Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Long non-coding RNA DLGAP1-AS1 modulates the development of non-small-cell lung cancer via the microRNA-193a-5p/DTL axis

Abstract

Non-small cell lung cancer (NSCLC) is one of the most malignant cancers worldwide. A growing number of studies have suggested that long noncoding RNAs (lncRNAs) play a key role in the progression of non-small cell lung cancer (NSCLC). Here, we report a novel lncRNA DLGAP1 antisense RNA 1 (DLGAP1-AS1) that exhibits oncogenic properties in NSCLC. The lncRNA DLGAP1-AS1 and denticleless protein homolog (DTL) presented upregulated expression, but microRNA-193a-5p (miR-193a-5p) showed downregulated expression in cancerous tissues of human lung samples from 48 patients with NSCLC. Partial loss of lncRNA DLGAP1-AS1 reduced malignant cell viability, migration, and invasion but induced apoptosis. Dual-luciferase reporter gene, RNA pull-down and RNA binding protein immunoprecipitation assays demonstrated enrichment of lncRNA DLGAP1-AS1 in miR-193a-5p and Argonaute 2, suggesting that lncRNA DLGAP1-AS1 modulated DTL, a putative target of miR-193a-5p. We also found that restoration of miR-193a-5p rescued NSCLC cell biological functions affected by overexpression of lncRNA DLGAP1-AS1. Silencing lncRNA DLGAP1-AS1 was found to reduce the tumorigenesis of NSCLC cells xenografted into nude mice, which was rescued by DTL overexpression. In conclusion, our study highlights a novel regulatory network of the lncRNA DLGAP1-AS1/miR-193a-5p/DTL axis in NSCLC, providing a potential therapeutic strategy for NSCLC.

This is a preview of subscription content, access via your institution

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1: Upregulated lncRNA DLGAP1-AS1 is found in NSCLC tissues and cells.
Fig. 2: Silencing of lncRNA DLGAP1-AS1 restricts NCl-H1975 cell viability, migration, and invasion but induces apoptosis in NCl-H1975 cells.
Fig. 3: Elevated expression of miR-193a-5p suppresses NSCLC cell viability, migration, and invasion, but induces apoptosis.
Fig. 4: LncRNA DLGAP1-AS1 upregulates DTL by binding to miR-193a-5p.
Fig. 5: Silencing lncRNA DLGAP1-AS1 suppresses NSCLC cell viability, migration, and invasion, but accelerates apoptosis via the miR-193a-5p/DTL axis.
Fig. 6: Silencing of lncRNA DLGAP1-AS1 inhibits NSCLC tumor growth in vivo via the miR-193a-5p/DTL axis.

Data availability

The datasets generated/analysed during the current study are available.

References

  1. Siegel, RL, Miller, KD, Jemal, A. Cancer statistics, 2015. CA Cancer J Clin 65, 5–29 (2015)

    Article  Google Scholar 

  2. Molina, JR, Yang, P, Cassivi, SD, Schild, SE, Adjei, AA. Non-small cell lung cancer: Epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc 83, 584–594 (2008)

    Article  Google Scholar 

  3. Shigematsu, H, Gazdar, AF. Somatic mutations of epidermal growth factor receptor signaling pathway in lung cancers. Int J Cancer 118, 257–262 (2006)

    Article  CAS  Google Scholar 

  4. Li, T, Kung, HJ, Mack, PC, Gandara, DR. Genotyping and genomic profiling of non-small-cell lung cancer: implications for current and future therapies. J Clin Oncol 31, 1039–1049 (2013)

    Article  CAS  Google Scholar 

  5. Farazi, TA, Hoell, JI, Morozov, P, Tuschl, T. MicroRNAs in human cancer. Adv Exp Med Biol 774, 1–20 (2013)

    Article  CAS  Google Scholar 

  6. Hu, Z, Chen, X, Zhao, Y, Tian, T, Jin, G, Shu, Y, et al. Serum microRNA signatures identified in a genome-wide serum microRNA expression profiling predict survival of non-small-cell lung cancer. J Clin Oncol 28, 1721–1726 (2010)

