Skip to main content
SpringerLink
Log in

LncRNA NORAD, sponging miR-363-3p, promotes invasion and EMT by upregulating PEAK1 and activating the ERK signaling pathway in NSCLC cells

  • Published:
Journal of Bioenergetics and Biomembranes Aims and scope Submit manuscript

Abstract

Lung cancer is one of the most common malignant tumors in the world. Non-small cell lung cancer (NSCLC) accounts for about 80% of all lung cancers. About 75% of patients are in the middle and advanced stages at the time of discovery, and the 5-year survival rate is very low. The aim of this study was to investigate the role of long non-coding RNA (lncRNA) NORAD in the pathogenesis of NSCLC. We found that lncRNA NORAD was highly expressed in human NSCLC tissues and cell lines. The CCK-8 assay results showed that lncRNA NORAD had no effect on cell proliferation. The Transwell assay and Western blotting results showed that overexpression of lncRNA NORAD promoted the invasion and epithelial-mesenchymal transition (EMT) of NSCLC cells. Then bioinformatics analysis was used to screen for candidate miRNA bound with lncRNA NORAD and the target gene of miRNA in NSCLC. The luciferase reporter gene assay and RNA pull-down assay were used to verify the relationship. We found that miR-363-3p expression was down-regulated, whereas PEAK1 expression was upregulated in NSCLC cells. We performed gain and loss function test of lncRNA NORAD, miR-363-3p and PEAK1, the results showed that while miR-363-3p-mimic inhibited cell invasion and EMT by targeting PEAK1, lncRNA NORAD acted as a sponge of miR-363-3p and promoted cell invasion and EMT by increasing the expression of PEAK1. In addition, p-ERK expression was detected by Western blotting to observe the effects of lncRNA NORAD, miR-363-3p and PEAK1 on activation of the ERK signaling pathway. Taken together, lncRNA NORAD upregulated the expression of PEAK1 through sponging miR-363-3p, and then activated the ERK signaling pathway, thereby promoting the development of NSCLC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  • Bian WG, Zhou XN, Song S, Chen HT, Shen Y, Chen P (2019) Reduced miR-363-3p expression in non-small cell lung cancer is associated with gemcitabine resistance via targeting of CUL4A. Eur Rev Med Pharmacol Sci 23(2):649–659

    PubMed  Google Scholar 

  • Cai J, Fang L, Huang Y, Li R, Xu X, Hu Z, Zhang L, Yang Y, Zhu X, Zhang H, Wu J, Huang Y, Li J, Zeng M, Song E, He Y, Zhang L, Li M (2017) Simultaneous overactivation of Wnt/beta-catenin and TGFbeta signalling by miR-128-3p confers chemoresistance-associated metastasis in NSCLC. Nat Commun 8:15870

    Article  CAS  Google Scholar 

  • Chang J, Gao F, Chu H, Lou L, Wang H, Chen Y (2019) miR-363-3p inhibits migration, invasion, and epithelial-mesenchymal transition by targeting NEDD9 and SOX4 in non-small-cell lung cancer. J Cell Physiol 235(2):1808–1820

    Article  Google Scholar 

  • Chen E, Xu X, Liu R, Liu T (2018) Small but heavy role: MicroRNAs in hepatocellular carcinoma progression. Biomed Res Int 2018:6784607

    PubMed  PubMed Central  Google Scholar 

  • Chen T, Qin S, Gu Y, Pan H, Bian D (2019) Long non-coding RNA NORAD promotes the occurrence and development of non-small cell lung cancer by adsorbing MiR-656-3p. Mol Genet Genomic Med 7(8):e757

    PubMed  PubMed Central  Google Scholar 

  • Croucher DR, Hochgrafe F, Zhang L, Liu L, Lyons RJ, Rickwood D, Tactacan CM, Browne BC, Ali N, Chan H, Shearer R, Gallego-Ortega D, Saunders DN, Swarbrick A, Daly RJ (2013) Involvement of Lyn and the atypical kinase SgK269/PEAK1 in a basal breast cancer signaling pathway. Cancer Res 73(6):1969–1980

  • Ding C, Tang W, Fan X, Wang X, Wu H, Xu H, Xu W, Gao W, Wu G (2018) Overexpression of PEAK1 contributes to epithelial–mesenchymal transition and tumor metastasis in lung cancer through modulating ERK1/2 and JAK2 signaling. Cell Death Dis 9(8):802

