MicroRNA‑198 suppresses tumour growth and metastasis in oral squamous cell carcinoma by targeting CDK4

Kang,Yuanyuan; Zhang,Ying; Sun,Yan

doi:10.3892/ijo.2021.5219

MicroRNA‑198 suppresses tumour growth and metastasis in oral squamous cell carcinoma by targeting CDK4

Authors:
- Yuanyuan Kang
- Ying Zhang
- Yan Sun
View Affiliations

Affiliations: Department of Emergency and Oral Medicine, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, Liaoning 110002, P.R. China
Published online on: May 11, 2021 https://doi.org/10.3892/ijo.2021.5219
Article Number: 39
Copyright: © Kang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

MicroRNAs (miRNAs/miR) often contribute to the progression of oral squamous cell carcinoma (OSCC) via the regulation of mRNA. The present study aimed to investigate the role of miR‑198 in OSCC pathogenesis and explore the underlying mechanism. Reverse transcription‑quantitative (RT‑q)PCR was performed to determine miR‑198 expression in OSCC tissues and cell lines, and univariate and multivariate analyses were applied to evaluate the survival of patients with OSCC. The effects of miR‑198 on OSCC cell lines were studied in vitro and in vivo. A set of epithelial‑mesenchymal transition (EMT) markers were detected to determine whether miR‑198 was involved in EMT. Lastly, using luciferase assays, a novel target of miR‑198 was identified and the effect of the new target gene of miR‑198 on cell proliferation and invasion was also studied. It was identified that miR‑198 expression was decreased in OSCC tissues and cell lines, and low expression of miR‑198 was associated with poor overall survival and disease‑free survival. Overexpression of miR‑198 appeared to significantly inhibit the proliferation, invasion and EMT of OSCC cells. Moreover, the luciferase assay results showed that miR‑198 interacted with cyclin‑dependent kinase 4 (CDK4) by directly targeting the miRNA‑binding site in the CDK4 sequence, and RT‑qPCR results showed that CDK4 expression was increased in OSCC tissues and cell lines. In addition, transfection of small interfering RNA against CDK4 in OSCC cells showed similar inhibitory effects on cell proliferation, invasion and EMT, whereas CDK4 overexpression in OSCC cells partially reversed the inhibitory effects of the miR‑198 mimic. The present results indicated that miR‑198 suppressed OSCC tumour growth and metastasis by directly targeting CDK4 expression. Thus, miR‑198 may be a potential therapeutic target in the treatment of OSCC.

