https://doi.org/10.4081/ejh.2022.3333
microRNA-16-5p suppresses cell proliferation and angiogenesis in colorectal cancer by negatively regulating forkhead box K1 to block the PI3K/Akt/mTOR pathway
Submitted: 23 September 2021
Accepted: 23 March 2022
Published: 10 May 2022
Accepted: 23 March 2022
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All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
Authors
MicroRNAs (miRNAs/miRs) have aroused increasing attention in colorectal cancer (CRC) therapy. This study is designed for a detailed analysis of the roles of miR-16-5p and forkhead box K1 (FOXK1) in cell angiogenesis and proliferation during CRC in addition to their underlying mechanisms. CRC tissues and colon cancer cell lines (SW620 and HCT8) were investigated. qRT-PCR and Western blot were utilized to evaluate miR-16-5p and FOXK1 expression. Following gain- and loss-of-function assays on miR-16-5p or FOXK1, the effects of miR-16-5p and FOXK1 were assessed on cell angiogenesis and proliferation in CRC cells. A dual-luciferase reporter assay was employed to evaluate the binding relationship of miR-16-5p and FOXK1. Western blot was used to determine the effects of miR-16-5p and FOXK1 on key molecules of the PI3K/Akt/mTOR pathway. Highly expressed FOXK1 and lowly expressed miR-16-5p were observed in CRC cells and tissues. miR-16-5p overexpression or FOXK1 knockdown reduced CRC cell proliferation and angiogenesis of human umbilical vein endothelial cells co-cultured with the supernatant of CRC cells, whereas miR-16-5p silencing or FOXK1 upregulation caused opposite trends. Additionally, miR-16-5p negatively modulated FOXK1 expression. The blockade of the PI3K/Akt/mTOR pathway was triggered by miR-16-5p overexpression or FOXK1 silencing. In conclusion, miR-16-5p hampers cell angiogenesis and proliferation during CRC by targeting FOXK1 to block the PI3K/Akt/mTOR pathway.
Lan J, Li H, Luo X, Hu J, Wang G. BRG1 promotes VEGF-A expression and angiogenesis in human colorectal cancer cells. Exp Cell Res 2017;360:236-42.
DOI: https://doi.org/10.1016/j.yexcr.2017.09.013
Wei R, Yang Q, Han B, Li Y, Yao K, Yang X, et al. microRNA-375 inhibits colorectal cancer cells proliferation by downregulating JAK2/STAT3 and MAP3K8/ERK signaling pathways. Oncotarget 2017;8:16633-41.
DOI: https://doi.org/10.18632/oncotarget.15114
Jeon J, Du M, Schoen RE, Hoffmeister M, Newcomb PA, Berndt SI, et al. Determining risk of colorectal cancer and starting age of screening based on lifestyle, environmental, and genetic factors. Gastroenterology 2018;154:2152-64.e19.
DOI: https://doi.org/10.1053/j.gastro.2018.02.021
Zhu P, Wu Y, Yang A, Fu X, Mao M, Liu Z. Catalpol suppressed proliferation, growth and invasion of CT26 colon cancer by inhibiting inflammation and tumor angiogenesis. Biomed Pharmacother 2017;95:68-76.
DOI: https://doi.org/10.1016/j.biopha.2017.08.049
Sun D, Zhang F, Qian J, Shen W, Fan H, Tan J, et al. 4'-hydroxywogonin inhibits colorectal cancer angiogenesis by disrupting PI3K/AKT signaling. Chem Biol Interact 2018;296:26-33.
DOI: https://doi.org/10.1016/j.cbi.2018.09.003
Tawfik MK, Mohamed MI. Exenatide suppresses 1,2-dimethylhydrazine-induced colon cancer in diabetic mice: Effect on tumor angiogenesis and cell proliferation. Biomed Pharmacother 2016;82:106-16.
DOI: https://doi.org/10.1016/j.biopha.2016.05.005
Yang Y, Bao Y, Yang GK, Wan J, Du LJ, Ma ZH. MiR-214 sensitizes human colon cancer cells to 5-FU by targeting Hsp27. Cell Mol Biol Lett 2019;24:22.
DOI: https://doi.org/10.1186/s11658-019-0143-3
Ding L, Yu LL, Han N, Zhang BT. miR-141 promotes colon cancer cell proliferation by inhibiting MAP2K4. Oncol Lett 2017;13:1665-71.
DOI: https://doi.org/10.3892/ol.2017.5653
Vychytilova-Faltejskova P, Radova L, Sachlova M, Kosarova Z, Slaba K, Fabian P, et al. Serum-based microRNA signatures in early diagnosis and prognosis prediction of colon cancer. Carcinogenesis 2016;37:941-50.
DOI: https://doi.org/10.1093/carcin/bgw078
Zeng M, Zhu L, Li L, Kang C. miR-378 suppresses the proliferation, migration and invasion of colon cancer cells by inhibiting SDAD1. Cell Mol Biol Lett 2017;22:12.