    Article  Google Scholar 

  • Gao W, Weng T, Wang L, Shi B, Meng W, Wang X, Wu Y, Jin L, Fei L (2019) Long noncoding RNA NORAD promotes cell proliferation and glycolysis in nonsmall cell lung cancer by acting as a sponge for miR1365p. Mol Med Rep 19(6):5397–5405

    CAS  PubMed  PubMed Central  Google Scholar 

  • Heigener DF, Gandara DR, Reck M (2015) Targeting of MEK in lung cancer therapeutics. Lancet Respir Med 3(4):319–327

    Article  CAS  Google Scholar 

  • Huang L, Wen C, Yang X, Lou Q, Wang X, Che J, Chen J, Yang Z, Wu X, Huang M, Lan P, Wang L, Iwamoto A, Wang J, Liu H (2018) PEAK1, acting as a tumor promoter in colorectal cancer, is regulated by the EGFR/KRas signaling axis and miR-181d. Cell Death Dis 9(3):271

    Article  Google Scholar 

  • Jiang C, Cao Y, Lei T, Wang Y, Fu J, Wang Z, Lv Z (2018) microRNA-363-3p inhibits cell growth and invasion of nonsmall cell lung cancer by targeting HMGA2. Mol Med Rep 17(2):2712–2718

    CAS  PubMed  Google Scholar 

  • Kawasaki N, Miwa T, Hokari S, Sakurai T, Ohmori K, Miyauchi K, Miyazono K, Koinuma D (2018) Long noncoding RNA NORAD regulates transforming growth factor-beta signaling and epithelial-to-mesenchymal transition-like phenotype. Cancer Sci 109(7):2211–2220

    Article  CAS  Google Scholar 

  • Kondo Y, Shinjo K, Katsushima K (2017) Long non-coding RNAs as an epigenetic regulator in human cancers. Cancer Sci 108(10):1927–1933

    Article  CAS  Google Scholar 

  • Li H, Wang X, Wen C, Huo Z, Wang W, Zhan Q, Cheng D, Chen H, Deng X, Peng C, Shen B (2017) Long noncoding RNA NORAD, a novel competing endogenous RNA, enhances the hypoxia-induced epithelial-mesenchymal transition to promote metastasis in pancreatic cancer. Mol Cancer 16(1):169

    Article  Google Scholar 

  • Li T, Xie J, Shen C, Cheng D, Shi Y, Wu Z, Deng X, Chen H, Shen B, Peng C, Li H, Zhan Q, Zhu Z (2016) Upregulation of long noncoding RNA ZEB1-AS1 promotes tumor metastasis and predicts poor prognosis in hepatocellular carcinoma. Oncogene 35(12):1575–1584

    Article  CAS  Google Scholar 

  • Liu H, Li J, Koirala P, Ding X, Chen B, Wang Y, Wang Z, Wang C, Zhang X, Mo YY (2016) Long non-coding RNAs as prognostic markers in human breast cancer. Oncotarget 7(15):20584–20596

  • Lu YB, Jiang Q, Yang MY, Zhou JX, Zhang Q (2017) Long noncoding RNA NNT-AS1 promotes hepatocellular carcinoma progression and metastasis through miR-363/CDK6 axis. Oncotarget 8(51):88804–88814

    Article  Google Scholar 

  • Mao QD, Zhang W, Zhao K, Cao B, Yuan H, Wei LZ, Song MQ, Liu XS (2017) MicroRNA-455 suppresses the oncogenic function of HDAC2 in human colorectal cancer. Braz J Med Biol Res 50(6):e6103

    Article  CAS  Google Scholar 

  • Pan H, Jiang T, Cheng N, Wang Q, Zhou C (2016) Long non-coding RNA BC087858 induces non-T790M mutation acquired resistance to EGFR-TKIs by activating PI3K/AKT and MEK/ERK pathways and EMT in non-small-cell lung cancer. Oncotarget 7(31):49948–49960

    Article  Google Scholar 

  • Qiao J, Lee S, Paul P, Theiss L, Tiao J, Qiao L, Kong A, Chung DH (2013) miR-335 and miR-363 regulation of neuroblastoma tumorigenesis and metastasis. Surgery 154(2):226–233

