Long non-coding RNA KCNQ1OT1 mediates the growth of hepatocellular carcinoma by functioning as a competing endogenous RNA of miR-504

Li,Chao; Miao,Runchen; Zhang,Jingyao; Qu,Kai; Liu,Chang

doi:10.3892/ijo.2018.4313

Long non-coding RNA KCNQ1OT1 mediates the growth of hepatocellular carcinoma by functioning as a competing endogenous RNA of miR-504

Authors:
- Chao Li
- Runchen Miao
- Jingyao Zhang
- Kai Qu
- Chang Liu
View Affiliations

Affiliations: Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
Published online on: March 12, 2018 https://doi.org/10.3892/ijo.2018.4313
Pages: 1603-1612

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

Accumulating evidence highlights the fact that long non‑coding RNAs (lncRNAs) serve as critical factors in the growth of hepatocellular carcinoma (HCC). The dysregulation of lncRNA KCNQ1 opposite strand/antisense transcript 1 (KCNQ1OT1) has been reported in numerous human benign diseases. However, the role of KCNQ1OT1 in human HCC remains poorly understood. In this study, we demonstrated that the expression of KCNQ1OT1 was abnormally increased in HCC tissues. The ectopic high expression of KCNQ1OT1 was associated with liver cirrhosis, a larger tumor size, an advanced TNM stage, and a worse overall survival and tumor‑free survival. For the first time, to the best of our knowledge, we report that KCNQ1OT1 knockdown results in a decreased cell viability and colony formation ability, and an increased rate of apoptosis in vitro. The results from our in vivo results demonstrated that KCNQ1OT1 silencing attenuated tumor growth by impairing cell proliferation. Additionally, we found that KCNQ1OT1 exerted its effects partly by relying on the microRNA‑504 (miR‑504)‑mediated regulation of cyclin‑dependent kinase 16 (CDK16), in addition to the regulation of the glycogen synthase kinase 3β (GSK3β)/β‑catenin/Bcl‑2 signaling pathway. The present study revealed the functions and mechanisms of action of lncRNA KCNQ1OT1 regarding its role in promoting the growth of HCC. Thus, lncRNA KCNQ1OT1 may prove to be a potential therapeutic target for human HCC.

