Skip to main content
SpringerLink
Log in

Long noncoding RNA HOXC-AS3 facilitates the progression of invasive mucinous adenocarcinomas of the lung via modulating FUS/FOXM1

  • Published:
In Vitro Cellular & Developmental Biology - Animal Aims and scope Submit manuscript

Abstract

Invasive mucinous adenocarcinoma of the lung (IMA), a mucinous variant of lung adenocarcinoma, is strongly linked with a worse prognosis. Therefore, a deeper understanding about its molecular mechanism may conduce to a promising IMA therapy. Long non-coding RNAs (lncRNAs) have recently caught great attention for their crucial roles in diverse diseases regarding tumor initiation and progression. However, the potential role of the lncRNA HOXC-AS3 IMA is not well established. Hence, the purpose of present study is to manifest HOXC-AS3-regulated inner mechanism in IMA development. It revealed that HOXC-AS3 was highly expressed in IMA cells. Additionally, it was identified that the significant down-regulation of HOXC-AS3 obstructed cell proliferation and migration in IMA. As far as mechanism is concerned, it found that HOXC-AS3 recruited FUS to stabilize FOXM1 mRNA, accelerating IMA progression. Taken together, these data suggested that HOXC-AS3 may be recognized as a novel therapeutic target for patients with IMA or at least offer new views for molecular therapy.

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

Figure 1.
Figure 2.
Figure 3.
Figure 4.

Similar content being viewed by others

References

  • Colombrita C, Onesto E, Megiorni F, Pizzuti A, Baralle FE, Buratti E, Silani V, Ratti A (2012) TDP-43 and FUS RNA-binding proteins bind distinct sets of cytoplasmic messenger RNAs and differently regulate their post-transcriptional fate in motoneuron-like cells. J Biol Chem 287:15635–15647

    CAS  PubMed  PubMed Central  Google Scholar 

  • Garcia-Maurino SM, Rivero-Rodriguez F, Velazquez-Cruz A, Hernandez-Vellisca M, Diaz-Quintana A, De la Rosa MA, Diaz-Moreno I (2017) RNA Binding Protein Regulation and Cross-Talk in the Control of AU-rich mRNA Fate. Front Mol Biosci 4:71

    PubMed  PubMed Central  Google Scholar 

  • Ge Z, Cheng Z, Yang X, Huo X, Wang N, Wang H, Wang C, Gu D, Zhao F, Yao M, Fan J, Qin W (2017) Long noncoding RNA SchLAH suppresses metastasis of hepatocellular carcinoma through interacting with fused in sarcoma. Cancer Sci 108:653–662

    CAS  PubMed  PubMed Central  Google Scholar 

  • Harada K, Ferdous T, Minami H, Mishima K (2019) Prognostic significance of FOXM1 in oral squamous cell carcinoma patients treated by docetaxel-containing regimens. Mol Clin Oncol 10:29–36

    CAS  PubMed  Google Scholar 

  • He A, He S, Li X, Zhou L (2019) ZFAS1: A novel vital oncogenic lncRNA in multiple human cancers. Cell Prolif 52:e12513

    PubMed  Google Scholar 

  • Hon CC, Ramilowski JA, Harshbarger J, Bertin N, Rackham OJ, Gough J, Denisenko E, Schmeier S, Poulsen TM, Severin J, Lizio M, Kawaji H, Kasukawa T, Itoh M, Burroughs AM, Noma S, Djebali S, Alam T, Medvedeva YA, Testa AC, Lipovich L, Yip CW, Abugessaisa I, Mendez M, Hasegawa A, Tang D, Lassmann T, Heutink P, Babina M, Wells CA, Kojima S, Nakamura Y, Suzuki H, Daub CO, de Hoon MJ, Arner E, Hayashizaki Y, Carninci P, Forrest AR (2017) An atlas of human long non-coding RNAs with accurate 5' ends. Nature. https://doi.org/10.1038/nature21374

