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.

  • Article
  • Published:

Upregulated lncRNA DLX6-AS1 underpins hepatocellular carcinoma progression via the miR-513c/Cul4A/ANXA10 axis

Cancer Gene Therapy volume 28, pages 486–501 (2021)Cite this article

Subjects

Abstract

Recent studies have illustrated the role of aberrant regulatory interactions in the mediation of malignant phenotypes of cancer cells, which could potentially provide novel therapeutic targets to limit the destructive recurrence and metastasis of hepatocellular carcinoma (HCC). Herein, we clarify the oncogenic role of the long noncoding RNA (lncRNA) distal-less homeobox 6 antisense 1 (DLX6-AS1) in HCC in vivo and in vitro. To this end, we knocked down lncRNA DLX6-AS1 and manipulated the expression of miR-513c to characterize their effects in HCC cell viability, migration, invasion, and apoptosis. Furthermore, we probed the interactions with miR-513c’s target gene Cullin4A (Cul4A) and the degradation of Annexin A10 (ANXA10) protein. Our data show that lncRNA DLX6-AS1 and Cul4A were highly expressed, while miR-513c and ANXA10 were poorly expressed in HCC tissues and cells. Moreover, the silencing of lncRNA DLX6-AS1 impeded the viability, invasion, and migration of HCC cells, while stimulating cell apoptosis. Further data indicated that lncRNA DLX6-AS1 targeted and repressed miR-513c expression, where the tumor-inhibiting effects of lncRNA DLX6-AS1 silencing was achieved by elevating miR-513c expression. Importantly, the lncRNA DLX6-AS1 upregulated the expression of Cul4A through sponging of miR-513c. The silencing of Cul4A restricted the malignant phenotypes of HCC cells by repressing the ubiquitination-mediated degradation of ANXA10. In vivo experiments verified that lncRNA DLX6-AS1 promoted the progression of HCC through the miR-513c/Cul4A/ANXA10 axis. Thus, the silencing of lncRNA DLX6-AS1 impaired miR-513c-dependent Cul4A inhibition and subsequently elevated ubiquitination-mediated degradation of ANXA10, thereby preventing the occurrence and development of HCC.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: LncRNA DLX6-AS1 is highly expressed in HCC tissues and cells.
Fig. 2: Silencing lncRNA DLX6-AS1 represses the viability, invasion, and migration of HCC cells.
Fig. 3: LncRNA DLX6-AS1 targets and inhibits miR-513c expression.
Fig. 4: Silencing lncRNA DLX6-AS1 represses the HCC cell viability, invasion, and migration by promoting miR-513c.
Fig. 5: LncRNA DLX6-AS1 upregulates Cul4A expression by competitively binding to miR-513c.
Fig. 6: miR-513c overexpression restricts HCC cell viability, invasion, and migration by targeting Cul4A.
Fig. 7: Silencing Cul4A represses HCC cell viability, invasion, and migration by inhibiting ubiquitination-mediated degradation of ANXA10.
Fig. 8: LncRNA DLX6-AS1 regulates the Cul4A/ANXA10 axis through inhibition of miR-513c to accelerate the development of HCC in vivo.
Fig. 9: Schematic illustration of the regulatory network and function of lncRNA DLX6-AS1.

Similar content being viewed by others

References

  1. Sun L, Wang Y, Cen J, Ma X, Cui L, Qiu Z, et al. Modelling liver cancer initiation with organoids derived from directly reprogrammed human hepatocytes. Nat Cell Biol. 2019;21:1015–26.

    Article  CAS  Google Scholar 

  2. Jiang Y, Sun A, Zhao Y, Ying W, Sun H, Yang X, et al. Proteomics identifies new therapeutic targets of early-stage hepatocellular carcinoma. Nature. 2019;567:257–61.

    Article  CAS  Google Scholar 

  3. Ringelhan M, Pfister D, O’Connor T, Pikarsky E, Heikenwalder M. The immunology of hepatocellular carcinoma. Nat Immunol. 2018;19:222–32.

    Article  CAS  Google Scholar 

  4. Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet. 2018;391:1301–14.

    Article  Google Scholar 

  5. European Association for the Study of the Liver. Electronic address eee, European Association for the Study of the L. EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. J Hepatol. 2018;69:182–236.

    Article  Google Scholar 

  6. Chisari FV, Klopchin K, Moriyama T, Pasquinelli C, Dunsford HA, Sell S, et al. Molecular pathogenesis of hepatocellular carcinoma in hepatitis B virus transgenic mice. Cell. 1989;59:1145–56.

