Abstract
Colon cancer has been recognized as the major reason for global cancer-associated mortality. microRNA (miRNA, miR)-4429-5p has been documented to act as a tumor-suppressive miRNA in some cancers, but its effect on colon cancer remains elusive. In this study, the biological effects of miR-4429-5p were investigated both in vitro by MTT, 5-ethynyl-2′-deoxyuridine (EdU), wound healing, and transwell assays and in vivo by a xenograft mice model. Western blot, quantitative reverse transcription-polymerase chain reaction (qRT-PCR), and dual-luciferase assay were used to identify the binding of miR-4429-5p on matrix metalloproteinase 16 (MMP16) 3′-UTR. Our results suggested that overexpression of miR-4429-5p hindered colon cancer cell proliferation, migration, and invasion, whereas knockdown of miR-4429-5p exhibited the opposite effect in colon cancer cells. Mechanistically, miR-4429-5p directly bound to the 3′-UTR of MMP16 and led to inhibition of MMP16 protein. Overexpression of miR-4429-5p inhibited colon tumor growth by targeting MMP16. Taken together, our study revealed that miR-4429-5p prevented colon cancer progression through targeting MMP16, indicating miR-4429-5p as a promising target for treatment improvement for colon cancer.
Similar content being viewed by others
Data availability
The data that support the findings of this study are available from the corresponding author upon reasonable request.
References
Brenner H, Kloor M, Pox CP (2014) Colorectal cancer. Lancet 383(9927):1490–1502
Cao L, Chen C, Zhu H, Gu X, Deng D, Tian X, Liu J, Xiao Q (2016) MMP16 is a marker of poor prognosis in gastric cancer promoting proliferation and invasion. Oncotarget 7(32):51865–51874
Esquela-Kerscher A, Slack FJ (2006) Oncomirs - microRNAs with a role in cancer. Nat Rev Cancer 6(4):259–269
Gungormez C, Gumushan Aktas H, Dilsiz N, Borazan E (2019) Novel miRNAs as potential biomarkers in stage II colon cancer: microarray analysis. Mol Biol Rep 46(4):4175–4183
He H, Wu W, Sun Z, Chai L (2019) MiR-4429 prevented gastric cancer progression through targeting METTL3 to inhibit m(6)A-caused stabilization of SEC62. Biochem Biophys Res Commun 517(4):581–587
Kim VN, Han J, Siomi MC (2009) Biogenesis of small RNAs in animals. Nat Rev Mol Cell Biol 10(2):126–139
Li Y, Wang Y, Yu L, Sun C, Cheng D, Yu S, Wang Q, Yan Y, Kang C, Jin S, An T, Shi C, Xu J, Wei C, Liu J, Sun J, Wen Y, Zhao S, Kong Y (2013) miR-146b-5p inhibits glioma migration and invasion by targeting MMP16. Cancer Lett 339(2):260–269
Liang L, Zheng YW, Wang YL (2020) miR-4429 Regulates the proliferation, migration, invasion, and epithelial-mesenchymal transition of cervical cancer by targeting FOXM1. Cancer Manag Res 12:5301–5312
Lin S, Gregory RI (2015) MicroRNA biogenesis pathways in cancer. Nat Rev Cancer 15(6):321–333
Liu X, Chen R, Liu L (2019) SP1-DLEU1-miR-4429 feedback loop promotes cell proliferative and anti-apoptotic abilities in human glioblastoma. Biosci Rep 39(12)
Liu Y, Chen X, Cheng R, Yang F, Yu M, Wang C, Cui S, Hong Y, Liang H, Liu M, Zhao C, Ding M, Sun W, Liu Z, Sun F, Zhang C, Zhou Z, Jiang X, Chen X (2018) The Jun/miR-22/HuR regulatory axis contributes to tumourigenesis in colorectal cancer. Mol Cancer 17(1):11
Nakada M, Nakamura H, Ikeda E, Fujimoto N, Yamashita J, Sato H, Seiki M, Okada Y (1999) Expression and tissue localization of membrane-type 1, 2, and 3 matrix metalloproteinases in human astrocytic tumors. Am J Pathol 154(2):417–428
Nishihara R, Wu K, Lochhead P, Morikawa T, Liao X, Qian ZR, Inamura K, Kim SA, Kuchiba A, Yamauchi M, Imamura Y, Willett WC, Rosner BA, Fuchs CS, Giovannucci E, Ogino S, Chan AT (2013) Long-term colorectal-cancer incidence and mortality after lower endoscopy. N Engl J Med 369(12):1095–1105
Pan H, Hong Y, Yu B, Li L, Zhang X (2019) miR-4429 inhibits tumor progression and epithelial-mesenchymal transition via targeting CDK6 in clear cell renal cell carcinoma. Cancer Biother Radiopharm 34(5):334–341
Ren F, Tang R, Zhang X, Madushi WM, Luo D, Dang Y, Li Z, Wei K, Chen G (2015) Overexpression of MMP family members functions as prognostic biomarker for breast cancer patients: a systematic review and meta-analysis. PLoS One 10(8):e0135544
