Long non-coding RNA FOXO1 inhibits lung cancer cell growth through down-regulating PI3K/AKT signaling pathway

Document Type : Original Article

Authors

1 Department of Respiratory, The Affiliated Hospital of Qingdao University, Qingdao 266000, Shandong, China

2 Department of Radiology, Qingdao West Coast New Area Central Hospital, Qingdao 266555, Shandong, China

Abstract

Objective(s): Lung cancer is one of the most common malignant tumors, which seriously threatens the health and life of the people. Recently, a novel long non-coding RNA (lncRNA) termed lncFOXO1 was found and investigated in breast cancer. However, the effect of lncFOXO1 on lung cancer is still ambiguous. The current study aimed to uncover the functions of lncFOXO1 in lung cancer cell proliferation, metastasis and apoptosis.
Materials and Methods: LncFOXO1 expression levels in lung cancer tissues or cells were detected using qRT-PCR. Then, overexpression and knockdown vectors of lncFOXO1 were transfected into A549 cells to investigate the effect of lncFOXO1 on cell proliferation, invasion, migration and apoptosis. These experiments were assessed using MTT, colony formation, transwell, flow cytometry and western blot assays, respectively. In vivo experiment was performed to examine the tumor weight using Xenograft tumor model assay. The important pathway of PI3K/AKT was finally examined using western blot.
Results: The decreased expression level of lncFOXO1 was observed in lung cancer tissues and cells (A549, H460, HCC827 and H1299). Knockdown of lncFOXO1 significantly promoted A549 cells viability, colony formation and invasion. However, lncFOXO1 overexpression obviously reversed the results. Moreover, lncFOXO1 overexpression induced A549 cells apoptosis by regulating Bax, cleaved-caspase-3 and Bcl-2. In vivo experiment revealed that lncFOXO1 overexpression inhibited tumor weight. Furthermore, lncFOXO1 knockdown promoted colony formation and mediated Myc and Cyclin D1 expressions by regulating PI3K/AKT signaling pathway.
Conclusion: LncFOXO1 inhibited lung cancer cell proliferation, metastasis, and induced apoptosis through down-regulating PI3K/AKT pathway.

