Long non‑coding RNA fer‑1‑like family member 4 serves as a tumor suppressor in laryngeal squamous cell carcinoma cells via regulating the AKT/ERK signaling pathway

Jiao,Lulu; Liu,Siming; Liu,Lili; Hao,Pengpeng; Gong,Zheng; Yan,Zhanfeng; Xiang,Yinzhou

doi:10.3892/mmr.2020.11598

Long non‑coding RNA fer‑1‑like family member 4 serves as a tumor suppressor in laryngeal squamous cell carcinoma cells via regulating the AKT/ERK signaling pathway

Authors:
- Lulu Jiao
- Siming Liu
- Lili Liu
- Pengpeng Hao
- Zheng Gong
- Zhanfeng Yan
- Yinzhou Xiang
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Affiliations: Department of Otorhinolaryngology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, P.R. China, Department of Otorhinolaryngology, Taizhou First People's Hospital, Taizhou, Zhejiang 318020, P.R. China
Published online on: October 14, 2020 https://doi.org/10.3892/mmr.2020.11598
Pages: 5304-5312
Copyright: © Jiao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Laryngeal squamous cell carcinoma (LSCC) is a common type of malignant tumor of the head and neck. An increasing number of studies have illustrated that long non‑coding RNAs (lncRNAs) serve an important role in the occurrence and development of LSCC. Therefore, the present study aimed to investigate the expression changes and mechanism of lncRNA fer‑1‑like family member 4 (FER1L4) in the progression of LSCC. The expression levels of FER1L4 in LSCC cell lines (AMC‑HN‑8, Tu 686, M4E and M2E) and a normal cell line (HBE135‑E6E7) were analyzed using reverse transcription‑quantitative PCR. The FER1L4 overexpression plasmid (plasmid‑FER1L4) was subsequently transfected into Tu 686 cells to upregulate the expression levels of FER1L4. Cell viability was detected using a Cell Counting Kit‑8 assay, cell proliferation was analyzed using a colony formation assay, apoptosis was examined by flow cytometry, and cell migration and invasion were determined using wound healing and Transwell assays, respectively. In addition, the plasmid‑FER1L4 cells were also treated with insulin‑like growth factor 1 (IGF‑1) to determine the effect of FER1L4 on the AKT/ERK signaling pathway, and the effect of the plasmid‑FER1L4 on the expression levels of AKT/ERK signaling pathway‑related proteins were analyzed using western blotting. The results of the present study revealed that FER1L4 expression levels were downregulated in AMC‑HN‑8 and Tu 686 cells. Notably, FER1L overexpression significantly reduced the cell viability, proliferation, migration and invasion of LSCC cells, while promoting apoptosis. Meanwhile, the plasmid‑FER1L4 also significantly suppressed the phosphorylation levels of AKT and ERK. Further studies indicated that the aforementioned changes could be reversed by IGF‑1, indicating FER1L4 may regulate the progression of LSCC cells by inhibiting the AKT/ERK signaling pathway. In conclusion, the present study provided a potential novel direction for the treatment of LSCC in the future and suggested that FER1L4 may be a new target in this field.

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1	Almadori G, Bussu F, Cadoni G, Galli J, Paludetti G and Maurizi M: Molecular markers in laryngeal squamous cell carcinoma: Towards an integrated clinicobiological approach. Eur J Cancer. 41:683–693. 2005.PubMed/NCBI
2	Christensen A, Kristensen E, Therkildsen MH, Specht L, Reibel JP and Homøe P: Ten-year retrospective study of head and neck carcinoma in situ: Incidence, treatment, and clinical outcome. Oral Surg Oral Med Oral Pathol Oral Radiol. 116:174–178. 2013.PubMed/NCBI
3	Nunes Da Silva GHB, Miranda MG, Rodrigues DS, De Souza GR and Ribeiro CV: Epidemiological factors in patients with larynx cancer treated by surgery, radiotherapy or therapeutic associations. Arch Otolaryngol Rhinol. 5:43–49. 2019.
