Knockdown of lncRNA MIR4435‑2HG and ST8SIA1 expression inhibits the proliferation, invasion and migration of prostate cancer cells <em>in vitro</em> and <em>in vivo</em> by blocking the activation of the FAK/AKT/β‑catenin signaling pathway

Xing,Pengyi; Wang,Ye; Zhang,Li; Ma,Chao; Lu,Jianping

doi:10.3892/ijmm.2021.4926

Knockdown of lncRNA MIR4435‑2HG and ST8SIA1 expression inhibits the proliferation, invasion and migration of prostate cancer cells in vitro and in vivo by blocking the activation of the FAK/AKT/β‑catenin signaling pathway

Authors:
- Pengyi Xing
- Ye Wang
- Li Zhang
- Chao Ma
- Jianping Lu
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Affiliations: Department of Radiology, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, P.R. China, Department of Urology, Chinese People's Liberation Army (PLA) General Hospital/PLA Medical School, Beijing 100853, P.R. China, Department of Endocrinology, PLA Joint Logistics Support Force No. 989 Hospital, Luoyang, Henan 471600, P.R. China
Published online on: April 1, 2021 https://doi.org/10.3892/ijmm.2021.4926
Article Number: 93
Copyright: © Xing et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Prostate cancer is a main health risk for males with a high incidence and mortality. The present study aimed to examine the effects of long non‑coding RNA (lncRNA) MIR4435‑2HG binding with ST8SIA1 on the proliferation, invasion and migration of prostate cancer cells via the activation of the FAK/AKT/β‑catenin signaling pathway. The expression of MIR4435‑2HG and ST8SIA1 in prostate cancer cell lines, and the transfection efficacy were analyzed by RT‑qPCR. The proliferation, clone formation ability, and the invasion and migration of transfected cells were detected by CCK‑8 assay, clone formation assay, Transwell assay and wound healing assay, respectively. Plasmids were injected subcutaneously into mice to construct a xenograft tumor model. The expression levels of proteins related to proliferation, apoptosis, invasion and migration, and the FAK/AKT/β‑catenin pathway were detected by western blot analysis. The results revealed that MIR4435‑2HG expression was increased in the prostate cancer cell lines and MIR4435‑2HG expression was the highest in the PC‑3 cells. Interference with MIR4435‑2HG inhibited the proliferation, clone formation ability, and the invasion and migration of PC‑3 cells, as well as tumor growth by suppressing the activation of the FAK/AKT/β‑catenin signaling pathway. MIR4435‑2HG was demonstrated to target ST8SIA1. ST8SIA1 expression was also increased in the prostate cancer cell lines and MIR4435‑2HG expression was the highest in the PC‑3 cells. Interference with ST8SIA1 inhibited the promoting effects of MIR4435‑2HG on the proliferation, invasion and migration of PC‑3 cells, as well as tumor growth by suppressing the activation of the FAK/AKT/β‑catenin signaling pathway. On the whole, the present study demonstrates that interference with MIR4435‑2HG, combined with ST8SIA1, inhibits the proliferation, invasion and migration of prostate cancer cells in vitro and in vivo by blocking the activation of the FAK/AKT/β‑catenin signaling pathway.

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1	Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA and Jemal A: Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 68:394–424. 2018. View Article : Google Scholar : PubMed/NCBI
2	Zheng RS, Sun KX, Zhang SW, Zeng HM and He J: Report of cancer epidemiology in China, 2015. Zhonghua zhong liu za zhi (Article in Chinese). 41:19–28. 2019.