    Article  Google Scholar 

  7. Kumar, MS, Erkeland, SJ, Pester, RE, Chen, CY, Ebert, MS, Sharp, PA, et al. Suppression of non-small cell lung tumor development by the let-7 microRNA family. Proc Natl Acad Sci USA 105, 3903–3908 (2008)

    Article  CAS  Google Scholar 

  8. Chen, J, Gao, S, Wang, C, Wang, Z, Zhang, H, Huang, K, et al. Pathologically decreased expression of miR-193a contributes to metastasis by targeting WT1-E-cadherin axis in non-small cell lung cancers. J Exp Clin Cancer Res 35, 173 (2016)

    Article  Google Scholar 

  9. Nakagawa, T, Endo, H, Yokoyama, M, Abe, J, Tamai, K, Tanaka, N, et al. Large noncoding RNA HOTAIR enhances aggressive biological behavior and is associated with short disease-free survival in human non-small cell lung cancer. Biochem Biophys Res Commun 436, 319–324 (2013)

    Article  CAS  Google Scholar 

  10. Dong, Y, Liang, G, Yuan, B, Yang, C, Gao, R, Zhou, X. MALAT1 promotes the proliferation and metastasis of osteosarcoma cells by activating the PI3K/Akt pathway. Tumour Biol 36, 1477–1486 (2015)

    Article  CAS  Google Scholar 

  11. Deng, J, Zhang, Q, Lu, L, Fan, C. Long Noncoding RNA DLGAP1-AS1 promotes the aggressive behavior of gastric cancer by acting as a ceRNA for microRNA-628-5p and raising astrocyte elevated gene 1 Expression. Cancer Manag Res 12, 2947–2960 (2020)

    Article  CAS  Google Scholar 

  12. Gautier, L, Cope, L, Bolstad, BM, Irizarry, RA. affy-analysis of Affymetrix GeneChip data at the probe level. Bioinformatics 20, 307–315 (2004)

    Article  CAS  Google Scholar 

  13. Smyth GK. Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol 3, Article3 (2004) https://doi.org/10.2202/1544-6115.1027. Epub 2004 Feb 12. PMID: 16646809.

  14. Sun, Y, Li, D, Lv, XH, Hua, SC, Han, JC, Xu, F, et al. Roles of osteopontin and matrix metalloproteinase-7 in occurrence, progression, and prognosis of nonsmall cell lung cancer. J Res Med Sci 20, 1138–1146 (2015)

    Article  CAS  Google Scholar 

  15. Feng, J, Sun, Y, Zhang, EB, Lu, XY, Jin, SD, Guo, RH. A novel long noncoding RNA IRAIN regulates cell proliferation in non small cell lung cancer. Int J Clin Exp Pathol 8, 12268–12275 (2015)

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Lin, Y, Jian, Z, Jin, H, Wei, X, Zou, X, Guan, R, et al. Long non-coding RNA DLGAP1-AS1 facilitates tumorigenesis and epithelial-mesenchymal transition in hepatocellular carcinoma via the feedback loop of miR-26a/b-5p/IL-6/JAK2/STAT3 and Wnt/beta-catenin pathway. Cell Death Dis 11, 34 (2020)

    Article  CAS  Google Scholar 

  17. Peng, X, Wei, F, Hu, X. Long noncoding RNA DLGAP1-AS1 promotes cell proliferation in hepatocellular carcinoma via sequestering miR-486-5p. J Cell Biochem 121, 1953–1962 (2020)

    Article  CAS  Google Scholar 

  18. Salmena, L, Poliseno, L, Tay, Y, Kats, L, Pandolfi, PP. A ceRNA hypothesis: The Rosetta Stone of a hidden RNA language? Cell 146, 353–358 (2011)

    Article  CAS  Google Scholar 

  19. Lv, J, Qiu, M, Xia, W, Liu, C, Xu, Y, Wang, J, et al. High expression of long non-coding RNA SBF2-AS1 promotes proliferation in non-small cell lung cancer. J Exp Clin Cancer Res 35, 75 (2016)

    Article  Google Scholar 

  20. National Lung Screening Trial Research, T, Aberle, DR, Adams, AM, Berg, CD, Black, WC, Clapp, JD, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 365, 395–409 (2011)