4	Edefonti V, Bravi F, Garavello W, La Vecchia C, Parpinel M, Franceschi S, Dal Maso L, Bosetti C, Boffetta P, Ferraroni M and Decarli A: Nutrient-based dietary patterns and laryngeal cancer: Evidence from an exploratory factor analysis. Cancer Epidemiol Biomarkers Prev. 19:18–27. 2010.PubMed/NCBI
5	Nocini R, Molteni G, Mattiuzzi C and Lippi G: Updates on larynx cancer epidemiology. Chin J Cancer Res. 32:18–25. 2020.PubMed/NCBI
6	Wu X, Cui CL, Chen WL, Fu ZY, Cui XY and Gong X: MiR-144 suppresses the growth and metastasis of laryngeal squamous cell carcinoma by targeting IRS1. Am J Transl Res. 8:1–11. 2016.PubMed/NCBI
7	Forastiere AA, Goepfert H, Maor M, Pajak TF, Weber R, Morrison W, Glisson B, Trotti A, Ridge JA, Chao C, et al: Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med. 349:2091–2098. 2003.PubMed/NCBI
8	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011.PubMed/NCBI
9	Cui J, Hui LI and Linlin LU: Correlation between RECK gene methylation status and radiosensitivity in laryngeal squamous cell carcinoma. Chin J Clin Oncol. 5:315–318. 2014.
10	Sun X, Liu B, Wang J, Li J and Ji WY: Inhibition of p21-activated kinase 4 expression suppresses the proliferation of Hep-2 laryngeal carcinoma cells via activation of the ATM/Chk1/2/p53 pathway. Int J Oncol. 42:683–689. 2013.PubMed/NCBI
11	Fang XY, Pan HF, Leng RX and Ye DQ: Long noncoding RNAs: Novel insights into gastric cancer. Cancer Lett. 356((2 Pt B)): 357–366. 2015.PubMed/NCBI
12	Okazaki Y, Furuno M, Kasukawa T, Adachi J, Bono H, Kondo S, Nikaido I, Osato N, Saito R, Suzuki H, et al: Analysis of the mouse transcriptome based on functional annotation of 60, 770 full-length cDNAs. Nature. 420:563–573. 2002.PubMed/NCBI
13	Geisler S and Coller J: RNA in unexpected places: Long non-coding RNA functions in diverse cellular contexts. Nat Rev Mol Cell Biol. 14:699–712. 2013.PubMed/NCBI
14	Jiang C, Li X, Zhao H and Liu H: Long non-coding RNAs: Potential new biomarkers for predicting tumor invasion and metastasis. Mol Cancer. 15:622016.PubMed/NCBI
15	Wang KC, Yang YW, Liu B, Sanyal A, Corces-Zimmerman R, Chen Y, Lajoie BR, Protacio A, Flynn RA, Gupta RA, et al: A long noncoding RNA maintains active chromatin to coordinate homeotic gene expression. Nature. 472:120–124. 2011.PubMed/NCBI
16	Yang QQ and Deng YF: Long non-coding RNAs as novel biomarkers and therapeutic targets in head and neck cancers. Int J Clin Exp Pathol. 7:1286–1292. 2014.PubMed/NCBI
17	Barsyte-Lovejoy D, Lau SK, Boutros PC, Khosravi F, Jurisica I, Andrulis IL, Tsao MS and Penn LZ: The c-Myc oncogene directly induces the H19 noncoding RNA by allele-specific binding to potentiate tumorigenesis. Cancer Res. 66:5330–5337. 2006.PubMed/NCBI
18	Luo H, Sun Y, Wei G, Luo J, Yang X, Liu W, Guo M and Chen R: Functional characterization of long noncoding RNA Lnc_bc060912 in human lung carcinoma cells. Biochemistry. 54:2895–2902. 2015.PubMed/NCBI
19	Li D, Feng J, Wu T, Wang Y, Sun Y, Ren J and Liu M: Long intergenic noncoding RNA HOTAIR is overexpressed and regulates PTEN methylation in laryngeal squamous cell carcinoma. Am J Pathol. 182:64–70. 2013.PubMed/NCBI
20	Feng J, Tian L, Sun Y, Li D, Wu T, Wang Y and Liu M: Expression of long non-coding ribonucleic acid metastasis-associated lung adenocarcinoma transcript-1 is correlated with progress and apoptosis of laryngeal squamous cell carcinoma. Head Neck Oncol. 4:462012.