Keywords

Main Subjects

References

1.Travis WD, Travis LB, Devesa SS. Lung cancer. Cancer 2015; 75:191-202.
2.Simonato L, Agudo A, Ahrens W, Benhamou E, Benhamou S, Boffetta P, et al. Lung cancer and cigarette smoking in Europe: An update of risk estimates and an assessment of inter-country heterogeneity. Int J Cancer 2015; 91:876-887.
3.Zhang LR, Morgenstern H, Greenland S, Chang SC, Lazarus P, Teare MD, et al. Cannabis smoking and lung cancer risk: pooled analysis in the international lung cancer consortium. J Int Cancer 2015; 136:894-903.
4.Collins LG, Haines C, Perkel R, Enck RE. Lung cancer: diagnosis and management. Am Fam Physician 2007; 75:56-63.
5.Navani N, Nankivell M, Lawrence DR, Lock S, Makker H, Baldwin DR, et al. Lung cancer diagnosis and staging with endobronchial ultrasound-guided transbronchial needle aspiration compared with conventional approaches: an open-label, pragmatic, randomised controlled trial. Lancet Respir Med 2015; 3:282-289.
6.Akhtar-Danesh N, Finley C. Temporal trends in the incidence and relative survival of non-small cell lung cancer in Canada: A population-based study. Lung Cancer 2015; 90:8-14.
7.Qi P, Zhou X, Du X. Circulating long non-coding RNAs in cancer: current status and future perspectives. Mol Cancer 2016; 15:39-50.
8.Silva A, Bullock M, Calin G. The clinical relevance of long non-coding RNAs in cancer. Cancers 2015; 7:2169-2182.
9.Yarmishyn AA, Kurochkin IV. Long noncoding RNAs: a potential novel class of cancer biomarkers. Front Genet 2015; 6:145-155.
10.Weiss M, Plass C, Gerhauser C. Role of lncRNAs in prostate cancer development and progression. Biol Chem 2014; 395:1275-1290.
11.Chen B, Yu M, Chang Q, Lu Y, Thakur C, Ma D, et al. Mdig de-represses H19 large intergenic non-coding RNA (lincRNA) by down-regulating H3K9me3 and heterochromatin. Oncotarget 2013; 4:1427-1437.
12.Kruer TL, Dougherty SM, Reynolds L, Long E, Silva TD, Lockwood WW, et al. Expression of the lncRNA maternally expressed gene 3 (MEG3) contributes to the control of lung cancer cell proliferation by the rb pathway. PloS One 2016; 11:0166363-0166380.
13.Gao S, Lin Z, Li C, Wang Y, Yang L, Zou B, et al. TFPI2AS1, a novel lncRNA that inhibits cell proliferation and migration in lung cancer. Cell Cycle 2017; 16:2249-2258.
14.Xi J, Feng J, Li Q, Li X, Zeng S. The long non-coding RNA lncFOXO1 suppresses growth of human breast cancer cells through association with BAP1. Int J Oncol 2017; 50:1663-1670.
15.Andersen CL, Jensen JL, Orntoft TF. Normalization of real-time quantitative reverse transcription-PCR data: a model-based variance estimation approach to identify genes suited for normalization, applied to bladder and colon cancer data sets. Cancer Res 2004; 64:5245-5250.
16.Ihira K, Dong P, Xiong Y, Watari H, Konno Y, Hanley SJ, et al. EZH2 inhibition suppresses endometrial cancer progression via miR-361/Twist axis. Oncotarget 2017; 8:13509-13520.
17.Chatterjee D, Sanchez AM, Goldgur Y, Shuman S, Schwer B. Transcription of lncRNA prt, clustered prt RNA sites for Mmi1 binding, and RNA polymerase II CTD phospho-sites govern the repression of pho1 gene expression under phosphate-replete conditions in fission yeast. Rna 2016; 22:1011-1025.
18.Zhou Y, Meng X, Zhang J, Zhao Y, Pharmacy DO. Research progress of long non-coding RNA in cardiovascular disease. Genom Appl Biol 2017; 36:1876-1881.
19.Luo G, Wang M, Wu X, Tao D, Xiao X, Wang L, et al. Long non-coding RNA MEG3 inhibits cell proliferation and induces apoptosis in prostate cancer. Cell physiol biochem 2015; 37:2209-2220.
20.Prensner JR, Chinnaiyan AM. The emergence of lncRNAs in cancer biology. Cancer Discov 2011; 1:391-407.
21.Li H, Lv X. Functional annotation of noncoding variants and prioritization of cancer-associated lncRNAs in lung cancer. Oncol Lett 2016; 12:222-230.
22.Nie F, Sun M, Yang J, Xie M, Xu T, Xia R, et al. Long noncoding RNA ANRIL promotes non–small cell lung cancer cell proliferation and inhibits apoptosis by silencing KLF2 and P21 expression. Mol Cancer Ther 2015; 14:268-277.
23.Zhao W, An Y, Liang Y, Xie XW. Role of HOTAIR long noncoding RNA in metastatic progression of lung cancer. Eur Rev Med Pharmacol Sci 2014; 18:1930-1936.
24.Wu YR, Qi HJ, Deng DF, Luo YY, Yang SL. MicroRNA-21 promotes cell proliferation, migration, and resistance to apoptosis through PTEN/PI3K/AKT signaling pathway in esophageal cancer. Tumour Biol 2016; 37:1-10.
25.Liang W, Lai Y, Zhu M, Huang S, Feng W, Gu X. combretastatin A4 regulates proliferation, migration, invasion, and apoptosis of thyroid cancer cells via PI3K/Akt signaling pathway. Med Sci Monit 2016; 22:4911-4917.
26.Liu GL, Yang HJ, Liu B, Liu T. Effects of microRNA-19b on the proliferation, apoptosis, and migration of wilms' tumor cells via the PTEN/PI3K/AKT signaling pathway. J Cell Biochem 2017; 118:3424-3434.
27.Zhou Y, Li S, Li J, Wang D, Li Q. Effect of microRNA-135a on cell proliferation, migration, invasion, apoptosis and tumor angiogenesis through the IGF-1/PI3K/Akt signaling pathway in non-small cell lung cancer. Cell Physiol Biochem 2017; 42:1431-1446.
28.Liu Y, Zheng J, Zhang Y, Wang Z, Yang Y, Bai M, et al. Fucoxanthin activates apoptosis via inhibition of PI3K/Akt/mTOR pathway and suppresses invasion and migration by restriction of p38-MMP-2/9 pathway in human glioblastoma cells. Neurochem Res 2016; 41:1-24.
29.Wang Y, Kuang H, Xue J, Liao L, Yin F, Zhou X. LncRNA AB073614 regulates proliferation and metastasis of colorectal cancer cells via the PI3K/AKT signaling pathway. Biomed Pharmacother 2017; 93:1230-1237.
30.Liu XX, Xiong HP, Huang JS, Qi K, Xu JJ. Highly expressed long non-coding RNA CRNDE promotes cell proliferation through PI3K/AKT signalling in non-small cell lung carcinoma. Clin Exp Pharmacol Physiol 2017; 44:895
Iranian Journal of Basic Medical Sciences
Volume 22, Issue 5
May 2019
Pages 491-498

Files

Share

How to cite

Statistics