MicroRNA‑153‑3p suppresses retinoblastoma cell growth and invasion via targeting the IGF1R/Raf/MEK and IGF1R/PI3K/AKT signaling pathways

Guo,Long; Bai,Yu; Ni,Tianyu; Li,Yuan; Cao,Rong; Ji,Shuzhe; Li,Shuzhen

doi:10.3892/ijo.2021.5227

MicroRNA‑153‑3p suppresses retinoblastoma cell growth and invasion via targeting the IGF1R/Raf/MEK and IGF1R/PI3K/AKT signaling pathways

Authors:
- Long Guo
- Yu Bai
- Tianyu Ni
- Yuan Li
- Rong Cao
- Shuzhe Ji
- Shuzhen Li
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Affiliations: Department of Ophthalmology, The First People's Hospital of Shangqiu, Shangqiu, Henan 476100, P.R. China, Department of Pathology, Xinxiang Medical University, Xinxiang, Henan 453000, P.R. China
Published online on: May 21, 2021 https://doi.org/10.3892/ijo.2021.5227
Article Number: 47
Copyright: © Guo et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Mounting evidence has demonstrated that microRNAs (miRNAs or miRs) play significant roles in various types of human tumors, including retinoblastoma (RB). However, the biological role and regulatory mechanisms of miRNAs in RB remain to be fully elucidated. The present study was designed to identify the regulatory effects of miRNAs in RB and the underlying mechanisms. Differentially expressed miRNAs in RB tissue were screened out based on the Gene Expression Omnibus (GEO) dataset, GSE7072, which revealed that miR‑153 in particular, displayed the highest fold change in expression. It was identified that miR‑153 was significantly downregulated in RB tissues, and its downregulation was closely associated with a larger tumor base and differentiation. Functional analysis revealed that the overexpression of miR‑153 inhibited RB cell proliferation, migration and invasion, and promoted the apoptosis of WERI‑RB‑1 and Y79 cells. In addition, insulin‑like growth factor 1 receptor (IGF1R) was identified as a target of miR‑153 in RB cells. More importantly, it was demonstrated that miR‑153 upregulation inhibited the expression of its target gene, IGF1R, which inhibited the activation of the Raf/MEK and PI3K/AKT signaling pathways. Collectively, the present study demonstrates for the first time, to the best of our knowledge, that miR‑153 functions as a tumor suppressor in RB by targeting the IGF1R/Raf/MEK and IGF1R/PI3K/AKT signaling pathways. Collectively, the findings presented herein demonstrate that miR‑153 targets IGF1R and blocks the activation of the Raf/MEK and PI3K/AKT signaling pathway, thus preventing the progression of RB. Thus, this miRNA may serve as a novel prognostic biomarker and therapeutic target for RB.