3	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2020. CA Cancer J Clin. 70:7–30. 2020. View Article : Google Scholar : PubMed/NCBI
4	Prensner JR, Iyer MK, Sahu A, Asangani IA, Cao Q, Patel L, Vergara IA, Davicioni E, Erho N, et al: The long noncoding RNA SChLAP1 promotes aggressive prostate cancer and antagonizes the SWI/SNF complex. Nat Genet. 45:1392–1398. 2013. View Article : Google Scholar : PubMed/NCBI
5	Yang J, Hao T, Sun J, Wei P and Zhang H: Long noncoding RNA GAS5 modulates α-Solanine-induced radiosensitivity by negatively regulating miR-18a in human prostate cancer cells. Biomed Pharmacother. 112:1086562019. View Article : Google Scholar
6	Wu M, Huang Y, Chen T, Wang W, Yang S, Ye Z and Xi X: LncRNA MEG3 inhibits the progression of prostate cancer by modulating miR-9-5p/QKI-5 axis. J Cell Mol Med. 23:29–38. 2019. View Article : Google Scholar
7	Zhang Y, Zhang D, Lv J, Wang S and Zhang Q: LncRNA SNHG15 acts as an oncogene in prostate cancer by regulating miR-338-3p/FKBP1A axis. Gene. 705:44–50. 2019. View Article : Google Scholar : PubMed/NCBI
8	Yuan Q, Chu H, Ge Y, Ma G, Du M, Wang M, Zhang Z and Zhang W: LncRNA PCAT1 and its genetic variant rs1902432 are associated with prostate cancer risk. J Cancer. 9:1414–1420. 2018. View Article : Google Scholar :
9	Li X, Ren Y and Zuo T: Long noncoding RNA LINC00978 promotes cell proliferation and invasion in non-small cell lung cancer by inhibiting miR-6754-5p. Mol Med Rep. 18:4725–4732. 2018.PubMed/NCBI
10	Wang W, Xu Z, Wang J and Chen R: LINC00978 promotes bladder cancer cell proliferation, migration and invasion by sponging miR-4288. Mol Med Rep. 20:1866–1872. 2019.PubMed/NCBI
11	Wang H, Wu M, Lu Y, He K, Cai X, Yu X, Lu J and Teng L: LncRNA MIR4435-2HG targets desmoplakin and promotes growth and metastasis of gastric cancer by activating Wnt/β-catenin signaling. Aging (Albany NY). 11:6657–6673. 2019. View Article : Google Scholar
12	Shen X, Ding Y, Lu F, Yuan H and Luan W: Long noncoding RNA MIR4435-2HG promotes hepatocellular carcinoma proliferation and metastasis through the miR-22-3p/YWHAZ axis. Am J Transl Res. 12:6381–6394. 2020.PubMed/NCBI
13	Nguyen K, Yan Y, Yuan B, Dasgupta A, Sun V, Mu H, Do KA, Ueno NT, Andreeff M and Battula VL: ST8SIA1 regulates tumor growth and metastasis in TNBC by activating the FAK-AKT-mTOR signaling pathway. Mol Cancer Ther. 17:2689–2701. 2018. View Article : Google Scholar : PubMed/NCBI
14	Shan Y, Liu Y, Zhao L, Liu B, Li Y and Jia L: MicroRNA-33a and let-7e inhibit human colorectal cancer progression by targeting ST8SIA1. Int J Biochem Cell Biol. 90:48–58. 2017. View Article : Google Scholar : PubMed/NCBI
15	Chen Y, Deng X, Chen W, Shi P, Lian M, Wang H, Wang K, Qian D, Xiao D and Long H: Silencing of microRNA-708 promotes cell growth and epithelial-to-mesenchymal transition by activating the SPHK2/AKT/β-catenin pathway in glioma. Cell Death Dis. 10:4482019. View Article : Google Scholar
16	Sun X, Xing G, Zhang C, Lu K, Wang Y and He X: Knockdown of Trop2 inhibits proliferation and migration and induces apoptosis of endometrial cancer cells via AKT/β-catenin pathway. Cell Biochem Funct. 38:141–148. 2020. View Article : Google Scholar : PubMed/NCBI