21	Xia T, Chen S, Jiang Z, Shao Y, Jiang X, Li P, Xiao B and Guo J: Long noncoding RNA FER1L4 suppresses cancer cell growth by acting as a competing endogenous RNA and regulating PTEN expression. Sci Rep. 5:134452015.PubMed/NCBI
22	Wu J, Huang J, Wang W, Xu J, Yin M, Cheng N and Yin J: Long non-coding RNA Fer-1-like protein 4 acts as a tumor suppressor via miR-106a-5p and predicts good prognosis in hepatocellular carcinoma. Cancer Biomark. 20:55–65. 2017.PubMed/NCBI
23	Yue B, Sun B, Liu C, Zhao S, Zhang D, Yu F and Yan D: Long non-coding RNA Fer-1-like protein 4 suppresses oncogenesis and exhibits prognostic value by associating with miR-106a-5p in colon cancer. Cancer Sci. 106:1323–1332. 2015.PubMed/NCBI
24	Ma W, Zhang CQ, Li HL, Gu J, Miao GY, Cai HY, Wang JK, Zhang LJ, Song YM, Tian YH and Song YH: LncRNA FER1L4 suppressed cancer cell growth and invasion in esophageal squamous cell carcinoma. Eur Rev Med Pharmacol Sci. 22:2638–2645. 2018.PubMed/NCBI
25	Gao X, Wang N, Wu S, Cui H, An X and Yang Y: Long non-coding RNA FER1L4 inhibits cell proliferation and metastasis through regulation of the PI3K/AKT signaling pathway in lung cancer cells. Mol Med Rep. 20:182–190. 2019.PubMed/NCBI
26	Huo W, Qi F and Wang K: Long non-coding RNA FER1L4 inhibits prostate cancer progression via sponging miR-92a-3p and upregulation of FBXW7. Cancer Cell Int. 20:642020.PubMed/NCBI
27	Sun W, Yang Y, Xu C, Xie Y and Guo J: Roles of long noncoding RNAs in gastric cancer and their clinical applications. J Cancer Res Clin Oncol. 142:2231–2237. 2016.PubMed/NCBI
28	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.PubMed/NCBI
29	Zhang W, Yan Y, Gu M, Wang X, Zhu H, Zhang S and Wang W: High expression levels of Wnt5a and Ror2 in laryngeal squamous cell carcinoma are associated with poor prognosis. Oncol Lett. 14:2232–2238. 2017.PubMed/NCBI
30	Ilm K, Fuchs S, Mudduluru G and Stein U: MACC1 is post-transcriptionally regulated by miR-218 in colorectal cancer. Oncotarget. 7:53443–53458. 2016.PubMed/NCBI
31	Wu Y, Jia Z, Cao D, Wang C, Wu X, You L, Wen S, Pan Y, Cao X and Jiang J: Predictive value of miR-219-1, miR-938, miR-34b/c, and miR-218 polymorphisms for gastric cancer susceptibility and prognosis. Dis Markers. 2017:47318912017.PubMed/NCBI
32	Si L, Zheng L, Xu L, Yin L, Han X, Qi Y, Xu Y, Wang C and Peng J: Dioscin suppresses human laryngeal cancer cells growth via induction of cell-cycle arrest and MAPK-mediated mitochondrial-derived apoptosis and inhibition of tumor invasion. Eur J Pharmacol. 774:105–117. 2016.PubMed/NCBI
33	Morlando M and Fatica A: Alteration of epigenetic regulation by long noncoding RNAs in cancer. Int J Mol Sci. 19:5702018.