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1	Dimaras H, Dimba EA and Gallie BL: Challenging the global retinoblastoma survival disparity through a collaborative research effort. Br J Ophthalmol. 94:1415–1416. 2010. View Article : Google Scholar : PubMed/NCBI
2	Narang S, Mashayekhi A, Rudich D and Shields CL: Predictors of long-term visual outcome after chemoreduction for management of intraocular retinoblastoma. Clin Exp Ophthalmol. 40:736–742. 2012. View Article : Google Scholar : PubMed/NCBI
3	Shields CL and Shields JA: Basic understanding of current classification and management of retinoblastoma. Curr Opin Ophthalmol. 17:228–234. 2006. View Article : Google Scholar : PubMed/NCBI
4	Chen HM, Ong SJ, Chao AN, Liou KL, Jung SM and Kao LY: Histopathologic findings after selective ophthalmic arterial injection of melphalan for retinoblastoma. Taiwan J Ophthalmol. 9:262–266. 2019. View Article : Google Scholar
5	Bartel DP: MicroRNAs: Target recognition and regulatory functions. Cell. 136:215–233. 2009. View Article : Google Scholar : PubMed/NCBI
6	Bartel DP: MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell. 116:281–297. 2004. View Article : Google Scholar : PubMed/NCBI
7	Shukla GC, Singh J and Barik S: MicroRNAs: Processing, maturation, target recognition and regulatory functions. Mol Cell Pharmacol. 3:83–92. 2011.PubMed/NCBI
8	Croce CM: Causes and consequences of microRNA dysregulation in cancer. Nat Rev Genet. 10:704–714. 2009. View Article : Google Scholar : PubMed/NCBI
9	Zuo Z, Ye F, Liu Z, Huang J and Gong Y: MicroRNA-153 inhibits cell proliferation, migration, invasion and epithelial-mesenchymal transition in breast cancer via direct targeting of RUNX2. Exp Ther Med. 17:4693–4702. 2019.PubMed/NCBI
10	Zhang Z, Sun J, Bai Z, Li H, He S, Chen R and Che X: MicroRNA-153 acts as a prognostic marker in gastric cancer and its role in cell migration and invasion. Onco Targets Ther. 8:357–364. 2015.PubMed/NCBI
11	Niu G, Li B, Sun L and An C: MicroRNA-153 inhibits osteosarcoma cells proliferation and invasion by targeting TGF-β2. PLoS One. 10:e01192252015. View Article : Google Scholar
12	Chen WJ, Zhang EN, Zhong ZK, Jiang MZ, Yang XF, Zhou DM and Wang XW: MicroRNA-153 expression and prognosis in non-small cell lung cancer. Int J Clin Exp Pathol. 8:8671–8675. 2015.PubMed/NCBI
13	Jiang J, Liu Y, Zhao Y, Tian F and Wang G: miR-153-3p suppresses inhibitor of growth protein 2 expression to function as tumor suppressor in acute lymphoblastic leukemia. Technol Cancer Res Treat. 18:15330338198529902019. View Article : Google Scholar : PubMed/NCBI
14	Li C, Zhang Y, Zhao W, Cui S and Song Y: miR-153-3p regulates progression of ovarian carcinoma in vitro and in vivo by targeting MCL1 gene. J Cell Biochem. 120:19147–19158. 2019. View Article : Google Scholar : PubMed/NCBI
15	Liang H, Ge F, Xu Y, Xiao J, Zhou Z, Liu R and Chen C: miR-153 inhibits the migration and the tube formation of endothelial cells by blocking the paracrine of angiopoietin 1 in breast cancer cells. Angiogenesis. 21:849–860. 2018. View Article : Google Scholar : PubMed/NCBI
16	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
17	Villar J, Cabrera-Benitez NE, Valladares F, García-Hernández S, Ramos-Nuez Á, Martín-Barrasa JL, Muros M, Kacmarek RM and Slutsky AS: Tryptase is involved in the development of early ventilator-induced pulmonary fibrosis in sepsis-induced lung injury. Crit Care. 19:1382015. View Article : Google Scholar : PubMed/NCBI