DOI: https://doi.org/10.1186/s11658-017-0041-5
Basu A, Jiang X, Negrini M, Haldar S. MicroRNA-mediated regulation of pancreatic cancer cell proliferation. Oncol Lett 2010;1:565-8.
DOI: https://doi.org/10.3892/ol_00000100
Jia X, Li X, Shen Y, Miao J, Liu H, Li G, et al. MiR-16 regulates mouse peritoneal macrophage polarization and affects T-cell activation. J Cell Mol Med 2016;20:1898-907.
DOI: https://doi.org/10.1111/jcmm.12882
Li N, Yang L, Sun Y, Wu X. MicroRNA-16 inhibits migration and invasion via regulation of the Wnt/beta-catenin signaling pathway in ovarian cancer. Oncol Lett 2019;17:2631-8.
DOI: https://doi.org/10.3892/ol.2019.9923
Wu H, Wei M, Jiang X, Tan J, Xu W, Fan X, et al. lncRNA PVT1 promotes tumorigenesis of colorectal cancer by stabilizing miR-16-5p and interacting with the VEGFA/VEGFR1/AKT axis. Mol Ther Nucleic Acids 2020;20:438-50.
DOI: https://doi.org/10.1016/j.omtn.2020.03.006
Zhu T, Lin Z, Han S, Wei Y, Lu G, Zhang Y, et al. Low miR-16 expression induces regulatory CD4(+)NKG2D(+) T cells involved in colorectal cancer progression. Am J Cancer Res 2021;11:1540-56.
Huang X, Hou Y, Weng X, Pang W, Hou L, Liang Y, et al. Diethyldithiocarbamate-copper complex (CuET) inhibits colorectal cancer progression via miR-16-5p and 15b-5p/ALDH1A3/PKM2 axis-mediated aerobic glycolysis pathway. Oncogenesis 2021;10:4.
DOI: https://doi.org/10.1038/s41389-020-00295-7
Gao F, Tian J. FOXK1, regulated by miR-365-3p, promotes cell growth and EMT indicates unfavorable prognosis in breast cancer. Onco Targets Ther 2020;13:623-34.
DOI: https://doi.org/10.2147/OTT.S212702
Garry DJ, Maeng G, Garry MG. Foxk1 regulates cancer progression. Ann Transl Med 2020;8:1041.
DOI: https://doi.org/10.21037/atm-2020-94
Wang Y, Qiu W, Liu N, Sun L, Liu Z, Wang S, et al. Forkhead box K1 regulates the malignant behavior of gastric cancer by inhibiting autophagy. Ann Transl Med 2020;8:107.
DOI: https://doi.org/10.21037/atm.2019.12.123
Feng Y, Bai Z, Song J, Zhang Z. FOXK1 plays an oncogenic role in the progression of hilar cholangiocarcinoma. Mol Med Rep 2021;23:91.
DOI: https://doi.org/10.3892/mmr.2020.11730
Wang J, Liu G, Liu M, Xiang L, Xiao Y, Zhu H, et al. The FOXK1-CCDC43 axis promotes the invasion and metastasis of colorectal cancer cells. Cell Physiol Biochem 2018;51:2547-63.
DOI: https://doi.org/10.1159/000495924
Xie R, Wang J, Liu X, Wu L, Zhang H, Tang W, et al. RUFY3 interaction with FOXK1 promotes invasion and metastasis in colorectal cancer. Sci Rep 2017;7:3709.
DOI: https://doi.org/10.1038/s41598-017-04011-1
Li C, Xu N, Li YQ, Wang Y, Zhu ZT. Inhibition of SW620 human colon cancer cells by upregulating miRNA-145. World J Gastroenterol 2016;22:2771-8.
DOI: https://doi.org/10.3748/wjg.v22.i9.2771
Zheng B, Chen L, Pan CC, Wang JZ, Lu GR, Yang SX, et al. Targeted delivery of miRNA-204-5p by PEGylated polymer nanoparticles for colon cancer therapy. Nanomedicine (Lond) 2018;13:769-85.
DOI: https://doi.org/10.2217/nnm-2017-0345
Fang X, Hong Y, Dai L, Qian Y, Zhu C, Wu B, et al. CRH promotes human colon cancer cell proliferation via IL-6/JAK2/STAT3 signaling pathway and VEGF-induced tumor angiogenesis. Mol Carcinog 2017;56:2434-45.
DOI: https://doi.org/10.1002/mc.22691
Liu Y, Zhou J, Wang S, Song Y, Zhou J, Ren F. Long non-coding RNA SNHG12 promotes proliferation and invasion of colorectal cancer cells by acting as a molecular sponge of microRNA-16. Exp Ther Med 2019;18:1212-20.
DOI: https://doi.org/10.3892/etm.2019.7650
Cheng B, Ding F, Huang CY, Xiao H, Fei FY, Li J. Role of miR-16-5p in the proliferation and metastasis of hepatocellular carcinoma. Eur Rev Med Pharmacol Sci 2019;23:137-45.