    CAS  PubMed  PubMed Central  Google Scholar 

  • Intuyod K, Saavedra-García P, Zona S, Lai CF, Jiramongkol Y, Vaeteewoottacharn K, Pairojkul C, Yao S, Yong JS, Trakansuebkul S, Waraasawapati S, Luvira V, Wongkham S, Pinlaor S, Lam EW (2018) FOXM1 modulates 5-fluorouracil sensitivity in cholangiocarcinoma through thymidylate synthase (TYMS): implications of FOXM1-TYMS axis uncoupling in 5-FU resistance. Cell Death Dis 9:1185

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ishigaki S, Masuda A, Fujioka Y, Iguchi Y, Katsuno M, Shibata A, Urano F, Sobue G, Ohno K (2012) Position-dependent FUS-RNA interactions regulate alternative splicing events and transcriptions. Sci Rep 2:529

    PubMed  PubMed Central  Google Scholar 

  • Kawasaki Y, Komiya M, Matsumura K, Negishi L, Suda S, Okuno M, Yokota N, Osada T, Nagashima T, Hiyoshi M, Okada-Hatakeyama M, Kitayama J, Shirahige K, Akiyama T (2016) MYU, a Target lncRNA for Wnt/c-Myc Signaling, Mediates Induction of CDK6 to Promote Cell Cycle Progression. Cell Rep 16:2554–2564

    CAS  PubMed  Google Scholar 

  • Kim J, Piao HL, Kim BJ, Yao F, Han Z, Wang Y, Xiao Z, Siverly AN, Lawhon SE, Ton BN, Lee H, Zhou Z, Gan B, Nakagawa S, Ellis MJ, Liang H, Hung MC, You MJ, Sun Y, Ma L (2018) Long noncoding RNA MALAT1 suppresses breast cancer metastasis. Nat Genet. https://doi.org/10.1038/s41588-018-0252-3

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lee HY, Cha MJ, Lee KS, Lee HY, Kwon OJ, Choi JY, Kim HK, Choi YS, Kim J, Shim YM (2016) Prognosis in Resected Invasive Mucinous Adenocarcinomas of the Lung: Related Factors and Comparison with Resected Nonmucinous Adenocarcinomas. J Thorac Oncol. https://doi.org/10.1016/j.jtho.2016.03.011

    PubMed  Google Scholar 

  • Lee HY, Lee KS, Han J, Kim BT, Cho YS, Shim YM, Kim J (2009) Mucinous versus nonmucinous solitary pulmonary nodular bronchioloalveolar carcinoma: CT and FDG PET findings and pathologic comparisons. Lung Cancer 65:170–175

    PubMed  Google Scholar 

  • Li B, Han H, Song S, Fan G, Xu H, Zhou W, Qiu Y, Qian C, Wang Y, Yuan Z, Gao Y, Zhang Y, Zhuang W (2018) HOXC10 regulates osteogenesis of mesenchymal stromal cells through interaction with its natural antisense transcript lncHOXC-AS3. Stem Cells. https://doi.org/10.1002/stem.2925

    PubMed  Google Scholar 

  • Lin Y, Zhang J, Cai J, Liang R, Chen G, Qin G, Han X, Yuan C, Liu Z, Li Y, Zou D, Mao Y (2018) Systematic Analysis of Gene Expression Alteration and Co-Expression Network of Eukaryotic Initiation Factor 4A-3 in Cancer. J Cancer 9:4568–4577

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ling H, Fabbri M, Calin GA (2013) MicroRNAs and other non-coding RNAs as targets for anticancer drug development. Nat Rev Drug Discov 12:847–865

    CAS  PubMed  PubMed Central  Google Scholar 

  • Liu L, Wu J, Guo Y, Xie W, Chen B, Zhang Y, Li S, Hua Y, Peng B, Shen S (2018) Overexpression of FoxM1 predicts poor prognosis of intrahepatic cholangiocarcinoma. Aging (Albany NY) 10:4120–4140