    Article  CAS  Google Scholar 

  7. El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 2007;132:2557–76.

    Article  CAS  Google Scholar 

  8. Huang JL, Zheng L, Hu YW, Wang Q. Characteristics of long non-coding RNA and its relation to hepatocellular carcinoma. Carcinogenesis 2014;35:507–14.

    Article  CAS  Google Scholar 

  9. Yang Y, Chen L, Gu J, Zhang H, Yuan J, Lian Q, et al. Recurrently deregulated lncRNAs in hepatocellular carcinoma. Nat Commun. 2017;8:14421.

    Article  CAS  Google Scholar 

  10. Zhang L, He X, Jin T, Gang L, Jin Z. Long non-coding RNA DLX6-AS1 aggravates hepatocellular carcinoma carcinogenesis by modulating miR-203a/MMP-2 pathway. Biomed Pharmacother. 2017;96:884–91.

    Article  CAS  Google Scholar 

  11. Wu DM, Zheng ZH, Zhang YB, Fan SH, Zhang ZF, Wang YJ, et al. Down-regulated lncRNA DLX6-AS1 inhibits tumorigenesis through STAT3 signaling pathway by suppressing CADM1 promoter methylation in liver cancer stem cells. J Exp Clin Cancer Res. 2019;38:237.

    Article  Google Scholar 

  12. Zhang K, Zhao Z, Yu J, Chen W, Xu Q, Chen L. LncRNA FLVCR1-AS1 acts as miR-513c sponge to modulate cancer cell proliferation, migration, and invasion in hepatocellular carcinoma. J Cell Biochem. 2018;119:6045–56.

    Article  CAS  Google Scholar 

  13. Xia HL, Lv Y, Xu CW, Fu MC, Zhang T, Yan XM, et al. MiR-513c suppresses neuroblastoma cell migration, invasion, and proliferation through direct targeting glutaminase (GLS). Cancer Biomark. 2017;20:589–96.

    Article  CAS  Google Scholar 

  14. Ni W, Zhang Y, Zhan Z, Ye F, Liang Y, Huang J, et al. A novel lncRNA uc.134 represses hepatocellular carcinoma progression by inhibiting CUL4A-mediated ubiquitination of sLATS1. J Hematol Oncol. 2017;10:91.

    Article  Google Scholar 

  15. Wang Y, Wen M, Kwon Y, Xu Y, Liu Y, Zhang P, et al. CUL4A induces epithelial-mesenchymal transition and promotes cancer metastasis by regulating ZEB1 expression. Cancer Res. 2014;74:520–31.

    Article  CAS  Google Scholar 

  16. Lv J, Zhang S, Wu H, Lu J, Lu Y, Wang F, et al. Deubiquitinase PSMD14 enhances hepatocellular carcinoma growth and metastasis by stabilizing GRB2. Cancer Lett. 2020;469:22–34.

    Article  CAS  Google Scholar 

  17. Xu JH, Chang WH, Fu HW, Yuan T, Chen P. The mRNA, miRNA and lncRNA networks in hepatocellular carcinoma: An integrative transcriptomic analysis from Gene Expression Omnibus. Mol Med Rep. 2018;17:6472–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Song J, Ye A, Jiang E, Yin X, Chen Z, Bai G, et al. Reconstruction and analysis of the aberrant lncRNA-miRNA-mRNA network based on competitive endogenous RNA in CESC. J Cell Biochem. 2018;119:6665–73.

    Article  CAS  Google Scholar 

  19. Wang P, Xue L, Wang L, Tang H, Lv C, Xue Q. Long noncoding RNA DLX6-AS1 promotes migration and invasion of breast cancer cells by upregulating FUS. Panminerva Med. 2020 https://doi.org/10.23736/S0031-0808.19.03773-X.

  20. Zhang HY, Xing MQ, Guo J, Zhao JC, Chen X, Jiang Z, et al. Long noncoding RNA DLX6-AS1 promotes neuroblastoma progression by regulating miR-107/BDNF pathway. Cancer Cell Int. 2019;19:313.

    Article  CAS  Google Scholar 

  21. Zhong ZB, Wu YJ, Luo JN, Hu XN, Yuan ZN, Li G, et al. Knockdown of long noncoding RNA DLX6-AS1 inhibits migration and invasion of thyroid cancer cells by upregulating UPF1. Eur Rev Med Pharm Sci. 2019;23:10867–73.