Wu W, Chen Y, Ye S, Yang H, Yang J, Quan J. Transcription factor forkhead box K1 regulates miR-32 expression and enhances cell proliferation in colorectal cancer. Oncol Lett 2021;21:407.
DOI: https://doi.org/10.3892/ol.2021.12668
Xu Y, Shen L, Li F, Yang J, Wan X, Ouyang M. microRNA-16-5p-containing exosomes derived from bone marrow-derived mesenchymal stem cells inhibit proliferation, migration, and invasion, while promoting apoptosis of colorectal cancer cells by downregulating ITGA2. J Cell Physiol 2019;234:21380-94.
DOI: https://doi.org/10.1002/jcp.28747
Zheng C, Zheng Z, Sun J, Zhang Y, Wei C, Ke X, et al. MiR-16-5p mediates a positive feedback loop in EV71-induced apoptosis and suppresses virus replication. Sci Rep 2017;7:16422.
DOI: https://doi.org/10.1038/s41598-017-16616-7
Toro R, Perez-Serra A, Mangas A, Campuzano O, Sarquella-Brugada G, Quezada-Feijoo M, et al. miR-16-5p suppression protects human cardiomyocytes against endoplasmic reticulum and oxidative stress-induced injury. Int J Mol Sci 2022;23:1036.
DOI: https://doi.org/10.3390/ijms23031036
Lv JN, Li JQ, Cui YB, Ren YY, Fu YJ, Jiang YJ, et al. Plasma microRNA signature panel predicts the immune response after antiretroviral therapy in HIV-infected patients. Front Immunol 2021;12:753044.
DOI: https://doi.org/10.3389/fimmu.2021.753044
Ji ZG, Jiang HT, Zhang PS. FOXK1 promotes cell growth through activating wnt/beta-catenin pathway and emerges as a novel target of miR-137 in glioma. Am J Transl Res 2018;10:1784-92.
Xu H, Huang S, Zhu X, Zhang W, Zhang X. FOXK1 promotes glioblastoma proliferation and metastasis through activation of Snail transcription. Exp Ther Med 2018;15:3108-16.
DOI: https://doi.org/10.3892/etm.2018.5732
Li L, Gong M, Zhao Y, Zhao X, Li Q. FOXK1 facilitates cell proliferation through regulating the expression of p21, and promotes metastasis in ovarian cancer. Oncotarget 2017;8:70441-51.
DOI: https://doi.org/10.18632/oncotarget.19713
Wu M, Wang J, Tang W, Zhan X, Li Y, Peng Y, et al. FOXK1 interaction with FHL2 promotes proliferation, invasion and metastasis in colorectal cancer. Oncogenesis 2016;5:e271.
DOI: https://doi.org/10.1038/oncsis.2016.68
Wu Y, Peng Y, Wu M, Zhang W, Zhang M, Xie R, et al. Oncogene FOXK1 enhances invasion of colorectal carcinoma by inducing epithelial-mesenchymal transition. Oncotarget 2016;7:51150-62.
DOI: https://doi.org/10.18632/oncotarget.9457
Zhang D, Wang S, Chen J, Liu H, Lu J, Jiang H, et al. Fibulin-4 promotes osteosarcoma invasion and metastasis by inducing epithelial to mesenchymal transition via the PI3K/Akt/mTOR pathway. Int J Oncol 2017;50:1513-30.
DOI: https://doi.org/10.3892/ijo.2017.3921
Ghafouri-Fard S, Abak A, Tondro Anamag F, Shoorei H, Majidpoor J, Taheri M. The emerging role of non-coding RNAs in the regulation of PI3K/AKT pathway in the carcinogenesis process. Biomed Pharmacother 2021;137:111279.
DOI: https://doi.org/10.1016/j.biopha.2021.111279
Zhang X, Shi H, Tang H, Fang Z, Wang J, Cui S. miR-218 inhibits the invasion and migration of colon cancer cells by targeting the PI3K/Akt/mTOR signaling pathway. Int J Mol Med 2015;35:1301-8.
DOI: https://doi.org/10.3892/ijmm.2015.2126
Liu Y, Bi T, Wang Z, Wu G, Qian L, Gao Q, et al. Oxymatrine synergistically enhances antitumor activity of oxaliplatin in colon carcinoma through PI3K/AKT/mTOR pathway. Apoptosis 2016;21:1398-407.
DOI: https://doi.org/10.1007/s10495-016-1297-3
How to Cite
Huang, X. ., Xu, X. ., Ke, H. ., Pan, X. ., Ai, J. ., Xie, R. ., … Wu, Y. (2022). microRNA-16-5p suppresses cell proliferation and angiogenesis in colorectal cancer by negatively regulating forkhead box K1 to block the PI3K/Akt/mTOR pathway. European Journal of Histochemistry, 66(2). https://doi.org/10.4081/ejh.2022.3333
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