Skip to main content
SpringerLink
Log in

Upregulation of lncRNA NIFK-AS1 in hepatocellular carcinoma by m6A methylation promotes disease progression and sorafenib resistance

  • Research Article
  • Published:
Human Cell Aims and scope Submit manuscript

Abstract

Long non-coding RNAs (LncRNAs) have recently emerged as vital regulators in the development and progression of hepatocellular carcinoma (HCC), providing new opportunities as novel therapeutic targets. Here we identified the lncRNA NIFK-AS1 as being highly expressed in HCC tissues and cells and showed this up-regulation resulted from METTL3-dependent m6A methylation. Functionally, knockdown of NIFK-AS1 inhibited the proliferation, colony formation, migration, and invasion of HCC cells. Moreover, these effects were elicited though AKT1 and we uncovered a ceRNA network involving an NIFK-AS1/miR-637/AKT1 axis with downstream effects on HCC progression involving regulation of MMP-7 and MMP-9 expression. From the clinical perspective, we showed that knockdown of NIFK-AS1 sensitized HCC cells to sorafenib through the up-regulation of the drug transporters OATP1B1 and OATP1B3. Clinical investigations showed HCC patients with low NIFK-AS1 expression benefited from sorafenib therapy and this phenomenon was reproduced in patient-derived tumor xenograft models (PDX) comparing HCC with low and high expression of NIFK-AS1. Taken together, these results suggest an essential role for NIFK-AS1 in HCC progression and promote NIFK-AS1 as a new therapeutic target and predictor of sorafenib benefit in HCC patients.

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

Similar content being viewed by others

Availability of data and materials

All data generated and analyzed during this study are included in this published article.

References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424.

    Article  Google Scholar 

  2. Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015. CA Cancer J Clin. 2016;66(2):115–32.

    Article  Google Scholar 

  3. Altekruse SF, Henley SJ, Cucinelli JE, McGlynn KA. Changing hepatocellular carcinoma incidence and liver cancer mortality rates in the United States. Am J Gastroenterol. 2014;109(4):542–53.

    Article  Google Scholar 

  4. Si T, Chen Y, Ma D, et al. Transarterial chemoembolization prior to liver transplantation for patients with hepatocellular carcinoma: a meta-analysis. J Gastroenterol Hepatol. 2017;32(7):1286–94.

    Article  CAS  Google Scholar 

  5. Wang KC, Chang HY. Molecular mechanisms of long noncoding RNAs. Mol Cell. 2011;43(6):904–14.

    Article  CAS  Google Scholar 

  6. Yan X, Hu Z, Feng Y, et al. Comprehensive genomic characterization of long non-coding RNAs across human cancers. Cancer Cell. 2015;28(4):529–40.

    Article  CAS  Google Scholar 

  7. Leucci E, Vendramin R, Spinazzi M, et al. Melanoma addiction to the long non-coding RNA SAMMSON. Nature. 2016;531(7595):518–22.

    Article  CAS  Google Scholar 

  8. Wang YG, Wang T, Shi M, Zhai B. Long noncoding RNA EPB41L4A-AS2 inhibits hepatocellular carcinoma development by sponging miR-301a-5p and targeting FOXL1. J Exp Clin Cancer Res. 2019;38(1):153.

    Article  Google Scholar 

  9. Wang Y, Yang L, Chen T, et al. A novel lncRNA MCM3AP-AS1 promotes the growth of hepatocellular carcinoma by targeting miR-194-5p/FOXA1 axis. Mol Cancer. 2019;18(1):28.

    Article  Google Scholar 

  10. Mercer TR, Dinger ME, Mattick JS. Long non-coding RNAs: insights into functions. Nat Rev Genet. 2009;10(3):155–9.

    Article  CAS  Google Scholar 

  11. Jin S, Yang X, Li J, et al. p53-targeted lincRNA-p21 acts as a tumor suppressor by inhibiting JAK2/STAT3 signaling pathways in head and neck squamous cell carcinoma. Mol Cancer. 2019;18(1):38.

    Article  Google Scholar 

  12. Gu JX, Zhang X, Miao RC, et al. Six-long non-coding RNA signature predicts recurrence-free survival in hepatocellular carcinoma. World J Gastroenterol. 2019;25(2):220–32.

    Article  Google Scholar 

  13. Yang X, Yao B, Niu Y, et al. Hypoxia-induced lncRNA EIF3J-AS1 accelerates hepatocellular carcinoma progression via targeting miR-122-5p/CTNND2 axis. Biochem Biophys Res Commun. 2019;518(2):239–45.

    Article  CAS  Google Scholar 

  14. Zimmerman EI, Roberts JL, Li L, et al. Ontogeny and sorafenib metabolism. Clin Cancer Res. 2012;18(20):5788–95.

    Article  CAS  Google Scholar 

  15. Huang H, Weng H, Sun W, et al. Recognition of RNA N(6)-methyladenosine by IGF2BP proteins enhances mRNA stability and translation. Nat Cell Biol. 2018;20(3):285–95.