Rowe RG, Weiss SJ (2008) Breaching the basement membrane: who, when and how? Trends Cell Biol 18(11):560–574
Sadanandam A, Lyssiotis CA, Homicsko K, Collisson EA, Gibb WJ, Wullschleger S, Ostos LC, Lannon WA, Grotzinger C, Del Rio M, Lhermitte B, Olshen AB, Wiedenmann B, Cantley LC, Gray JW, Hanahan D (2013) A colorectal cancer classification system that associates cellular phenotype and responses to therapy. Nat Med 19(5):619–625
Shen Z, Wang X, Yu X, Zhang Y, Qin L (2017) MMP16 promotes tumor metastasis and indicates poor prognosis in hepatocellular carcinoma. Oncotarget 8(42):72197–72204
Shinkai K, Nakano K, Cui L, Mizuuchi Y, Onishi H, Oda Y, Obika S, Tanaka M, Katano M (2016) Nuclear expression of Y-box binding protein-1 is associated with poor prognosis in patients with pancreatic cancer and its knockdown inhibits tumor growth and metastasis in mice tumor models. Int J Cancer 139(2):433–445
Song H, Li Y, Lee J, Schwartz AL, Bu G (2009) Low-density lipoprotein receptor-related protein 1 promotes cancer cell migration and invasion by inducing the expression of matrix metalloproteinases 2 and 9. Cancer Res 69(3):879–886
Sun H, Fan G, Deng C, Wu L (2020) miR-4429 sensitized cervical cancer cells to irradiation by targeting RAD51. J Cell Physiol 235(1):185–193
Tatti O, Gucciardo E, Pekkonen P, Holopainen T, Louhimo R, Repo P, Maliniemi P, Lohi J, Rantanen V, Hautaniemi S, Alitalo K, Ranki A, Ojala PM, Keski-Oja J, Lehti K (2015) MMP16 mediates a proteolytic switch to promote cell-cell adhesion, collagen alignment, and lymphatic invasion in melanoma. Cancer Res 75(10):2083–2094
Wang H, Li XT, Wu C, Wu ZW, Li YY, Yang TQ, Chen GL, Xie XS, Huang YL, Du ZW, Zhou YX (2015) miR-132 can inhibit glioma cells invasion and migration by target MMP16 in vitro. Onco Targets Ther 8:3211–3218
Wu S, Ma C, Shan S, Zhou L, Li W (2017) High expression of matrix metalloproteinases 16 is associated with the aggressive malignant behavior and poor survival outcome in colorectal carcinoma. Sci Rep 7:46531
Wu WJ, Yin H, Hu JJ, Wei XZ (2018) Long noncoding RNA LINC00313 modulates papillary thyroid cancer tumorigenesis via sponging miR-4429. Neoplasma 65(6):933–942
Xu M, Chen X, Lin K, Zeng K, Liu X, Pan B, Xu X, Xu T, Hu X, Sun L, He B, Pan Y, Sun H, Wang S (2018) The long noncoding RNA SNHG1 regulates colorectal cancer cell growth through interactions with EZH2 and miR-154-5p. Mol Cancer 17(1):141
Xu XT, Xu Q, Tong JL, Zhu MM, Nie F, Chen X, Xiao SD, Ran ZH (2012) MicroRNA expression profiling identifies miR-328 regulates cancer stem cell-like SP cells in colorectal cancer. Br J Cancer 106(7):1320–1330
Zeng K, Chen X, Xu M, Liu X, Hu X, Xu T, Sun H, Pan Y, He B, Wang S (2018) CircHIPK3 promotes colorectal cancer growth and metastasis by sponging miR-7. Cell Death Dis 9(4):417
Zhang Y, Wang Y, Wei Y, Li M, Yu S, Ye M, Zhang H, Chen S, Liu W, Zhang J (2015) MiR-129-3p promotes docetaxel resistance of breast cancer cells via CP110 inhibition. Sci Rep 5:15424
Zhu YM, Chen P, Shi L, Zhu T, Chen X (2020) MiR-4429 suppresses the malignant development of ovarian cancer by targeting YOD1. Eur Rev Med Pharmacol Sci 24(17):8722–8730
Author information
Authors and Affiliations
Contributions
Wei Li and Liang Wang contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Wei Li, Zhe Song, Nan Jia, and Cui Zhang. The first draft of the manuscript was written by Wei Li. Weina Gao and Liang Wang contributed reagents, materials, and analysis tools. All authors read and approved the final manuscript.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare they have no conflict of interest.
Additional information
Editor: Tetsuji Okamoto
Supplementary information
ESM 1
(PNG 340 kb)
Rights and permissions
About this article
Cite this article
Li, W., Song, Z., Jia, N. et al. microRNA-4429-5p suppresses the malignant development of colon cancer by targeting matrix metalloproteinase 16. In Vitro Cell.Dev.Biol.-Animal 57, 715–725 (2021). https://doi.org/10.1007/s11626-021-00603-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11626-021-00603-4