View Figures

View References

1	Sim HW, Knox J and Dawson LA: An update on randomized clinical trials in hepatocellular carcinoma. Surg Oncol Clin N Am. 26:647–666. 2017. View Article : Google Scholar : PubMed/NCBI
2	Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ and He J: Cancer statistics in China, 2015. CA Cancer J Clin. 66:115–132. 2016. View Article : Google Scholar : PubMed/NCBI
3	Kalogeraki A, Papadakis GZ, Tamiolakis D, Karvela-Kalogeraki I, Karvelas-Kalogerakis M, Segredakis J and Moustou E: Fine Needle Aspiration Biopsy (FNAB) in the Diagnosis of Hepatocellular Carcinoma: A Review. Rom J Intern Med. 53:209–217. 2015.PubMed/NCBI
4	Chi HC, Tsai CY, Tsai MM, Yeh CT and Lin KH: Roles of long noncoding RNAs in recurrence and metastasis of radiotherapy-resistant cancer stem cells. Int J Mol Sci. 18:182017. View Article : Google Scholar
5	Klingenberg M, Matsuda A, Diederichs S and Patel T: Non-coding RNA in hepatocellular carcinoma: Mechanisms, biomarkers and therapeutic targets. J Hepatol. 67:603–618. 2017. View Article : Google Scholar : PubMed/NCBI
6	Huang MD, Chen WM, Qi FZ, Sun M, Xu TP, Ma P and Shu YQ: Long non-coding RNA TUG1 is up-regulated in hepatocellular carcinoma and promotes cell growth and apoptosis by epigenetically silencing of KLF2. Mol Cancer. 14:1652015. View Article : Google Scholar : PubMed/NCBI
7	Wei S, Fan Q, Yang L, Zhang X, Ma Y, Zong Z, Hua X, Su D, Sun H, Li H, et al: Promotion of glycolysis by HOTAIR through GLUT1 upregulation via mTOR signaling. Oncol Rep. 38:1902–1908. 2017. View Article : Google Scholar : PubMed/NCBI
8	Inoue T, Nakamura A, Matsubara K, Nyuzuki H, Nagasaki K, Oka A, Fukami M and Kagami M: Continuous hypomethylation of the KCNQ1OT1:TSS-DMR in monochorionic twins discordant for Beckwith-Wiedemann syndrome. Am J Med Genet A. 173:2847–2850. 2017. View Article : Google Scholar : PubMed/NCBI
9	Zhang Z, Weaver DL, Olsen D, deKay J, Peng Z, Ashikaga T and Evans MF: Long non-coding RNA chromogenic in situ hybridisation signal pattern correlation with breast tumour pathology. J Clin Pathol. 69:76–81. 2016. View Article : Google Scholar
10	Yoshizawa S, Fujiwara K, Sugito K, Uekusa S, Kawashima H, Hoshi R, Watanabe Y, Hirano T, Furuya T, Masuko T, et al: Pyrrole-imidazole polyamide-mediated silencing of KCNQ1OT1 expression induces cell death in Wilms' tumor cells. Int J Oncol. 47:115–121. 2015. View Article : Google Scholar : PubMed/NCBI
11	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
12	Li C, Miao R, Liu S, Wan Y, Zhang S, Deng Y, Bi J, Qu K, Zhang J and Liu C: Down-regulation of miR-146b-5p by long noncoding RNA MALAT1 in hepatocellular carcinoma promotes cancer growth and metastasis. Oncotarget. 8:28683–28695. 2017.
13	Liu L, Zhang S, Hu L, Liu L, Guo W and Zhang J: HMGA1 participates in MHCC97H cell proliferation and invasion through the ILK/Akt/GSK3β signaling pathway. Mol Med Rep. 16:9287–9294. 2017. View Article : Google Scholar : PubMed/NCBI
14	Ren K, Xu R, Huang J, Zhao J and Shi W: Knockdown of long non-coding RNA KCNQ1OT1 depressed chemoresistance to paclitaxel in lung adenocarcinoma. Cancer Chemother Pharmacol. 80:243–250. 2017. View Article : Google Scholar : PubMed/NCBI
15	Gong W, Zheng J, Liu X, Liu Y, Guo J, Gao Y, Tao W, Chen J, Li Z, Ma J, et al: Knockdown of long non-coding RNA KCNQ1OT1 restrained glioma cells' malignancy by activating miR-370/CCNE2 axis. Front Cell Neurosci. 11:842017. View Article : Google Scholar : PubMed/NCBI
16	Qu J, Li M, Zhong W and Hu C: Competing endogenous RNA in cancer: A new pattern of gene expression regulation. Int J Clin Exp Med. 8:17110–17116. 2015.
17	Deng L, Yang SB, Xu FF and Zhang JH: Long noncoding RNA CCAT1 promotes hepatocellular carcinoma progression by functioning as let-7 sponge. J Exp Clin Cancer Res. 34:182015. View Article : Google Scholar : PubMed/NCBI
18	Wang ZH, Guo XQ, Zhang QS, Zhang JL, Duan YL, Li GF and Zheng DL: Long non-coding RNA CCAT1 promotes glioma cell proliferation via inhibiting microRNA-410. Biochem Biophys Res Commun. 480:715–720. 2016. View Article : Google Scholar : PubMed/NCBI
19	Wang Q, Zhang W and Hao S: LncRNA CCAT1 modulates the sensitivity of paclitaxel in nasopharynx cancers cells via miR-181a/CPEB2 axis. Cell Cycle. 16:795–801. 2017. View Article : Google Scholar : PubMed/NCBI
20	Mikolcevic P, Rainer J and Geley S: Orphan kinases turn eccentric: A new class of cyclin Y-activated, membrane-targeted CDKs. Cell Cycle. 11:3758–3768. 2012. View Article : Google Scholar : PubMed/NCBI
21	Shehata SN, Deak M, Morrice NA, Ohta E, Hunter RW, Kalscheuer VM and Sakamoto K: Cyclin Y phosphorylation- and 14-3-3-binding-dependent activation of PCTAIRE-1/CDK16. Biochem J. 469:409–420. 2015. View Article : Google Scholar : PubMed/NCBI
22	Ćwiek P, Leni Z, Salm F, Dimitrova V, Styp-Rekowska B, Chiriano G, Carroll M, Höland K, Djonov V, Scapozza L, et al: RNA interference screening identifies a novel role for PCTK1/CDK16 in medulloblastoma with c-Myc amplification. Oncotarget. 6:116–129. 2015. View Article : Google Scholar :
23	Iwano S, Satou A, Matsumura S, Sugiyama N, Ishihama Y and Toyoshima F: PCTK1 regulates integrin-dependent spindle orientation via protein kinase A regulatory subunit KAP0 and myosin X. Mol Cell Biol. 35:1197–1208. 2015. View Article : Google Scholar : PubMed/NCBI
24	Yanagi T, Shi R, Aza-Blanc P, Reed JC and Matsuzawa S: PCTAIRE1-knockdown sensitizes cancer cells to TNF family cytokines. PLoS One. 10:e01194042015. View Article : Google Scholar : PubMed/NCBI
25	Huang L, Zhang C, Su L and Song Z: GSK3β attenuates TGF-β1 induced epithelial-mesenchymal transition and metabolic alterations in ARPE-19 cells. Biochem Biophys Res Commun. 486:744–751. 2017. View Article : Google Scholar : PubMed/NCBI
26	Ye X, Lin J, Lin Z, Xue A, Li L, Zhao Z, Liu L, Shen Y and Cong B: Axin1 up-regulated 1 accelerates stress-induced cardiomyocytes apoptosis through activating Wnt/β-catenin signaling. Exp Cell Res. 359:441–448. 2017. View Article : Google Scholar : PubMed/NCBI
27	Wang Y, Zhou J, Xu YJ and Hu HB: Long non-coding RNA LINC00968 acts as oncogene in NSCLC by activating the Wnt signaling pathway. J Cell Physiol. 233:3397–3406. 2018. View Article : Google Scholar
28	Sunamura N, Ohira T, Kataoka M, Inaoka D, Tanabe H, Nakayama Y, Oshimura M and Kugoh H: Regulation of functional KCNQ1OT1 lncRNA by β-catenin. Sci Rep. 6:206902016. View Article : Google Scholar