    Article  CAS  Google Scholar 

  16. Zhao N, Sun H, Sun B, et al. miR-27a-3p suppresses tumor metastasis and VM by down-regulating VE-cadherin expression and inhibiting EMT: an essential role for Twist-1 in HCC. Sci Rep. 2016;6:23091.

    Article  CAS  Google Scholar 

  17. Zhou T, Li S, Xiang D, et al. m6A RNA methylation-mediated HNF3γ reduction renders hepatocellular carcinoma dedifferentiation and sorafenib resistance. Signal Transduct Target Ther. 2020;5(1):296.

    Article  CAS  Google Scholar 

  18. Ma JZ, Yang F, Zhou CC, et al. METTL14 suppresses the metastatic potential of hepatocellular carcinoma by modulating N(6) -methyladenosine-dependent primary MicroRNA processing. Hepatology. 2017;65(2):529–43.

    Article  CAS  Google Scholar 

  19. Zhu P, Wang Y, Huang G, et al. lnc-β-Catm elicits EZH2-dependent β-catenin stabilization and sustains liver CSC self-renewal. Nat Struct Mol Biol. 2016;23(7):631–9.

    Article  CAS  Google Scholar 

  20. Guo D, Li Y, Chen Y, et al. DANCR promotes HCC progression and regulates EMT by sponging miR-27a-3p via ROCK1/LIMK1/COFILIN1 pathway. Cell Prolif. 2019;52(4):e12628.

    PubMed  PubMed Central  Google Scholar 

  21. Ji D, Wang Y, Li H, Sun B, Luo X. Long non-coding RNA LINC00461/miR-149-5p/LRIG2 axis regulates hepatocellular carcinoma progression. Biochem Biophys Res Commun. 2019;512(2):176–81.

    Article  CAS  Google Scholar 

  22. Yang L, Peng X, Jin H, Liu J. Long non-coding RNA PVT1 promotes autophagy as ceRNA to target ATG3 by sponging microRNA-365 in hepatocellular carcinoma. Gene. 2019;697:94–102.

    Article  CAS  Google Scholar 

  23. Li Y, Li C, Li D, Yang L, Jin J, Zhang B. lncRNA KCNQ1OT1 enhances the chemoresistance of oxaliplatin in colon cancer by targeting the miR-34a/ATG4B pathway. Onco Targets Ther. 2019;12:2649–60.

    Article  CAS  Google Scholar 

  24. Tang D, Yang Z, Long F, et al. Long noncoding RNA MALAT1 mediates stem cell-like properties in human colorectal cancer cells by regulating miR-20b-5p/Oct4 axis. J Cell Physiol. 2019;234(11):20816–28.

    Article  CAS  Google Scholar 

  25. Wang YG, Liu J, Shi M, Chen FX. LncRNA DGCR5 represses the development of hepatocellular carcinoma by targeting the miR-346/KLF14 axis. J Cell Physiol. 2018;234(1):572–80.

    Article  CAS  Google Scholar 

  26. Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018;391(10126):1163–73.

    Article  CAS  Google Scholar 

  27. Gu Q, Zhang B, Sun H, et al. Genomic characterization of a large panel of patient-derived hepatocellular carcinoma xenograft tumor models for preclinical development. Oncotarget. 2015;6(24):20160–76.

    Article  Google Scholar 

  28. Han T, Xiang DM, Sun W, et al. PTPN11/Shp2 overexpression enhances liver cancer progression and predicts poor prognosis of patients. J Hepatol. 2015;63(3):651–60.

    Article  CAS  Google Scholar 

  29. Risom T, Langer EM, Chapman MP, et al. Differentiation-state plasticity is a targetable resistance mechanism in basal-like breast cancer. Nat Commun. 2018;9(1):3815.

    Article  Google Scholar 

  30. Xiang DM, Sun W, Zhou T, et al. Oncofetal HLF transactivates c-Jun to promote hepatocellular carcinoma development and sorafenib resistance. Gut. 2019;68(10):1858–71.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was funded by the National Natural Science Foundation of China (No. 81972332).

Author information

Author notes

  1. Yi-tian Chen, Dan Xiang, and Xiao-yue Zhao contributed equally.

Authors and Affiliations

  1. Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Zhongshan East Road 305, Nanjing, 210002, Jiangsu, China

    Yi-tian Chen, Dan Xiang, Xiao-yue Zhao & Xiao-yuan Chu

Authors
  1. Yi-tian Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dan Xiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiao-yue Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xiao-yuan Chu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xiao-yuan Chu.

Ethics declarations

Competing interests

The authors declare that they have no competing interests.

Ethical approval

Ethical statement: our study was approved by Jinling Hospital Ethics Committee (Approval No. JLH2016-5-9). All patients provided written informed consent prior to enrollment in the study.

Additional information

Publisher's Note

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

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 2212 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, Yt., Xiang, D., Zhao, Xy. et al. Upregulation of lncRNA NIFK-AS1 in hepatocellular carcinoma by m6A methylation promotes disease progression and sorafenib resistance. Human Cell 34, 1800–1811 (2021). https://doi.org/10.1007/s13577-021-00587-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13577-021-00587-z

Keywords

Search

Navigation