    Google Scholar 

  22. Lei X, Yang S, Yang Y, Zhang J, Wang Y, Cao M. Long noncoding RNA DLX6-AS1 targets miR-124-3p/CDK4 to accelerate Ewing’s sarcoma. Am J Transl Res. 2019;11:6569–76.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Fang C, Xu L, He W, Dai J, Sun F. Long noncoding RNA DLX6-AS1 promotes cell growth and invasiveness in bladder cancer via modulating the miR-223-HSP90B1 axis. Cell Cycle. 2019;18:3288–99.

    Article  CAS  Google Scholar 

  24. Liang Y, Zhang CD, Zhang C, Dai DQ. DLX6-AS1/miR-204-5p/OCT1 positive feedback loop promotes tumor progression and epithelial-mesenchymal transition in gastric cancer. Gastric Cancer. 2020;23:212–27.

    Article  CAS  Google Scholar 

  25. Xu J, Sun T, Hu X. microRNA-513c suppresses the proliferation of human glioblastoma cells by repressing low-density lipoprotein receptor-related protein 6. Mol Med Rep. 2015;12:4403–9.

    Article  CAS  Google Scholar 

  26. Xu Y, Wang Y, Ma G, Wang Q, Wei G. CUL4A is overexpressed in human pituitary adenomas and regulates pituitary tumor cell proliferation. J Neurooncol. 2014;116:625–32.

    Article  CAS  Google Scholar 

  27. Hannah J, Zhou PB. The CUL4A ubiquitin ligase is a potential therapeutic target in skin cancer and other malignancies. Chin J Cancer. 2013;32:478–82.

    Article  CAS  Google Scholar 

  28. Pan Y, Wang B, Yang X, Bai F, Xu Q, Li X, et al. CUL4A facilitates hepatocarcinogenesis by promoting cell cycle progression and epithelial-mesenchymal transition. Sci Rep. 2015;5:17006.

    Article  CAS  Google Scholar 

  29. Liu X, Peng X, Hu Z, Zhao Q, He J, Li J, et al. Effects of over-expression of ANXA10 gene on proliferation and apoptosis of hepatocellular carcinoma cell line HepG2. J Huazhong Univ Sci Technol Med Sci. 2012;32:669–74.

    Article  CAS  Google Scholar 

  30. Hung MS, Chen YC, Lin P, Li YC, Hsu CC, Lung JH et al. Cul4A modulates invasion and metastasis of lung cancer through regulation of ANXA10. Cancers (Basel). 2019;11:618.

Download references

Acknowledgements

The authors would like to extend our sincere appreciation to the reviewers for their critical comments on this article.

Funding

This study was supported by the Science and Technology Project of Jiangxi Province (Social Development) (20152ACG70020).

Author information

Author notes

  1. These authors contributed equally: Xiaoming Liu, Dandan Peng

Authors and Affiliations

  1. Department of Thoracic Surgery, The First Affiliated Hospital of Nanchang University, 330006, Nanchang, P.R. China

    Xiaoming Liu

  2. Department of Radiotherapy, General Hospital of Pingmei Shenma Medical Group, 450000, Pingdingshan, P.R. China

    Dandan Peng

  3. Department of Oncology, The First Affiliated Hospital of Nanchang University, 330006, Nanchang, P.R. China

    Yixin Cao, Yuanzhe Zhu, Xiaodong Peng & Yanqiu Meng

  4. Department of Oncology, Yugan Renhe Hospital, 335100, Shangrao, P.R. China

    Jianjun Yin

  5. Graduate School of Medicine, Nanchang University, Nanchang, P.R. China

    Guangxing Zhang

Authors
  1. Xiaoming Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dandan Peng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yixin Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yuanzhe Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jianjun Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Guangxing Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xiaodong Peng
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yanqiu Meng
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

X.L. and D.P. designed the study. Y.C. and Y.Z. collated the data, J.Y. and G.Z. carried out data analyses and produced the initial draft of the manuscript. X.P. and Y.M. contributed to drafting the manuscript. All authors have read and approved the final submitted manuscript.

Corresponding authors

Correspondence to Xiaodong Peng or Yanqiu Meng.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

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

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, X., Peng, D., Cao, Y. et al. Upregulated lncRNA DLX6-AS1 underpins hepatocellular carcinoma progression via the miR-513c/Cul4A/ANXA10 axis. Cancer Gene Ther 28, 486–501 (2021). https://doi.org/10.1038/s41417-020-00233-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41417-020-00233-0

This article is cited by

Search

Advanced search

Quick links