Knockdown of long noncoding RNA DLEU1 suppresses the progression of renal cell carcinoma by downregulating the Akt pathway

Yue,Genquan; Chen,Caixia; Bai,Ligang; Wang,Guoqiang; Huang,Yong; Wang,Yunbin; Cui,Hongwei; Xiao,Yunfeng

doi:10.3892/mmr.2019.10705

Knockdown of long noncoding RNA DLEU1 suppresses the progression of renal cell carcinoma by downregulating the Akt pathway

Authors:
- Genquan Yue
- Caixia Chen
- Ligang Bai
- Guoqiang Wang
- Yong Huang
- Yunbin Wang
- Hongwei Cui
- Yunfeng Xiao
View Affiliations

Affiliations: Department of Urology, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia 010000, P.R. China, Clinical Medical Research Center, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia 010000, P.R. China, The Center for New Drug Safety Evaluation and Research of Inner Mongolia Medical University, Hohhot, Inner Mongolia 010110, P.R. China
Published online on: September 25, 2019 https://doi.org/10.3892/mmr.2019.10705
Pages: 4551-4557
Copyright: © Yue 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

Increasing evidence has indicated that long noncoding RNAs (lncRNAs) are involved in the tumorigenesis and progression of various types of cancer. The lncRNA deleted in lymphocytic leukemia 1 (DLEU1) has been reported to be dysregulated in cancer cells and thus associated with tumor development; however, the role of DLEU1 in renal cell carcinoma (RCC) remains unclear. In the present study, DLEU1 was knocked down using small interfering RNA in the RCC cell lines KETR3 and 786‑O to determine the role of DLEU1. Cell Counting Kit‑8, colony formation, Transwell and flow cytometry assays were performed to assess the effects of DLEU1 on cell proliferation, migration, invasion and apoptosis in KETR3 and 786‑O cells. The protein expression levels of factors associated with apoptosis and epithelial‑mesenchymal transition (EMT) were examined by western blot. The results demonstrated that silencing DLEU1 decreased the growth capacity, migration and invasion of KETR3 and 786‑O cells. Additionally, loss of DLEU1 was observed to stimulate the mitochondrial pathway of cell apoptosis via regulation of the expression of Bcl‑2/Bax, cleaved caspase‑3 and cleaved caspase‑9 in KETR3 and 786‑O cells. Furthermore, DLEU1 knockdown significantly inhibited the protein kinase B (Akt) pathway by downregulating the expression of phosphorylated‑Akt, cyclin D1 and P70S6 kinase. In addition, depletion of DLEU1 was observed to impair the process of EMT in RCC cells via the upregulation of E‑cadherin, and downregulation of N‑cadherin and vimentin. Collectively, these results indicated a pro‑oncogenic role of DLEU1 in the progression and development of RCC via modulation of the Akt pathway and EMT phenotype.