    CAS  Google Scholar 

  • Lu Y, Liu X, Xie M, Liu M, Ye M, Li M, Chen XM, Li X, Zhou R (2017a) The NF-kappaB-Responsive Long Noncoding RNA FIRRE Regulates Posttranscriptional Regulation of Inflammatory Gene Expression through Interacting with hnRNPU. J Immunol 199:3571–3582

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lu Y, Zhao X, Liu Q, Li C, Graves-Deal R, Cao Z, Singh B, Franklin JL, Wang J, Hu H, Wei T, Yang M, Yeatman TJ, Lee E, Saito-Diaz K, Hinger S, Patton JG, Chung CH, Emmrich S, Klusmann JH, Fan D, Coffey RJ (2017b) lncRNA MIR100HG-derived miR-100 and miR-125b mediate cetuximab resistance via Wnt/β-catenin signaling. Nat Med. https://doi.org/10.1038/nm.4424

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lubelsky Y, Ulitsky I (2018) Sequences enriched in Alu repeats drive nuclear localization of long RNAs in human cells. Nature. https://doi.org/10.1038/nature25757

    CAS  PubMed  PubMed Central  Google Scholar 

  • Maeda Y, Tsuchiya T, Hao H, Tompkins DH, Xu Y, Mucenski ML, Du L, Keiser AR, Fukazawa T, Naomoto Y, Nagayasu T, Whitsett JA (2012) Kras(G12D) and Nkx2-1 haploinsufficiency induce mucinous adenocarcinoma of the lung. J Clin Invest 122:4388–4400

    CAS  PubMed  PubMed Central  Google Scholar 

  • Milewski D, Balli D, Ustiyan V, Le T, Dienemann H, Warth A, Breuhahn K, Whitsett JA, Kalinichenko VV, Kalin TV (2017) FOXM1 activates AGR2 and causes progression of lung adenomas into invasive mucinous adenocarcinomas. PLoS Genet 13:e1007097

    PubMed  PubMed Central  Google Scholar 

  • Moon SW, Choi SY, Moon MH (2018) Effect of invasive mucinous adenocarcinoma on lung cancer-specific survival after surgical resection: a population-based study. J Thorac Dis 10:3595–3608

    PubMed  PubMed Central  Google Scholar 

  • Ouyang H, Zhang K, Fox-Walsh K, Yang Y, Zhang C, Huang J, Li H, Zhou Y, Fu XD (2017) The RNA binding protein EWS is broadly involved in the regulation of pri-miRNA processing in mammalian cells. Nucleic Acids Res 45:12481–12495

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ring A, Nguyen C, Smbatyan G, Tripathy D, Yu M, Press M, Kahn M, Lang JE (2018) CBP/β-Catenin/FOXM1 Is a Novel Therapeutic Target in Triple Negative Breast Cancer. Cancers (Basel) 10

  • Silva JM, Rodrigues S, Sampaio-Marques B, Gomes P, Neves-Carvalho A, Dioli C, Soares-Cunha C, Mazuik BF, Takashima A, Ludovico P, Wolozin B, Sousa N, Sotiropoulos I (2018) Dysregulation of autophagy and stress granule-related proteins in stress-driven Tau pathology. Cell Death Differ. https://doi.org/10.1038/s41418-018-0217-1

    Google Scholar 

  • Travis WD, Brambilla E, Noguchi M, Nicholson AG, Geisinger KR, Yatabe Y, Beer DG, Powell CA, Riely GJ, Van Schil PE, Garg K, Austin JH, Asamura H, Rusch VW, Hirsch FR, Scagliotti G, Mitsudomi T, Huber RM, Ishikawa Y, Jett J, Sanchez-Cespedes M, Sculier JP, Takahashi T, Tsuboi M, Vansteenkiste J, Wistuba I, Yang PC, Aberle D, Brambilla C, Flieder D, Franklin W, Gazdar A, Gould M, Hasleton P, Henderson D, Johnson B, Johnson D, Kerr K, Kuriyama K, Lee JS, Miller VA, Petersen I, Roggli V, Rosell R, Saijo N, Thunnissen E, Tsao M, Yankelewitz D (2011) International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol 6:244–285