18	Wan W, Wan W, Long Y, Li Q, Jin X, Wan G, Zhang F, Lv Y, Zheng G, Li Z and Zhu Y: MiR-25-3p promotes malignant phenotypes of retinoblastoma by regulating PTEN/Akt pathway. Biomed Pharmacother. 118:1091112019. View Article : Google Scholar : PubMed/NCBI
19	Wu S, Han M and Zhang C: Overexpression of microRNA-186 inhibits angiogenesis in retinoblastoma via the hedgehog signaling pathway by targeting ATAD2. J Cell Physiol. 234:19059–19072. 2019. View Article : Google Scholar : PubMed/NCBI
20	Liao Y, Yin X, Deng Y and Peng X: MiR-140-5p suppresses retinoblastoma cell growth via inhibiting c-Met/AKT/mTOR pathway. Biosci Rep. 38:BSR201807762018. View Article : Google Scholar : PubMed/NCBI
21	Shan N, Shen L, Wang J, He D and Duan C: MiR-153 inhibits migration and invasion of human non-small-cell lung cancer by targeting ADAM19. Biochem Biophys Res Commun. 456:385–391. 2015. View Article : Google Scholar
22	Thiery JP: Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer. 2:442–454. 2002. View Article : Google Scholar : PubMed/NCBI
23	Guarino M: Epithelial-mesenchymal transition and tumour invasion. Int J Biochem Cell Biol. 39:2153–2160. 2007. View Article : Google Scholar : PubMed/NCBI
24	Hakuno F and Takahashi SI: IGF1 receptor signaling pathways. J Mol Endocrinol. 61:T69–T86. 2018. View Article : Google Scholar : PubMed/NCBI
25	Zhu S, Soutto M, Chen Z, Blanca Piazuelo M, Kay Washington M, Belkhiri A, Zaika A, Peng D and El-Rifai W: Activation of IGF1R by DARPP-32 promotes STAT3 signaling in gastric cancer cells. Oncogene. 38:5805–5816. 2019. View Article : Google Scholar : PubMed/NCBI
26	Li Z, Pan W, Shen Y, Chen Z, Zhang L, Zhang Y, Luo Q and Ying X: IGF1/IGF1R and microRNA let-7e down-regulate each other and modulate proliferation and migration of colorectal cancer cells. Cell Cycle. 17:1212–1219. 2018. View Article : Google Scholar : PubMed/NCBI
27	Kooijman R, Lauf JJ, Kappers AC and Rijkers GT: Insulin-like growth factor induces phosphorylation of immunoreactive insulin receptor substrate and its association with phosphatidylinositol-3 kinase in human thymocytes. J Exp Med. 182:593–597. 1995. View Article : Google Scholar : PubMed/NCBI
28	Fu HW, Lin X, Zhu YX, Lan X, Kuang Y, Wang YZ, Ke ZG, Yuan T and Chen P: Circ-IGF1R has pro-proliferative and anti-apoptotic effects in HCC by activating the PI3K/AKT pathway. Gene. 716:1440312019. View Article : Google Scholar : PubMed/NCBI
29	Huang J, Yang Y, Fang F and Liu K: MALAT1 modulates the autophagy of retinoblastoma cell through miR-124-mediated stx17 regulation. J Cell Biochem. 119:3853–3863. 2018. View Article : Google Scholar
30	Li W, Zhai L, Zhao C and Lv S: MiR-153 inhibits epithelial-mesenchymal transition by targeting metadherin in human breast cancer. Breast Cancer Res Treat. 150:501–509. 2015. View Article : Google Scholar : PubMed/NCBI
31	Shi D, Li Y, Fan L, Zhao Q, Tan B and Cui G: Upregulation of miR-153 inhibits triple-negative breast cancer progression by targeting ZEB2-mediated EMT and contributes to better prognosis. Onco Targets Ther. 12:9611–9625. 2019. View Article : Google Scholar
32	Zuo J, Zhao M, Fan Z, Liu B, Wang Y, Li Y, Lv P, Xing L, Zhang X and Shen H: MicroRNA-153-3p regulates cell proliferation and cisplatin resistance via Nrf-2 in esophageal squamous cell carcinoma. Thorac Cancer. 11:738–747. 2020. View Article : Google Scholar : PubMed/NCBI
33	Zeng HF, Yan S and Wu SF: MicroRNA-153-3p suppress cell proliferation and invasion by targeting SNAI1 in melanoma. Biochem Biophys Res Commun. 487:140–145. 2017. View Article : Google Scholar : PubMed/NCBI