View Figures

View References

1	Zhang S, Wang X, Gupta A, Fang X, Wang L and Zhang C: Expression of IL-17 with tumor budding as a prognostic marker in oral squamous cell carcinoma. Am J Transl Res. 11:1876–1883. 2019.PubMed/NCBI
2	Wu K, Jiang Y, Zhou W, Zhang B, Li Y, Xie F, Zhang J, Wang X, Yan M, Xu Q, et al: Long noncoding RNA RC3H2 facilitates cell proliferation and invasion by targeting MicroRNA-101-3p/EZH2 Axis in OSCC. Mol Ther Nucleic Acids. 20:97–110. 2020. View Article : Google Scholar : PubMed/NCBI
3	Chen L, Zhang S, Wu J, Cui J, Zhong L, Zeng L and Ge S: circRNA_100290 plays a role in oral cancer by functioning as a sponge of the miR-29 family. Oncogene. 36:4551–4561. 2017. View Article : Google Scholar : PubMed/NCBI
4	Zhao Z, Gao D, Ma T and Zhang L: MicroRNA-141 suppresses growth and metastatic potential of head and neck squamous cell carcinoma. Aging (Albany NY). 11:921–932. 2019. View Article : Google Scholar
5	Wang Y, Guo W, Li Z, Wu Y, Jing C, Ren Y, Zhao M, Kong L, Zhang C, Dong J, et al: Role of the EZH2/miR-200 axis in STAT3-mediated OSCC invasion. Int J Oncol. 52:1149–1164. 2018.PubMed/NCBI
6	Bartel DP: MicroRNAs: Target recognition and regulatory functions. Cell. 136:215–233. 2009. View Article : Google Scholar : PubMed/NCBI
7	Flynt AS and Lai EC: Biological principles of microRNA-mediated regulation: Shared themes amid diversity. Nat Rev Genet. 9:831–842. 2008. View Article : Google Scholar : PubMed/NCBI
8	Zhang B, Li Y, Hou D, Shi Q, Yang S and Li Q: MicroRNA-375 inhibits growth and enhances radiosensitivity in oral squamous cell carcinoma by targeting insulin like growth factor 1 receptor. Cell Physiol Biochem. 42:2105–2117. 2017. View Article : Google Scholar : PubMed/NCBI
9	Wang K, Jin J, Ma T and Zhai H: MiR-139-5p inhibits the tumorigenesis and progression of oral squamous carcinoma cells by targeting HOXA9. J Cell Mol Med. 21:3730–3740. 2017. View Article : Google Scholar : PubMed/NCBI
10	Fu S, Chen HH, Cheng P, Zhang CB and Wu Y: MiR-155 regulates oral squamous cell carcinoma Tca8113 cell proliferation, cycle, and apoptosis via regulating p27Kip1. Eur Rev Med Pharmacol Sci. 21:937–944. 2017.PubMed/NCBI
11	Yu EH, Tu HF, Wu CH, Yang CC and Chang KW: MicroRNA-21 promotes perineural invasion and impacts survival in patients with oral carcinoma. J Chin Med Assoc. 80:383–388. 2017. View Article : Google Scholar : PubMed/NCBI
12	Hu Y, Tang Z, Jiang B, Chen J and Fu Z: MiR-198 functions as a tumor suppressor in breast cancer by targeting CUB domain-containing protein 1. Oncol Lett. 13:1753–1760. 2017. View Article : Google Scholar : PubMed/NCBI
13	Yang J, Zhao H, Xin Y and Fan L: MicroRNA-198 inhibits proliferation and induces apoptosis of lung cancer cells via targeting FGFR1. J Cell Biochem. 115:987–995. 2014. View Article : Google Scholar
14	Tan S, Li R, Ding K, Lobie PE and Zhu T: MiR-198 inhibits migration and invasion of hepatocellular carcinoma cells by targeting the HGF/c-MET pathway. FEBS Lett. 585:2229–2234. 2011. View Article : Google Scholar : PubMed/NCBI
15	Cui Z, Zheng X and Kong D: Decreased miR-198 expression and its prognostic significance in human gastric cancer. World J Surg Oncol. 14:332016. View Article : Google Scholar : PubMed/NCBI
16	Yamamoto K, Kawaguchi M, Shimomura T, Izumi A, Konari K, Honda A, Lin CY, Johnson MD, Yamashita Y, Fukushima T and Kataoka H: Hepatocyte growth factor activator inhibitor type-2 (HAI-2)/SPINT2 contributes to invasive growth of oral squamous cell carcinoma cells. Oncotarget. 9:11691–11706. 2018. View Article : Google Scholar : PubMed/NCBI
17	Hu Q, Wu T, Chen X, Li H, Du Z, Hao Y, Peng J, Tai S, Song M and Cheng B: The poor outcome of second primary oral squamous cell carcinoma is attributed to Bmi1 upregulation. Cancer Med. 7:1056–1069. 2018. View Article : Google Scholar : PubMed/NCBI
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	Zhong F, Chen H, Han L, Jin Y and Wang W: Curcumin attenuates lipopolysaccharide-induced renal inflammation. Biol Pharm Bull. 34:226–232. 2011. View Article : Google Scholar : PubMed/NCBI