    PubMed  PubMed Central  Google Scholar 

  • Travis WD, Brambilla E, Riely GJ (2013) New pathologic classification of lung cancer: relevance for clinical practice and clinical trials. J Clin Oncol 31:992–1001

    CAS  PubMed  Google Scholar 

  • Vanhauwaert S, Decaesteker B, De Brouwer S, Leonelli C, Durinck K, Mestdagh P, Vandesompele J, Sermon K, Denecker G, Van Neste C, Speleman F, Preter K (2018) In silico discovery of a FOXM1 driven embryonal signaling pathway in therapy resistant neuroblastoma tumors. Sci Rep 8:17468

    PubMed  PubMed Central  Google Scholar 

  • Wang P, Xu J, Wang Y, Cao X (2017) An interferon-independent lncRNA promotes viral replication by modulating cellular metabolism. Science. https://doi.org/10.1126/science.aao0409

    CAS  PubMed  Google Scholar 

  • Wang X, Chen D, Gao J, Long H, Zha H, Zhang A, Shu C, Zhou L, Yang F, Zhu B, Wu W (2018a) Centromere protein U expression promotes non-small-cell lung cancer cell proliferation through FOXM1 and predicts poor survival. Cancer Manag Res 10:6971–6984

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wang Y, Wu M, Lei Z, Huang M, Li Z, Wang L, Cao Q, Han D, Chang Y, Chen Y, Liu X, Xue L, Mao X, Geng J, Chen Y, Dai T, Ren L, Wang Q, Yu H, Chen C, Chu X (2018b) Dysregulation of miR-6868-5p/FOXM1 circuit contributes to colorectal cancer angiogenesis. J Exp Clin Cancer Res 37:292

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wei P, Zhang N, Wang Y, Li D, Wang L, Sun X, Shen C, Yang Y, Zhou X, Du X (2015) FOXM1 promotes lung adenocarcinoma invasion and metastasis by upregulating SNAIL. Int J Biol Sci 11:186–198

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wislez M, Antoine M, Baudrin L, Poulot V, Neuville A, Pradere M, Longchampt E, Isaac-Sibille S, Lebitasy MP, Cadranel J (2010) Non-mucinous and mucinous subtypes of adenocarcinoma with bronchioloalveolar carcinoma features differ by biomarker expression and in the response to gefitinib. Lung Cancer 68:185–191

    PubMed  Google Scholar 

  • Xiong D, Wu YB, Jin C, Li JJ, Gu J, Liao YF, Long X, Zhu SQ, Wu HB, Xu JJ, Ding JY (2018) Elevated FUS/TLS expression is negatively associated with E-cadherin expression and prognosis of patients with non-small cell lung cancer. Oncol Lett 16:1791–1800

    PubMed  PubMed Central  Google Scholar 

  • Xu CH, Wang W, Wei Y, Hu HD, Zou J, Yan J, Yu LK, Yang RS, Wang Y (2015) Prognostic value of the new International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification in stage IB lung adenocarcinoma. Eur J Surg Oncol 41:1430–1436

    PubMed  Google Scholar 

  • Yang L, Lin C, Jin C, Yang JC, Tanasa B, Li W, Merkurjev D, Ohgi KA, Meng D, Zhang J, Evans CP, Rosenfeld MG (2013) lncRNA-dependent mechanisms of androgen-receptor-regulated gene activation programs. Nature 500:598–602

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yao Y, Wang X, Jiang L, Shao X, Zhu X, He S (2018) Prognostic and clinicopathological value of FoxM1 expression in colorectal cancer: A systematic review and meta-analysis. Medicine (Baltimore) 97:e13899

    CAS  Google Scholar 

  • Yu HM, Wang C, Yuan Z, Chen GL, Ye T, Yang BW (2019) LncRNA NEAT1 promotes the tumorigenesis of colorectal cancer by sponging miR-193a-3p. Cell Prolif 52:e12526