View Figures

View References

1	Hsieh JJ, Purdue MP, Signoretti S, Swanton C, Albiges L, Schmidinger M, Heng DY, Larkin J and Ficarra V: Renal cell carcinoma. Nat Rev Dis Primers. 3:170092017. View Article : Google Scholar : PubMed/NCBI
2	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2015. CA Cancer J Clin. 65:5–29. 2015. View Article : Google Scholar : PubMed/NCBI
3	Thomas JS and Kabbinavar F: Metastatic clear cell renal cell carcinoma: A review of current therapies and novel immunotherapies. Crit Rev Oncol Hematol. 96:527–533. 2015. View Article : Google Scholar : PubMed/NCBI
4	Motzer RJ and Molina AM: Targeting renal cell carcinoma. J Clin Oncol. 27:3274–3276. 2009. View Article : Google Scholar : PubMed/NCBI
5	Xia M, Yao L, Zhang Q, Wang F, Mei H, Guo X and Huang W: Long noncoding RNA HOTAIR promotes metastasis of renal cell carcinoma by up-regulating histone H3K27 demethylase JMJD3. Oncotarget. 8:19795–19802. 2017.PubMed/NCBI
6	Li JK, Chen C, Liu JY, Shi JZ, Liu SP, Liu B, Wu DS, Fang ZY, Bao Y, Jiang MM, et al: Long noncoding RNA MRCCAT1 promotes metastasis of clear cell renal cell carcinoma via inhibiting NPR3 and activating p38-MAPK signaling. Mol Cancer. 16:1112017. View Article : Google Scholar : PubMed/NCBI
7	Esteller M: Non-coding RNAs in human disease. Nat Rev Genet. 12:861–874. 2011. View Article : Google Scholar : PubMed/NCBI
8	Ponting CP, Oliver PL and Reik W: Evolution and functions of long noncoding RNAs. Cell. 136:629–641. 2009. View Article : Google Scholar : PubMed/NCBI
9	Shi SJ, Wang LJ, Yu B, Li YH, Jin Y and Bai XZ: LncRNA-ATB promotes trastuzumab resistance and invasion-metastasis cascade in breast cancer. Oncotarget. 6:11652–11663. 2015. View Article : Google Scholar : PubMed/NCBI
10	Ong MS, Cai W, Yuan Y, Leong HC, Tan TZ, Mohammad A, You ML, Arfuso F, Goh BC, Warrier S, et al: ‘Lnc’-ing Wnt in female reproductive cancers: Therapeutic potential of long non-coding RNAs in Wnt signalling. Br J Pharmacol. 174:4684–4700. 2017. View Article : Google Scholar : PubMed/NCBI
11	Hosseini ES, Meryet-Figuiere M, Sabzalipoor H, Kashani HH, Nikzad H and Asemi Z: Dysregulated expression of long noncoding RNAs in gynecologic cancers. Mol Cancer. 16:1072017. View Article : Google Scholar : PubMed/NCBI
12	Wang F, Li L, Xu H, Liu Y, Yang C, Cowley AW Jr, Wang N, Liu P and Liang M: Characteristics of long non-coding RNAs in the Brown Norway rat and alterations in the Dahl salt-sensitive rat. Sci Rep. 4:71462014. View Article : Google Scholar : PubMed/NCBI
13	Iguchi T, Uchi R, Nambara S, Saito T, Komatsu H, Hirata H, Ueda M, Sakimura S, Takano Y, Kurashige J, et al: A long noncoding RNA, lncRNA-ATB, is involved in the progression and prognosis of colorectal cancer. Anticancer Res. 35:1385–1388. 2015.PubMed/NCBI
14	Xiong J, Liu Y, Jiang L, Zeng Y and Tang W: High expression of long non-coding RNA lncRNA-ATB is correlated with metastases and promotes cell migration and invasion in renal cell carcinoma. Jpn J Clin Oncol. 46:378–384. 2016. View Article : Google Scholar : PubMed/NCBI
15	Li J, Li Z, Zheng W, Li X, Wang Z, Cui Y and Jiang X: LncRNA-ATB: An indispensable cancer-related long noncoding RNA. Cell Prolif. 50:2017. View Article : Google Scholar :
16	Lei K, Liang X, Gao Y, Xu B, Xu Y, Li Y, Tao Y, Shi W and Liu J: Lnc-ATB contributes to gastric cancer growth through a MiR-141-3p/TGFβ2 feedback loop. Biochem Biophys Res Commun. 484:514–521. 2017. View Article : Google Scholar : PubMed/NCBI
17	Zeng X, Hu Z, Ke X, Tang H, Wu B, Wei X and Liu Z: Long noncoding RNA DLX6-AS1 promotes renal cell carcinoma progression via miR-26a/PTEN axis. Cell Cycle. 16:2212–2219. 2017. View Article : Google Scholar : PubMed/NCBI
18	Garding A, Bhattacharya N, Claus R, Ruppel M, Tschuch C, Filarsky K, Idler I, Zucknick M, Caudron-Herger M, Oakes C, et al: Epigenetic upregulation of lncRNAs at 13q14.3 in leukemia is linked to the In Cis downregulation of a gene cluster that targets NF-κB. PLoS Genet. 9:e10033732013. View Article : Google Scholar : PubMed/NCBI
