MicroRNA-196a promotes cell proliferation and inhibits apoptosis in human ovarian cancer by directly targeting DDX3 and regulating the PTEN/PI3K/AKT signaling pathway

Ni,Jie; Chen,Li; Ling,Li; Wu,Mengfei; Ren,Qiongzhen; Zhu,Weipei

doi:10.3892/mmr.2020.11236

MicroRNA-196a promotes cell proliferation and inhibits apoptosis in human ovarian cancer by directly targeting DDX3 and regulating the PTEN/PI3K/AKT signaling pathway

Authors:
- Jie Ni
- Li Chen
- Li Ling
- Mengfei Wu
- Qiongzhen Ren
- Weipei Zhu
View Affiliations

Affiliations: Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R. China
Published online on: June 15, 2020 https://doi.org/10.3892/mmr.2020.11236
Pages: 1277-1284
Copyright: © Ni 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/miRs) are small noncoding RNAs 19‑24 nucleotides in length, which can play an important role in tumor development. However, the influence of miRNAs on the tumorigenicity of ovarian cancer cells has not been fully elucidated. Previously, DEAD box protein (DDX) 1 has been shown to play a role in tumor suppression of ovarian cancer progression. However, the functions of other DDX members in ovarian cancer development remain largely unknown. In the present study, it was demonstrated that overexpression of miR‑196a promoted ovarian cancer cell proliferation. In addition, DDX3 was significantly downregulated in ovarian cancer cell lines relative to the normal ovarian cell line. Moreover, DDX3 was identified as a direct target of miR‑196a in ovarian cancer cells. In addition, a preliminary mechanistic investigation indicated that downregulation of DDX3 promoted ovarian cancer cell proliferation through the PTEN/PI3K/AKT pathway. Taken together, this confirmed an association between DDX3 and miR‑196a in ovarian cancer, and showed that miR‑196a promoted the proliferation of ovarian cancer cells and attenuated apoptosis by downregulating the expression of DDX3 through the PTEN/PI3K/AKT pathway. Overall, the results of the present study suggested that DDX3 could be a novel target for ovarian cancer treatment.