    PubMed  Google Scholar 

  • Zhang E, He X, Zhang C, Su J, Lu X, Si X, Chen J, Yin D, Han L, De W (2018a) A novel long noncoding RNA HOXC-AS3 mediates tumorigenesis of gastric cancer by binding to YBX1. Genome Biol 19:154

    PubMed  PubMed Central  Google Scholar 

  • Zhang Y, Huang Z, Sheng F, Yin Z (2018b) MYC upregulated LINC00319 promotes human acute myeloid leukemia (AML) cells growth through stabilizing SIRT6. Biochem Biophys Res Commun. https://doi.org/10.1016/j.bbrc.2018.12.133

    CAS  PubMed  Google Scholar 

  • Zhang Y, Sun Y, Pan Y, Li C, Shen L, Li Y, Luo X, Ye T, Wang R, Hu H, Li H, Wang L, Pao W, Chen H (2012) Frequency of driver mutations in lung adenocarcinoma from female never-smokers varies with histologic subtypes and age at diagnosis. Clin Cancer Res 18:1947–1953

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhu C, Cheng D, Qiu X, Zhuang M, Liu Z (2018) Long Noncoding RNA SNHG16 Promotes Cell Proliferation by Sponging MicroRNA-205 and Upregulating ZEB1 Expression in Osteosarcoma. Cell Physiol Biochem 51:429–440

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We would like to genuinely thank to all contributors involved in this study.

Data availability statement

n/a

Author information

Authors and Affiliations

  1. Department of Thoracic Surgery, HwaMei Hospital, University of Chinese Academy of Science, No.41 Northwest Street, Ningbo, 315000, Zhejiang, China

    Zhenhua Yang & Tianjun Hu

Authors
  1. Zhenhua Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tianjun Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tianjun Hu.

Ethics declarations

Conflict of interests

The authors declare that they have no conflicts of interest.

Additional information

Editor: Tetsuji Okamoto

Electronic supplementary material

Figure S1.

Functional role of FOXM1 in IMA cells. (A) Knockdown efficiency of FOXM1 in IMA cells (A549, SPC-A1) was confirmed by qRT-PCR, sh-NC as negative control. (B) Cell proliferation was determined using CCK-8 assay following transfection of sh-FOXM1#1, sh-FOXM1#2, sh-NC into A549 and SPC-A1 cells. (C) A549 and SPC-A1 cells were transfected with sh-FOXM1#1, sh-FOXM1#2, sh-NC, and cell apoptotic rate was detected by flow cytometry apoptosis assay. (D, E) A549 and SPC-A1 cell migration and invasion abilities were determined using Transwell assays after transfection with sh-FOXM1#1, sh-FOXM1#2, sh-NC. **P < 0.01. (PNG 270 kb)

High resolution image (TIF 7508 kb)

Figure S2

IMA cellular processes were changed after silencing of FUS. (A) Knockdown efficiency of FUS in IMA cells (A549, SPC-A1) was confirmed by qRT-PCR, sh-NC as negative control. (B) Cell proliferation was determined using CCK-8 assay following transfection of sh-FUS#1, sh-FUS#2, sh-NC into A549 and SPC-A1 cells. (C) A549 and SPC-A1 cells were transfected with sh-FUS#1, sh-FUS#2, sh-NC and cell apoptotic rate was detected by flow cytometry apoptosis assay. (D, E) A549 and SPC-A1 cell migration and invasion abilities were determined using Transwell assays after transfection with sh-FUS#1, sh-FUS#2, sh-NC. **P < 0.01. (PNG 259 kb)

High resolution image (TIF 8308 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yang, Z., Hu, T. Long noncoding RNA HOXC-AS3 facilitates the progression of invasive mucinous adenocarcinomas of the lung via modulating FUS/FOXM1. In Vitro Cell.Dev.Biol.-Animal 56, 15–23 (2020). https://doi.org/10.1007/s11626-019-00414-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11626-019-00414-8

Keywords

Search

Navigation