19	Dowd AA, Homeida S and Elkarem HA: Detection of chromosome 13 (13q14) deletion among Sudanese patients with multiple myeloma using a molecular genetics fluorescent in situ hybridization technique (FISH). Malays J Pathol. 37:95–100. 2015.PubMed/NCBI
20	Lee S, Luo W, Shah T, Yin C, O'Connell T, Chung TH, Perkins SL, Miles RR, Ayello J, Morris E, et al: The effects of DLEU1 gene expression in Burkitt lymphoma (BL): Potential mechanism of chemoimmunotherapy resistance in BL. Oncotarget. 8:27839–27853. 2017.PubMed/NCBI
21	Li X, Li Z, Liu Z, Xiao J, Yu S and Song Y: Long non-coding RNA DLEU1 predicts poor prognosis of gastric cancer and contributes to cell proliferation by epigenetically suppressing KLF2. Cancer Gene Therapy. 25:58–67. 2018. View Article : Google Scholar : PubMed/NCBI
22	Wu Q, Guo L, Jiang F, Li L, Li Z and Chen F: Analysis of the miRNA-mRNA-lncRNA networks in ER+ and ER- breast cancer cell lines. J Cell Mol Med. 19:2874–2887. 2015. View Article : Google Scholar : PubMed/NCBI
23	Wang LL, Sun KX, Wu DD, Xiu YL, Chen X, Chen S, Zong ZH, Sang XB, Liu Y and Zhao Y: DLEU1 contributes to ovarian carcinoma tumourigenesis and development by interacting with miR-490-3p and altering CDK1 expression. J Cell Mol Med. 21:3055–3065. 2017. View Article : Google Scholar : PubMed/NCBI
24	Du Y, Wang L, Chen S, Liu Y and Zhao Y: lncRNA DLEU1 contributes to tumorigenesis and development of endometrial carcinoma by targeting mTOR. Mol Carcinog. 57:1191–1200. 2018. View Article : Google Scholar : PubMed/NCBI
25	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
26	Chen JS, Wang Q, Fu XH, Huang XH, Chen XL, Cao LQ, Chen LZ, Tan HX, Li W, Bi J and Zhang LJ: Involvement of PI3K/PTEN/AKT/mTOR pathway in invasion and metastasis in hepatocellular carcinoma: Association with MMP-9. Hepatol Res. 39:177–186. 2009. View Article : Google Scholar : PubMed/NCBI
27	Ellinger J, Blondeau JJC, Deng M, Syring I, Schrödter S, Schmidt D, Perner S and Müller SC: 863 Identification and functional analysis of novel long non-coding RNAs in clear cell renal cell carcinoma. Eur Urol Suppl. 14:e8632015. View Article : Google Scholar
28	Kwong LN and Davies MA: Navigating the therapeutic complexity of PI3K pathway inhibition in melanoma. Clin Cancer Re. 19:5310–5319. 2013. View Article : Google Scholar
29	Guo H, German P, Bai S, Barnes S, Guo W, Qi X, Lou H, Liang J, Jonasch E, Mills GB and Ding Z: The PI3K/AKT pathway and renal cell carcinoma. J Genet Genomics. 42:343–353. 2015. View Article : Google Scholar : PubMed/NCBI
30	Sathe A and Nawroth R: Targeting the PI3K/AKT/mTOR pathway in bladder cancer. Methods Mol Biol. 1655:335–350. 2018. View Article : Google Scholar : PubMed/NCBI
31	Diehl JA: Cycling to Cancer with Cyclin D1. Cancer Biol Ther. 1:226–231. 2002. View Article : Google Scholar : PubMed/NCBI
32	Qie S and Diehl JA: Cyclin D1, cancer progression, and opportunities in cancer treatment. J Mol Med (Berl). 94:1313–1326. 2016. View Article : Google Scholar : PubMed/NCBI
33	Tavares MR, Pavan IC, Amaral CL, Meneguello L, Luchessi AD and Simabuco FM: The S6K protein family in health and disease. Life Sci. 131:1–10. 2015. View Article : Google Scholar : PubMed/NCBI
34	Bates RC and Mercurio A: The epithelial-mesenchymal tansition (EMT) and colorectal cancer progression. Cancer Biol Ther. 4:365–370. 2005. View Article : Google Scholar : PubMed/NCBI
35	Nakajima S, Doi R, Toyoda E, Tsuji S, Wada M, Koizumi M, Tulachan SS, Ito D, Kami K, Mori T, et al: N-cadherin expression and epithelial-mesenchymal transition in pancreatic carcinoma. Clin Cancer Res. 10:4125–4133. 2004. View Article : Google Scholar : PubMed/NCBI
36	Mao XW, Xiao JQ, Xu G, Li ZY, Wu HF, Li Y, Zheng YC and Zhang N: CUL4B promotes bladder cancer metastasis and induces epithelial-to-mesenchymal transition by activating the Wnt/β-catenin signaling pathway. Oncotarget. 8:77241–77253. 2017. View Article : Google Scholar : PubMed/NCBI