View Figures

View References

1	Webb PM and Jordan SJ: Epidemiology of epithelial ovarian cancer. Best Pract Res Clin Obstet Gynaecol. 41:3–14. 2017. View Article : Google Scholar : PubMed/NCBI
2	Fathalla MF: Incessant ovulation--a factor in ovarian neoplasia? Lancet. 2:1631971. View Article : Google Scholar : PubMed/NCBI
3	Cramer DW and Welch WR: Determinants of ovarian cancer risk. II. Inferences regarding pathogenesis. J Natl Cancer Inst. 71:717–721. 1983.PubMed/NCBI
4	Orr B and Edwards RP: Diagnosis and treatment of ovarian cancer. Hematol Oncol Clin North Am. 32:943–964. 2018. View Article : Google Scholar : PubMed/NCBI
5	Lu TX, Rothenberg ME and Micro RNA: MicroRNA. J Allergy Clin Immunol. 141:1202–1207. 2018. View Article : Google Scholar : PubMed/NCBI
6	Rupaimoole R and Slack FJ: MicroRNA therapeutics: Towards a new era for the management of cancer and other diseases. Nat Rev Drug Discov. 16:203–222. 2017. View Article : Google Scholar : PubMed/NCBI
7	Thorsen SB, Obad S, Jensen NF, Stenvang J and Kauppinen S: The therapeutic potential of microRNAs in cancer. Cancer J. 18:275–284. 2012. View Article : Google Scholar : PubMed/NCBI
8	Nana-Sinkam SP and Croce CM: Clinical applications for microRNAs in cancer. Clin Pharmacol Ther. 93:98–104. 2013. View Article : Google Scholar : PubMed/NCBI
9	Tutar L, Tutar E, Özgür A and Tutar Y: Therapeutic Targeting of microRNAs in Cancer: Future Perspectives. Drug Dev Res. 76:382–388. 2015. View Article : Google Scholar : PubMed/NCBI
10	Zhong LN, Zhang YZ, Li H, Fu HL, Lv CX and Jia XJ: Overexpressed miR-196a accelerates osteogenic differentiation in osteoporotic mice via GNAS-dependent Hedgehog signaling pathway. J Cell Biochem. 120:19422–19431. 2019. View Article : Google Scholar : PubMed/NCBI
11	Ren W, Wu S, Wu Y, Liu T, Zhao X and Li Y: MicroRNA-196a/-196b regulate the progression of hepatocellular carcinoma through modulating the JAK/STAT pathway via targeting SOCS2. Cell Death Dis. 10:3332019. View Article : Google Scholar : PubMed/NCBI
12	Fan Y, Fan J, Huang L, Ye M, Huang Z, Wang Y, Li Q and Huang J: Increased expression of microRNA-196a predicts poor prognosis in human ovarian carcinoma. Int J Clin Exp Pathol. 8:4132–4137. 2015.PubMed/NCBI
13	Lukács J, Soltész B, Penyige A, Nagy B and Póka R: Identification of miR-146a and miR-196a-2 single nucleotide polymorphisms at patients with high-grade serous ovarian cancer. J Biotechnol. 297:54–57. 2019. View Article : Google Scholar : PubMed/NCBI
14	Yang B, Li SZ, Ma L, Liu HL, Liu J and Shao JJ: Expression and mechanism of action of miR-196a in epithelial ovarian cancer. Asian Pac J Trop Med. 9:1105–1110. 2016. View Article : Google Scholar : PubMed/NCBI
15	Su CY, Lin TC, Lin YF, Chen MH, Lee CH, Wang HY, Lee YC, Liu YP, Chen CL and Hsiao M: DDX3 as a strongest prognosis marker and its downregulation promotes metastasis in colorectal cancer. Oncotarget. 6:18602–18612. 2015. View Article : Google Scholar : PubMed/NCBI
16	Botlagunta M, Vesuna F, Mironchik Y, Raman A, Lisok A, Winnard P Jr, Mukadam S, Van Diest P, Chen JH, Farabaugh P, et al: Oncogenic role of DDX3 in breast cancer biogenesis. Oncogene. 27:3912–3922. 2008. View Article : Google Scholar : PubMed/NCBI
17	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 : PubMed/NCBI
18	Blomquist CH, Leung BS, Zhang R, Zhu Y and Chang PM: Properties and regulation of 17 β-hydroxysteroid oxidoreductase of OVCAR-3, CAOV-3, and A431 cells: Effects of epidermal growth factor, estradiol, and progesterone. J Cell Biochem. 59:409–417. 1995. View Article : Google Scholar : PubMed/NCBI
19	Cheung LWT, Leung PCK and Wong AST: Gonadotropin-releasing hormone promotes ovarian cancer cell invasiveness through c-Jun NH2-terminal kinase-mediated activation of matrix metalloproteinase (MMP)-2 and MMP-9. Cancer Res. 66:10902–10910. 2006. View Article : Google Scholar : PubMed/NCBI
20	You S, Wang F, Hu Q, Li P, Zhang C, Yu Y, Zhang Y, Li Q, Bao Q, Liu P, et al: Abnormal expression of YEATS4 associates with poor prognosis and promotes cell proliferation of hepatic carcinoma cell by regulation the TCEA1/DDX3 axis. Am J Cancer Res. 8:2076–2087. 2018.PubMed/NCBI
21	Kim MJ, Lee SJ, Ryu JH, Kim SH, Kwon IC and Roberts TM: Combination of KRAS gene silencing and PI3K inhibition for ovarian cancer treatment. J Control Release. 318:98–108. 2020. View Article : Google Scholar : PubMed/NCBI
22	Patch AM, Christie EL, Etemadmoghadam D, Garsed DW, George J, Fereday S, Nones K, Cowin P, Alsop K, Bailey PJ, et al Australian Ovarian Cancer Study Group, : Whole-genome characterization of chemoresistant ovarian cancer. Nature. 521:489–494. 2015. View Article : Google Scholar : PubMed/NCBI
23	He Y, Zhang D, Yang Y, Wang X, Zhao X, Zhang P, Zhu H, Xu N and Liang S: A double-edged function of DDX3, as an oncogene or tumor suppressor, in cancer progression (Review). Oncol Rep. 39:883–892. 2018.(Review). PubMed/NCBI
24	Heerma van Voss MR, Schrijver WA, Ter Hoeve ND, Hoefnagel LD, Manson QF, van der Wall E, Raman V and van Diest PJ; Dutch Distant Breast Cancer Metastases Consortium, : The prognostic effect of DDX3 upregulation in distant breast cancer metastases. Clin Exp Metastasis. 34:85–92. 2017. View Article : Google Scholar : PubMed/NCBI
25	Gai M, Bo Q and Qi L: Epigenetic down-regulated DDX10 promotes cell proliferation through Akt/NF-κB pathway in ovarian cancer. Biochem Biophys Res Commun. 469:1000–1005. 2016. View Article : Google Scholar : PubMed/NCBI
26	Han C, Liu Y, Wan G, Choi HJ, Zhao L, Ivan C, He X, Sood AK, Zhang X and Lu X: The RNA-binding protein DDX1 promotes primary microRNA maturation and inhibits ovarian tumor progression. Cell Rep. 8:1447–1460. 2014. View Article : Google Scholar : PubMed/NCBI
27	Carnero A and Paramio JM: The PTEN/PI3K/AKT Pathway in vivo, Cancer Mouse Models. Front Oncol. 4:2522014. View Article : Google Scholar : PubMed/NCBI
28	Wise HM, Hermida MA and Leslie NR: Prostate cancer, PI3K, PTEN and prognosis. Clin Sci (Lond). 131:197–210. 2017. View Article : Google Scholar : PubMed/NCBI
29	Nakahata S, Ichikawa T, Maneesaay P, Saito Y, Nagai K, Tamura T, Manachai N, Yamakawa N, Hamasaki M, Kitabayashi I, et al: Loss of NDRG2 expression activates PI3K-AKT signalling via PTEN phosphorylation in ATLL and other cancers. Nat Commun. 5:33932014. View Article : Google Scholar : PubMed/NCBI
30	Xia M, Tong JH, Ji NN, Duan ML, Tan YH and Xu JG: Tramadol regulates proliferation, migration and invasion via PTEN/PI3K/AKT signaling in lung adenocarcinoma cells. Eur Rev Med Pharmacol Sci. 20:2573–2580. 2016.PubMed/NCBI