34	Scheidegger KJ, Du J and Delafontaine P: Distinct and common pathways in the regulation of insulin-like growth factor-1 receptor gene expression by angiotensin II and basic fibroblast growth factor. J Biol Chem. 274:3522–3530. 1999. View Article : Google Scholar : PubMed/NCBI
35	Guo L, Bai Y, Ji S and Ma H: MicroRNA-98 suppresses cell growth and invasion of retinoblastoma via targeting the IGF1R/k-Ras/Raf/MEK/ERK signaling pathway. Int J Oncol. 54:807–820. 2019.PubMed/NCBI
36	Chen Z, Yang H, Nie Y and Xing Y: miR-145 regulates the proliferation and apoptosis of Y79 human retinoblastoma cells by targeting IGF-1R. Int J Clin Exp Pathol. 11:4331–4338. 2018.PubMed/NCBI
37	Song L, Duan P, Guo P, Li D, Li S, Xu Y and Zhou Q: Downregulation of miR-223 and miR-153 mediates mechanical stretch-stimulated proliferation of venous smooth muscle cells via activation of the insulin-like growth factor-1 receptor. Arch Biochem Biophys. 528:204–211. 2012. View Article : Google Scholar : PubMed/NCBI
38	Knowlden JM, Hutcheson IR, Barrow D, Gee JM and Nicholson RI: Insulin-like growth factor-I receptor signaling in tamoxifen-resistant breast cancer: A supporting role to the epidermal growth factor receptor. Endocrinology. 146:4609–4618. 2005. View Article : Google Scholar : PubMed/NCBI
39	Rozen F and Pollak M: Inhibition of insulin-like growth factor I receptor signaling by the vitamin D analogue EB1089 in MCF-7 breast cancer cells: A role for insulin-like growth factor binding proteins. Int J Oncol. 15:589–594. 1999.PubMed/NCBI
40	LeRoith D, Werner H, Neuenschwander S, Kalebic T and Helman LJ: The role of the insulin-like growth factor-I receptor in cancer. Ann N Y Acad Sci. 766:402–408. 1995. View Article : Google Scholar : PubMed/NCBI
41	Zhu L: Tumour suppressor retinoblastoma protein Rb: A transcriptional regulator. Eur J Cancer. 41:2415–2427. 2005. View Article : Google Scholar : PubMed/NCBI
42	Mu G, Liu H, Zhou F, Xu X, Jiang H, Wang Y and Qu Y: Correlation of overexpression of HMGA1 and HMGA2 with poor tumor differentiation, invasion, and proliferation associated with let-7 down-regulation in retinoblastomas. Hum Pathol. 41:493–502. 2010. View Article : Google Scholar
43	Dalgard CL, Gonzalez M, de Niro JE and O'Brien JM: Differential microRNA-34a expression and tumor suppressor function in retinoblastoma cells. Invest Ophthalmol Vis Sci. 50:4542–4551. 2009. View Article : Google Scholar : PubMed/NCBI
44	Ganguly A and Shields CL: Differential gene expression profile of retinoblastoma compared to normal retina. Mol Vis. 16:1292–1303. 2010.PubMed/NCBI
45	Maddison LA, Sutherland BW, Barrios RJ and Greenberg NM: Conditional deletion of Rb causes early stage prostate cancer. Cancer Res. 64:6018–6025. 2004. View Article : Google Scholar : PubMed/NCBI
46	Hui AM, Li X, Makuuchi M, Takayama T and Kubota K: Over-expression and lack of retinoblastoma protein are associated with tumor progression and metastasis in hepatocellular carcinoma. Int J Cancer. 84:604–608. 1999. View Article : Google Scholar : PubMed/NCBI
47	Guihurt Santiago J, Burgos-Tirado N, Lafontaine DD, Mendoza Sierra JC, Camacho RH, Vecchini Rodríguez CM, Morales-Tirado V and Flores-Otero J: Adhesion G protein-coupled receptor, ELTD1, is a potential therapeutic target for retinoblastoma migration and invasion. BMC Cancer. 21:532021. View Article : Google Scholar : PubMed/NCBI