    Article  Google Scholar 

  21. Ricciuti, B, Mencaroni, C, Paglialunga, L, Paciullo, F, Crino, L, Chiari, R, et al. Long noncoding RNAs: new insights into non-small cell lung cancer biology, diagnosis and therapy. Med Oncol 33, 18 (2016)

    Article  Google Scholar 

  22. Qiu, M, Xu, Y, Yang, X, Wang, J, Hu, J, Xu, L, et al. CCAT2 is a lung adenocarcinoma-specific long non-coding RNA and promotes invasion of non-small cell lung cancer. Tumour Biol 35, 5375–5380 (2014)

    Article  CAS  Google Scholar 

  23. Yang, YR, Zang, SZ, Zhong, CL, Li, YX, Zhao, SS, Feng, XJ. Increased expression of the lncRNA PVT1 promotes tumorigenesis in non-small cell lung cancer. Int J Clin Exp Pathol 7, 6929–6935 (2014)

    PubMed  PubMed Central  Google Scholar 

  24. Nie, W, Ge, HJ, Yang, XQ, Sun, X, Huang, H, Tao, X, et al. LncRNA-UCA1 exerts oncogenic functions in non-small cell lung cancer by targeting miR-193a-3p. Cancer Lett 371, 99–106 (2016)

    Article  CAS  Google Scholar 

  25. Sun, C, Li, S, Zhang, F, Xi, Y, Wang, L, Bi, Y, et al. Long non-coding RNA NEAT1 promotes non-small cell lung cancer progression through regulation of miR-377-3p-E2F3 pathway. Oncotarget 7, 51784–51814 (2016)

    Article  Google Scholar 

  26. Xue, JM, Liu, Y, Wan, LH, Zhu, YX. Comprehensive analysis of differential gene expression to identify common gene signatures in multiple cancers. Med Sci Monit 26, e919953 (2020)

    Article  CAS  Google Scholar 

  27. Cai, X, Lin, L, Zhang, Q, Wu, W, Su, A. Bioinformatics analysis of the circRNA-miRNA-mRNA network for non-small cell lung cancer. J Int Med Res 48, 300060520929167 (2020)

  28. Perez-Pena, J, Corrales-Sanchez, V, Amir, E, Pandiella, A, Ocana, A. Ubiquitin-conjugating enzyme E2T (UBE2T) and denticleless protein homolog (DTL) are linked to poor outcome in breast and lung cancers. Sci Rep 7, 17530 (2017)

    Article  Google Scholar 

  29. Ma, T, Hu, Y, Guo, Y, Zhang, Q. Human umbilical vein endothelial cells-derived microRNA-203-containing extracellular vesicles alleviate non-small-cell lung cancer progression through modulating the DTL/p21 axis. Cancer Gene Ther Feb 8 (2021) https://doi.org/10.1038/s41417-020-00292-3

Download references

Funding

This work is supported by National Natural Science Foundation of China (No. 31101641) and the project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions.

Author information

Authors and Affiliations

Authors

Contributions

Xudong Pan conceived and designed research. Siwen Chen performed experiments and interpreted results of experiments. Lu Ye analyzed data. Shenjie Xu prepared figures. Ling Wang drafted paper. Yi Sun edited and revised manuscript. All authors read and approved final version of manuscript.

Corresponding authors

Correspondence to Ling Wang or Yi Sun.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

The study was performed with the approval of the Ethics Committee of The First Affiliated Hospital of Soochow University. Each patient provided informed written consent prior to study recruitment. All experiments in the present study were conducted in strict accordance with the Helsinki Declaration. The animal experiment strictly adhered to the principle to minimize the pain, suffering, and discomfort to experimental animals. The protocol was approved by the Animal Ethics Committee of The First Affiliated Hospital of Soochow University.

Additional information

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

Supplementary information

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Pan, X., Chen, S., Ye, L. et al. Long non-coding RNA DLGAP1-AS1 modulates the development of non-small-cell lung cancer via the microRNA-193a-5p/DTL axis. Lab Invest 102, 1182–1191 (2022). https://doi.org/10.1038/s41374-022-00831-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41374-022-00831-6

Search

Quick links