20	Wang M, Wang J, Kong X, Chen H, Wang Y, Qin M, Lin Y, Chen H, Xu J, Hong J, et al: MiR-198 represses tumor growth and metastasis in colorectal cancer by targeting fucosyl transferase 8. Sci Rep. 4:61452014. View Article : Google Scholar : PubMed/NCBI
21	Cheng CM, Shiah SG, Huang CC, Hsiao JR and Chang JY: Up-regulation of miR-455-5p by the TGF-β-SMAD signalling axis promotes the proliferation of oral squamous cancer cells by targeting UBE2B. J Pathol. 240:38–49. 2016. View Article : Google Scholar : PubMed/NCBI
22	Chang KW, Kao SY, Wu YH, Tsai MM, Tu HF, Liu CJ, Lui MT and Lin SC: Passenger strand miRNA miR-31* regulates the phenotypes of oral cancer cells by targeting RhoA. Oral Oncol. 49:27–33. 2013. View Article : Google Scholar
23	Liang L, Feng L and Wei B: MicroRNA-1297 involves in the progression of oral squamous cell carcinoma through PTEN. Saudi J Biol Sci. 25:923–927. 2018. View Article : Google Scholar : PubMed/NCBI
24	Nagai H, Hasegawa S, Uchida F, Terabe T, Ishibashi Kanno N, Kato K, Yamagata K, Sakai S, Kawashiri S, Sato H, et al: MicroRNA-205-5p suppresses the invasiveness of oral squamous cell carcinoma by inhibiting TIMP-2 expression. Int J Oncol. 52:841–850. 2018.PubMed/NCBI
25	Adel M, Kao HK, Hsu CL, Huang JJ, Lee LY, Huang Y, Browne T, Tsang NM, Chang YL and Chang KP: Evaluation of lymphatic and vascular invasion in relation to clinicopathological factors and treatment outcome in oral cavity squamous cell carcinoma. Medicine (Baltimore). 94:e15102015. View Article : Google Scholar
26	Mattiotti A, Prakash S, Barnett P and van den Hoff MJB: Follistatin-like 1 in development and human diseases. Cell Mol Life Sci. 75:2339–2354. 2018. View Article : Google Scholar : PubMed/NCBI
27	Liao C, Huang X, Gong Y and Lin Q: Discovery of core genes in colorectal cancer by weighted gene co-expression network analysis. Oncol Lett. 18:3137–3149. 2019.PubMed/NCBI
28	Shi Y, Fang N, Li Y, Guo Z, Jiang W, He Y, Ma Z and Chen Y: Circular RNA LPAR3 sponges microRNA-198 to facilitate esophageal cancer migration, invasion, and metastasis. Cancer Sci. 111:2824–2836. 2020. View Article : Google Scholar : PubMed/NCBI
29	Ye L, Li S, Ye D, Yang D, Yue F, Guo Y, Chen X, Chen F, Zhang J and Song X: Livin expression may be regulated by miR-198 in human prostate cancer cell lines. Eur J Cancer. 49:734–740. 2013. View Article : Google Scholar
30	Wang J, Dan G, Shangguan T, Hao H, Tang R, Peng K, Zhao J, Sun H and Zou Z: MiR-198 represses the proliferation of HaCaT cells by targeting cyclin D2. Int J Mol Sci. 16:17018–17028. 2015. View Article : Google Scholar : PubMed/NCBI
31	Ray J, Hoey C, Huang X, Jeon J, Taeb S, Downes MR, Boutros PC and Liu SK: MicroRNA-198 suppresses prostate tumorigenesis by targeting MIB1. Oncol Rep. 42:1047–1056. 2019.PubMed/NCBI
32	Wood DJ and Endicott JA: Structural insights into the functional diversity of the CDK-cyclin family. Open Biol. 8:1801122018. View Article : Google Scholar : PubMed/NCBI
33	Hamilton E and Infante JR: Targeting CDK4/6 in patients with cancer. Cancer Treat Rev. 45:129–138. 2016. View Article : Google Scholar : PubMed/NCBI
34	Gao X, Leone GW and Wang H: Cyclin D-CDK4/6 functions in cancer. Adv Cancer Res. 148:147–169. 2020. View Article : Google Scholar : PubMed/NCBI
35	Sheppard KE and AbuHammad S: CDK4/6 inhibition in cancer: The cell cycle splicing connection. Mol Cell Oncol. 6:e16736432019. View Article : Google Scholar : PubMed/NCBI
36	Feng H, Ge F, Du L, Zhang Z and Liu D: MiR-34b-3p represses cell proliferation, cell cycle progression and cell apoptosis in non-small-cell lung cancer (NSCLC) by targeting CDK4. J Cell Mol Med. 23:5282–5291. 2019. View Article : Google Scholar : PubMed/NCBI
37	Lang B and Zhao S: MiR-486 functions as a tumor suppressor in esophageal cancer by targeting CDK4/BCAS2. Oncol Rep. 39:71–80. 2018.
38	Tarasewicz E, Hamdan R, Straehla J, Hardy A, Nunez O, Zelivianski S, Dokic D and Jeruss JS: CDK4 inhibition and doxorubicin mediate breast cancer cell apoptosis through Smad3 and survivin. Cancer Biol Ther. 15:1301–1311. 2014. View Article : Google Scholar : PubMed/NCBI