Abstract
Neurofibromatosis type I (NF1) is a carcinoma mainly featured by malignant peripheral nerve sheath tumor (MPNST). Dysregulated microRNAs (miRNAs) play decisive roles in tumor initiation and development. Our study sought for the possible roles of miR-612 in NF1. RT-qPCR estimated the expression of nuclear factor kappa B subunit 1 (NFKB1), miR-612, and Fas apoptotic inhibitory molecule 2 (FAIM2) in NF1, separately. Cell proliferation and migration were detected by CCK-8 and transwell experiments. Cell apoptosis was measured via flow cytometry and detection of the expression and activity of caspase 3/8/9. Luciferase reporter, ChIP, and RIP assays testified the interplay between studied genes. Rescue and in vivo assays affirmed the whole mechanism of miR-612 in NF1. We indicated that miR-612 was significantly low in tumor tissues and cells. Mechanism experiments confirmed that miR-612 promotion repressed cell proliferation and migration, and induced cell apoptosis. Besides, NFKB1-regulated miR-612 targeted FAIM2. Spearman’s correlation analysis validated the correlation between each two genes. Finally, rescue and in vivo assays affirmed that miR-612 targeted FAIM2 to regulate cellular activities of NF1. The current investigation uncovered the molecular mechanism underlying miR-612 in NF1, establishing miR-612 as a novel therapeutic target for the treatment of NF1 patients.
Similar content being viewed by others
References
Bieg D, Sypniewski D, Nowak E, Bednarek I (2018) MiR-424-3p suppresses galectin-3 expression and sensitizes ovarian cancer cells to cisplatin. Arch Gynecol Obstet 299:1077–1087. https://doi.org/10.1007/s00404-018-4999-7
Cartwright T, Perkins ND, LW C (2016) NFKB1: a suppressor of inflammation, ageing and cancer. FEBS J 283:1812–1822
Chai G, Liu N, Ma J, Li H, Oblinger JL, Prahalad AK, Gong M, Chang LS, Wallace M, Muir D, Guha A, Phipps RJ, Hock JM, Yu X (2010) MicroRNA-10b regulates tumorigenesis in neurofibromatosis type 1. Cancer Sci 101:1997–2004
Chen J, Wu D, Zhang Y, Yang Y, Duan Y, An Y (2019) LncRNA DCST1-AS1 functions as a competing endogenous RNA to regulate FAIM2 expression by sponging miR-1254 in hepatocellular carcinoma. Clin Sci 133:367–379. https://doi.org/10.1042/cs20180814
Fang Y, Liang X, Xu J, Cai X (2018) miR-424 targets AKT3 and PSAT1 and has a tumor-suppressive role in human colorectal cancer. Cancer Manag Res 10:6537–6547
Garozzo D (2019) Peripheral nerve tumors in neurofibromatosis 1: an overview on management and indications for surgical treatment in our experience. Neurol India 67:S38–s44
Huang Y, Huang H, Li M, Zhang X, Liu Y, Wang Y (2017) MicroRNA-374c-5p regulates the invasion and migration of cervical cancer by acting on the Foxc1/snail pathway
Jiang M, Shi L, Yang C, Ge Y, Lin L, Fan H, He Y, Zhang D, Miao Y, Yang L (2019) miR-1254 inhibits cell proliferation, migration, and invasion by down-regulating Smurf1 in gastric cancer. Cell Death Dis 10:32–32
Kang MR, Park KH, Yang J-O, Lee CW, Oh SJ, Yun J, Lee MY, Han S-B, Kang JS (2016) miR-6734 up-regulates p21 gene expression and induces cell cycle arrest and apoptosis in colon cancer cells. PLoS One 11:e0160961-e0160961
Kendall JJ, Chaney KE, Patel AV, Rizvi TA, Largaespada DA, Ratner N (2016) CK2 blockade causes MPNST cell apoptosis and promotes degradation of β-catenin. Oncotarget 7:53191–53203. https://doi.org/10.18632/oncotarget.10668
Kundu R, Gupta S, Kaushik R, Punia RS, Kaur R (2018) Isolated giant ileal neurofibroma sans neurofibromatosis. Indian J Cancer 55:301–303
Li M, Liu Y, Wei Y, Wu C, Meng H, Niu W, Zhou Y, Wang H, Wen Q, Fan S, Li Z, Li X, Zhou J, Cao K, Xiong W, Zeng Z, Li X, Qiu Y, Li G, Zhou M (2019) Zinc-finger protein YY1 suppresses tumor growth of human nasopharyngeal carcinoma by inactivating c-Myc–mediated microRNA-141 transcription. J Biol Chem 294:6172–6187. https://doi.org/10.1074/jbc.RA118.006281
Liu M, Chen Y, Huang B, Mao S, Cai K, Wang L, Yao X (2018) Tumor-suppressing effects of microRNA-612 in bladder cancer cells by targeting malic enzyme 1 expression. Int J Oncol. https://doi.org/10.3892/ijo.2018.4342