    Article  Google Scholar 

  • Tan DSW, Chong FT, Leong HS, Toh SY, Lau DP, Kwang XL, Zhang X, Sundaram GM, Tan GS, Chang MM, Chua BT, Lim WT, Tan EH, Ang MK, Lim TKH, Sampath P, Chowbay B, Skanderup AJ, DasGupta R, Iyer NG (2017) Long noncoding RNA EGFR-AS1 mediates epidermal growth factor receptor addiction and modulates treatment response in squamous cell carcinoma. Nat Med 23(10):1167–1175

    Article  CAS  Google Scholar 

  • Tsuji S, Kawasaki Y, Furukawa S, Taniue K, Hayashi T, Okuno M, Hiyoshi M, Kitayama J, Akiyama T (2014) The miR-363-GATA6-Lgr5 pathway is critical for colorectal tumourigenesis. Nat Commun 5:3150

    Article  Google Scholar 

  • Wang K, Yan L, Lu F (2019) miR-363-3p inhibits osteosarcoma cell proliferation and invasion via targeting SOX4. Oncol Res 27(2):157–163

    Article  Google Scholar 

  • Wang Y, Chen T, Huang H, Jiang Y, Yang L, Lin Z, He H, Liu T, Wu B, Chen J, Kamp DW, Liu G (2017) miR-363-3p inhibits tumor growth by targeting PCNA in lung adenocarcinoma. Oncotarget 8(12):20133–20144

  • Wang Y, Kelber JA, Tran Cao HS, Cantin GT, Lin R, Wang W, Kaushal S, Bristow JM, Edgington TS, Hoffman RM, Bouvet M, Yates JR 3rd, Klemke RL (2010) Pseudopodium-enriched atypical kinase 1 regulates the cytoskeleton and cancer progression.  Proc Natl Acad Sci U S A 107(24):10920–10925

  • Yan XR, Wang LB, Chen DM, Li YK, Yang YX (2014) Expression of miR-363 in human colorectal cancer tissues and its effect on proliferation and migration of colorectal cancer cells. Chin J Canc Prev Treat 21(7):509–513

  • Xu Y, Ge Z, Zhang E, Zuo Q, Huang S, Yang N, Wu D, Zhang Y, Chen Y, Xu H, Huang H, Jiang Z, Sun L (2017) The lncRNA TUG1 modulates proliferation in trophoblast cells via epigenetic suppression of RND3. Cell Death Dis 8(10):e3104

    Article  CAS  Google Scholar 

  • Ye J, Zhang W, Liu S, Liu Y, Liu K (2017) miR-363 inhibits the growth, migration and invasion of hepatocellular carcinoma cells by regulating E2F3. Oncol Rep 38(6):3677–3684

    CAS  PubMed  Google Scholar 

  • Yoichiro T, Tomoko K (2006) MiRNA in disease and therapeutic development. Tanpakushitsu Kakusan Koso Protein Nucleic Acid Enzyme 51(16 Suppl):2509–2514

    Google Scholar 

  • Zhang J, Li XY, Hu P, Ding YS (2018) LncRNA NORAD contributes to colorectal cancer progression by inhibition of miR-202-5p. Oncol Res 26(9):1411–1418

    Article  Google Scholar 

Download references

Funding

This study was supported by Central University Fund (No. XJJ2018113) and National Natural Science Foundation of China (No. 81803015).

Author information

Authors and Affiliations

  1. Department of Nuclear Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061, China

    Qianqian Geng

  2. Department of Minimally Invasive Intervention, Shaanxi Province Tumor Hospital, Xi’an, 710061, China

    Zhubin Li

  3. The Second Department of Internal Medicine, Shaanxi Province Tumor Hospital, Xi’an, 710061, China

    Xintao Li

  4. Department of General Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061, China

    Yunhua Wu

  5. Department of Thoracic Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061, China

    Nanzheng Chen

Authors
  1. Qianqian Geng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhubin Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xintao Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yunhua Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nanzheng Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nanzheng Chen.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Geng, Q., Li, Z., Li, X. et al. LncRNA NORAD, sponging miR-363-3p, promotes invasion and EMT by upregulating PEAK1 and activating the ERK signaling pathway in NSCLC cells. J Bioenerg Biomembr 53, 321–332 (2021). https://doi.org/10.1007/s10863-021-09892-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10863-021-09892-6

Keywords

Search

Navigation