma stem-like cells maintenance and radioresistance. Oncogene. 37:522–533. 2018. View Article : Google Scholar : PubMed/NCBI
36	Peng W, Li J, Chen R, Gu Q, Yang P, Qian W, Ji D, Wang Q, Zhang Z, Tang J and Sun Y: Upregulated METTL3 promotes metastasis of colorectal cancer via miR-1246/SPRED2/MAPK signaling pathway. J Exp Clin Cancer Res. 38:3932019. View Article : Google Scholar : PubMed/NCBI
37	Liu X, Su K, Sun X, Jiang Y, Wang L, Hu C, Zhang C, Lu M, Du X and Xing B: Sec62 promotes stemness and chemoresistance of human colorectal cancer through activating Wnt/β-catenin pathway. J Exp Clin Cancer Res. 40:1322021. View Article : Google Scholar : PubMed/NCBI
38	Kong MY, Li LY, Lou YM, Chi HY and Wu JJ: Chinese herbal medicines for prevention and treatment of colorectal cancer: From molecular mechanisms to potential clinical applications. J Integr Med. 18:369–384. 2020. View Article : Google Scholar : PubMed/NCBI
39	Yan Z, Lai Z and Lin J: Anticancer properties of traditional Chinese medicine. Comb Chem High Throughput Screen. 20:423–429. 2017. View Article : Google Scholar : PubMed/NCBI
40	Zhang Y, Liu X, Yu M, Xu M, Xiao Y, Ma W, Huang L, Li X and Ye X: Berberine inhibits proliferation and induces G0/G1 phase arrest in colorectal cancer cells by downregulating IGF2BP3. Life Sci. 260:1184132020. View Article : Google Scholar : PubMed/NCBI
41	Qiao L, Han M, Gao S, Shao X, Wang X, Sun L, Fu X and Wei Q: Research progress on nanotechnology for delivery of active ingredients from traditional Chinese medicines. J Mater Chem B. 8:6333–6351. 2020. View Article : Google Scholar : PubMed/NCBI
42	Zhou C, Li J, Qian W, Yue Y, Xiao Y, Qin T, Ma Q and Li X: Huaier extract restrains pancreatic cancer by suppressing Wnt/β-catenin pathway. Biomed Pharmacother. 127:1101262020. View Article : Google Scholar : PubMed/NCBI
43	Sun WW, Dou JX, Zhang L, Qiao LK, Shen N, Zhao Q and Gao WY: Killing effects of Huaier Granule combined with DC-CIK on nude mice transplanted with colon carcinoma cell line. Oncotarget. 8:46081–46089. 2017. View Article : Google Scholar : PubMed/NCBI
44	Cong L, Shi J, Zhao J, Li K, Dai D, Zhang B and Zhao W: Huaier inhibits cholangiocarcinoma cells through the twist1/FBP1/Wnt/β-catenin axis. Mol Biol Rep. 51:8422024. View Article : Google Scholar : PubMed/NCBI