17	Wei B, Wang Y, Wang JW, Cai X, Xu L, Wu J, Wang Y, Liu W, Gu Y, Guo W and Xu Q: Apatinib suppresses tumor progression and enhances cisplatin sensitivity in esophageal cancer via the Akt/β-catenin pathway. Cancer Cell Int. 20:1982020. View Article : Google Scholar
18	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
19	Tosoian JJ, Gorin MA, Ross AE, Pienta KJ, Tran PT and Schaeffer EM: Oligometastatic prostate cancer: Definitions, clinical outcomes, and treatment considerations. Nat Rev Urol. 14:15–25. 2017. View Article : Google Scholar
20	Pan B, Ye Y, Liu H, Zhen J, Zhou H, Li Y, Qu L, Wu Y, Zeng C and Zhong W: URG11 regulates prostate cancer cell proliferation, migration, and invasion. Biomed Res Int. 2018:40607282018. View Article : Google Scholar : PubMed/NCBI
21	Bu JY, Lv WZ, Liao YF, Xiao XY and Lv BJ: Long non-coding RNA LINC00978 promotes cell proliferation and tumorigenesis via regulating microRNA-497/NTRK3 axis in gastric cancer. Int J Biol Macromol. 123:1106–1114. 2019. View Article : Google Scholar
22	Zhang Q, Cheng S, Cao L, Yang J, Wang Y and Chen Y: LINC00978 promotes hepatocellular carcinoma carcinogenesis partly via activating the MAPK/ERK pathway. Biosci Rep. 40:BSR201927902020. View Article : Google Scholar : PubMed/NCBI
23	Xu H, Zhang B, Yang Y, Yang Y, Li Z, Zhao P, Wu W, Zhang H and Mao J: LncRNA MIR4435-2HG potentiates the proliferation and invasion of glioblastoma cells via modulating miR-1224-5p/TGFBR2 axis. J Cell Mol Med. 24:6362–6372. 2020. View Article : Google Scholar : PubMed/NCBI
24	Dong X, Yang Z, Yang H, Li D and Qiu X: Long non-coding RNA MIR4435-2HG promotes colorectal cancer proliferation and metastasis through miR-206/YAP1 axis. Front Oncol. 10:1602020. View Article : Google Scholar : PubMed/NCBI
25	Shen H, Sun B, Yang Y, Cai X, Bi L, Deng L and Zhang L: MIR4435-2HG regulates cancer cell behaviors in oral squamous cell carcinoma cell growth by upregulating TGF-β1. Odontology. 108:553–559. 2020. View Article : Google Scholar : PubMed/NCBI
26	Takashima S, Matsumoto T, Tsujimoto M and Tsuji S: Effects of amino acid substitutions in the sialylmotifs on molecular expression and enzymatic activities of α2,8-sialyltransferases ST8Sia-I and ST8Sia-VI. Glycobiology. 23:603–612. 2013. View Article : Google Scholar : PubMed/NCBI
27	Rimoldi S, Papis E, Bernardini G, Prati M and Gornati R: Molecular cloning and expression of alpha2,8-sialyltransferase (ST8Sia I, GD3 Synthase) in xenopus. Mol Cell Biochem. 301:143–153. 2007. View Article : Google Scholar : PubMed/NCBI
28	Yamashiro S, Okada M, Haraguchi M and Furukawa K, Lloyd KO, Shiku H and Furukawa K: Expression of alpha 2,8-sialyltransferase (GD3 synthase) gene in human cancer cell lines: High level expression in melanomas and up-regulation in activated T lymphocytes. Glycoconjugate J. 12:894–900. 1995. View Article : Google Scholar
29	Sarkar TR, Battula VL, Werden SJ, Vijay GV, Ramirez-Peña EQ, Taube JH, Chang JT, Miura N, Porter W, Sphyris N, et al: GD3 synthase regulates epithelial-mesenchymal transition and metastasis in breast cancer. Oncogene. 34:2958–2967. 2015. View Article : Google Scholar :