34	Wang Y, Liu Z, Yao B, Li Q, Wang L, Wang C, Dou C, Xu M, Liu Q and Tu K: Long non-coding RNA CASC2 suppresses epithelial-mesenchymal transition of hepatocellular carcinoma cells through CASC2/miR-367/FBXW7 axis. Mol Cancer. 16:1232017.PubMed/NCBI
35	Ding N, Wu H, Tao T and Peng E: NEAT1 regulates cell proliferation and apoptosis of ovarian cancer by miR-34a-5p/BCL2. Onco Targets Ther. 10:4905–4915. 2017.PubMed/NCBI
36	Peng W, Wang Z and Fan H: LncRNA NEAT1 impacts cell proliferation and apoptosis of colorectal cancer via regulation of Akt signaling. Pathol Oncol Res. 23:651–656. 2017.PubMed/NCBI
37	Esteller M: Non-coding RNAs in human disease. Nat Rev Genet. 12:861–874. 2011.PubMed/NCBI
38	Mercer TR, Dinger ME and Mattick JS: Long non-coding RNAs: Insights into functions. Nat Rev Genet. 10:155–159. 2009.PubMed/NCBI
39	Liu S, Zou B, Tian T, Luo X, Mao B, Zhang X and Lei H: Overexpression of the lncRNA FER1L4 inhibits paclitaxel tolerance of ovarian cancer cells via the regulation of the MAPK signaling pathway. J Cell Biochem. 2018.(Epub ahead of print).
40	Chen Z, Ma Y, Pan Y, Zuo S, Zhu H, Yu C, Zhu C and Sun C: Long noncoding RNA RP5-833A20. 1 suppresses tumorigenesis in hepatocellular carcinoma through Akt/ERK pathway by targeting miR-18a-5p. Onco Targets Ther. 12:10717–10726. 2019.PubMed/NCBI
41	Ye Q, Cai W, Zheng Y, Evers BM and She QB: ERK and AKT signaling cooperate to translationally regulate survivin expression for metastatic progression of colorectal cancer. Oncogene. 33:1828–1839. 2014.PubMed/NCBI
42	Yao N, Sun JQ, Yu L, Ma L and Guo BQ: LINC00968 accelerates the progression of epithelial ovarian cancer via mediating the cell cycle progression. Eur Rev Med Pharmacol Sci. 23:4642–4649. 2019.PubMed/NCBI
43	Chang C, Xie J, Yang Q, Yang J, Luo Y, Xi L, Guo J, Yang G, Jin W and Wang G: Serine peptidase inhibitor Kazal type III (SPINK3) promotes BRL-3A cell proliferation by targeting the PI3K-AKT signaling pathway. J Cell Physiol. 235:2209–2219. 2020.PubMed/NCBI
44	Meng XP, Ma J, Wang B, Wu X and Liu Z: Long non-coding RNA OIP5-AS1 promotes pancreatic cancer cell growth through sponging miR-342-3p via AKT/ERK signaling pathway. J Physiol Biochem. 76:301–315. 2020.PubMed/NCBI
45	Liu X, Li J and Li X: MiR-142-5p regulates the progression of diabetic retinopathy by targeting IGF1. Int J Immunopathol Pharmacol. 34:20587384209090412020.PubMed/NCBI
46	Cordero-Herrera I, Martín MA, Bravo L, Goya L and Ramos S: Epicatechin gallate induces cell death via p53 activation and stimulation of p38 and JNK in human colon cancer SW480 cells. Nutr Cancer. 65:718–728. 2013.PubMed/NCBI