Liu Y, Liu DL, Dong LL, Wen D, Shi DM, Zhou J, Fan J, Wu WZ (2016) miR-612 suppresses stem cell-like property of hepatocellular carcinoma cells by modulating Sp1/Nanog signaling. Cell Death Dis 7:e2377
Moro K, Kameyama H, Abe K, Tsuchida J, Tajima Y, Ichikawa H, Nakano M, Ikarashi M, Nagahashi M, Shimada Y, Kato K, Okamoto T, Umezu H, Gabriel E, Tsuchida M, Wakai T (2019) Left colic artery aneurysm rupture after stent placement for abdominal aortic aneurysm associated with neurofibromatosis type 1. Surg Case Rep 5:12
Pang X, Zhou Z, Yu Z, Han L, Lin Z, Ao X, Liu C, He Y, Ponnusamy M, Li P, Wang J (2019) Foxo3a-dependent miR-633 regulates chemotherapeutic sensitivity in gastric cancer by targeting Fas-associated death domain. RNA Biol 16:233–248. https://doi.org/10.1080/15476286.2019.1565665
Park GB, Kim D (2019) MicroRNA-503-5p inhibits the CD97-mediated JAK2/STAT3 pathway in metastatic or paclitaxel-resistant ovarian cancer cells. Neoplasia (New York, NY) 21:206–215
Qu J-J, Qu X-Y, Zhou D-Z (2017) miR-4262 inhibits colon cancer cell proliferation via targeting of GALNT4. Mol Med Rep 16:3731–3736
Sam MR, Elliott BE, Mueller CR (2007) A novel activating role of SRC and STAT3 on HGF transcription in human breast cancer cells. Mol Cancer 6:69–69
Schmitt AM, Yamini B (2015) Nfkb1 suppresses DNA alkylation-induced tumor formation. Mol Cell Oncol 2:e968073
She K, Huang J, Zhou H, Huang T, Chen G, He J (2016) lncRNA-SNHG7 promotes the proliferation, migration and invasion and inhibits apoptosis of lung cancer cells by enhancing the FAIM2 expression. Oncol Rep 36:2673–2680
She K, Yan H, Huang J, Zhou H, He J (2017) miR-193b availability is antagonized by LncRNA-SNHG7 for FAIM2-induced tumour progression in non-small cell lung cancer. Cell Prolif 51. https://doi.org/10.1111/cpr.12406
Sheng L, He P, Yang X, Zhou M, Feng Q (2015) miR-612 negatively regulates colorectal cancer growth and metastasis by targeting AKT2. Cell Death Dis 6:e1808
Shi H, Ji Y, Zhang D, Liu Y, Fang P (2016) MicroRNA-3666-induced suppression of SIRT7 inhibits the growth of non-small cell lung cancer cells
Tang J, Tao ZH, Wen D, Wan JL, Liu DL, Zhang S, Cui JF, Sun HC, Wang L, Zhou J, Fan J, Wu WZ (2014) MiR-612 suppresses the stemness of liver cancer via Wnt/β-catenin signaling. Biochem Biophys Res Commun 447:210–215
Tao ZH, Wan JL, Zeng LY, Xie L, Sun HC, Qin LX, Wang L, Zhou J, Ren ZG, Li YX, Fan J, Wu WZ (2013) miR-612 suppresses the invasive-metastatic cascade in hepatocellular carcinoma. J Exp Med 210:789–803
Warfield L, Ramachandran S, Baptista T, Devys D, Tora L, Hahn S (2017) Transcription of nearly all yeast RNA polymerase II-transcribed genes is dependent on transcription factor TFIID. Mol Cell 68:118–129 e115
Wu Q-Q, Zheng B, Weng G-B, Yang H-M, Ren Y, Weng X-J, Zhang S-W, Zhu W-Z (2019) Downregulated NOX4 underlies a novel inhibitory role of microRNA-137 in prostate cancer. J Cell Biochem: 120:10215–10227
Yang L, Zhang S, Guo K, Huang H, Qi S, Yao J, Zhang Z (2018) miR-125a restrains cell migration and invasion by targeting STAT3 in gastric cancer cells. OncoTargets Ther 12:205–215
Zhang H, Jiang S, Guo L, Li X (2019) MicroRNA-1258, regulated by c-Myb, inhibits growth and epithelial-to-mesenchymal transition phenotype via targeting SP1 in oral squamous cell carcinoma. J Cell Mol Med 23:2813–2821
Zheng J, Xu T, Chen F, Zhang Y (2019) MiRNA-195-5p functions as a tumor suppressor and a predictive of poor prognosis in non-small cell lung cancer by directly targeting CIAPIN1. Pathol Oncol Res. https://doi.org/10.1007/s12253-018-0552-z
Zhu Y, Zhang HL, Wang QY, Chen MJ, Liu LB (2018) Overexpression of microRNA-612 restrains the growth, invasion, and tumorigenesis of melanoma cells by targeting Espin. Mol Cells. https://doi.org/10.14348/molcells.2018.2235
Acknowledgments
We sincerely thank all involvers in this research.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Editor: Tetsuji Okamoto
Rights and permissions
About this article
Cite this article
Wang, M., Wang, Z., Zhu, X. et al. NFKB1-miR-612-FAIM2 pathway regulates tumorigenesis in neurofibromatosis type 1. In Vitro Cell.Dev.Biol.-Animal 55, 491–500 (2019). https://doi.org/10.1007/s11626-019-00370-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11626-019-00370-3