30	Cazet A, Lefebvre J, Adriaenssens E, Julien S, Bobowski M, Grigoriadis A, Tutt A, Tulasne D, Le Bourhis X and Delannoy P: GD₃ synthase expression enhances proliferation and tumor growth of MDA-MB-231 breast cancer cells through c-Met activation. Mol Cancer Res. 8:1526–1535. 2010. View Article : Google Scholar : PubMed/NCBI
31	Birklé S, Gao L, Zeng G and Yu RK: Down-regulation of GD3 ganglioside and its O-acetylated derivative by stable transfection with antisense vector against GD3-synthase gene expression in hamster melanoma cells: Effects on cellular growth, melanogenesis, and dendricity. J Neurochem. 74:547–554. 2000. View Article : Google Scholar : PubMed/NCBI
32	Kang NY, Kim CH, Kim KS, Ko JH, Lee JH, Jeong YK and Lee YC: Expression of the human CMP-NeuAc:GM3 alpha2,8-sialyltransferase (GD3 synthase) gene through the NF-kappaB activation in human melanoma SK-MEL-2 cells. Biochim Biophys Acta. 1769:622–630. 2007. View Article : Google Scholar : PubMed/NCBI
33	Luo M and Guan JL: Focal adhesion kinase: A prominent determinant in breast cancer initiation, progression and metastasis. Cancer Lett. 289:127–139. 2010. View Article : Google Scholar :
34	Xia H, Nho RS, Kahm J, Kleidon J and Henke CA: Focal adhesion kinase is upstream of phosphatidylinositol 3-kinase/Akt in regulating fibroblast survival in response to contraction of type I collagen matrices via a beta 1 integrin viability signaling pathway. J Biol Chem. 279:33024–33034. 2004. View Article : Google Scholar : PubMed/NCBI
35	Jindra PT, Jin YP, Rozengurt E and Reed EF: HLA class I antibody-mediated endothelial cell proliferation via the mTOR pathway. J Immunol. 180:2357–2366. 2008. View Article : Google Scholar : PubMed/NCBI
36	Wan H, Li Z, Wang H, Cai F and Wang L: ST8SIA1 inhibition sensitizes triple negative breast cancer to chemotherapy via suppressing Wnt/β-catenin and FAK/Akt/mTOR. Clin Transl Oncol. 23:902–910. 2020. View Article : Google Scholar
37	Qiao M, Iglehart JD and Pardee AB: Metastatic potential of 21T human breast cancer cells depends on Akt/protein kinase B activation. Cancer Res. 67:5293–5299. 2007. View Article : Google Scholar : PubMed/NCBI
38	Zhang X, Chen T, Zhang J, Mao Q, Li S, Xiong W, Qiu Y, Xie Q and Ge J: Notch1 promotes glioma cell migration and invasion by stimulating β-catenin and NF-κB signaling via AKT activation. Cancer Sci. 103:181–190. 2012. View Article : Google Scholar
39	Liu J, Liu L, Chao S, Liu Y, Liu X, Zheng J, Chen J, Gong W, Teng H, Li Z, et al: The role of miR-330-3p/PKC-α signaling pathway in low-dose endothelial-monocyte activating polypeptide-II increasing the permeability of blood-tumor barrier. Front Cell Neurosci. 11:3582017. View Article : Google Scholar
40	Liu DC, Song LL, Liang Q, Hao L, Zhang ZG and Han CH: Long noncoding RNA LEF1-AS1 silencing suppresses the initiation and development of prostate cancer by acting as a molecular sponge of miR-330-5p via LEF1 repression. J Cell Physiol. 234:12727–12744. 2019. View Article : Google Scholar : PubMed/NCBI
41	Li Q, Wang W, Zhang M, Sun W, Shi W and Li F: Circular RNA circ-0016068 promotes the growth, migration, and invasion of prostate cancer cells by regulating the miR-330-3p/BMI-1 axis as a competing endogenous RNA. Front Cell Dev Biol. 8:8272020. View Article : Google Scholar : PubMed/NCBI