Article | Published:

Hypoxia-induced LncRNA-BX111 promotes metastasis and progression of pancreatic cancer through regulating ZEB1 transcription

Oncogenevolume 37pages58115828 (2018) | Download Citation

Abstract

The contribution of long noncoding RNAs (lncRNAs) to pancreatic cancer progression and the regulatory mechanisms of their expression are attractive areas. In the present study, the overexpression of lncRNA-BX111887 (BX111) in pancreatic cancer tissues was detected by microarray and further validated in a cohort of pancreatic cancer tissues. We further demonstrated that knockdown or overexpression of BX111 dramatically repressed or enhanced proliferation and invasion of pancreatic cancer cells. Mechanically, BX111 activated transcription of ZEB1, a key regulator for epithelia-mesenchymal transition (EMT), via recruiting transcriptional factor Y-box protein (YB1) to its promoter region. Moreover, we revealed that BX111 transcription was induced by hypoxia-inducible factor (HIF-1α) in response to hypoxia. In addition, BX111 contributed to the hypoxia-induced EMT of pancreatic cells by regulating expression of ZEB1 and its downstream proteins E-cadherin and MMP2. Coincidence with in vitro results, BX111 depletion effectively inhibited growth and metastasis of xenograft tumor in vivo. The clinical samples of pancreatic cancer further confirmed a positive association between BX111 and ZEB1. Moreover, high BX111 expression was correlated with late TNM stage, lymphatic invasion and distant metastasis, as well as short overall survival time in patients. Taken together, our findings implicate a hypoxia-induced lncRNA contributes to metastasis and progression of pancreatic cancer, and suggest BX111 might be applied as a potential biomarker and therapeutic target for pancreatic cancer.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    Jooste V, Dejardin O, Bouvier V, Arveux P, Maynadie M, Launoy G, et al. Pancreatic cancer: wait times from presentation to treatment and survival in a population-based study. Int J Cancer. 2016;139:1073–80.

  2. 2.

    Yachida S, Jones S, Bozic I, Antal T, Leary R, Fu BJ, et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature. 2010;467:1114–7.

  3. 3.

    Campbell PJ, Yachida S, Mudie LJ, Stephens PJ, Pleasance ED, Stebbings LA, et al. The patterns and dynamics of genomic instability in metastatic pancreatic cancer. Nature. 2010;467:1109–13.

  4. 4.

    Lau E, Non-coding RNA. Zooming in on lncRNA functions. Nat Rev Genet. 2014;15:574–5.

  5. 5.

    Muers M. RNA: genome-wide views of long non-coding RNAs. Nat Rev Genet. 2011;12:742–3.

  6. 6.

    Huarte M. The emerging role of lncRNAs in cancer. Nat Med. 2015;21:1253–61.

  7. 7.

    Schmitt AM, Chang HY. Long noncoding RNAs in cancer pathways. Cancer Cell. 2016;29:452–63.

  8. 8.

    Kim K, Jutooru I, Chadalapaka G, Johnson G, Frank J, Burghardt R, et al. HOTAIR is a negative prognostic factor and exhibits pro-oncogenic activity in pancreatic cancer. Oncogene. 2013;32:1616–25.

  9. 9.

    Cheng Y, Jutooru I, Chadalapaka G, Corton JC, Safe S. The long non-coding RNA HOTTIP enhances pancreatic cancer cell proliferation, survival and migration. Oncotarget. 2015;6:10840–52.

  10. 10.

    Sun YW, Chen YF, Li J, Huo YM, Liu DJ, Hua R, et al. A novel long non-coding RNA ENST00000480739 suppresses tumour cell invasion by regulating OS-9 and HIF-1|[alpha]| in pancreatic ductal adenocarcinoma. Br J Cancer. 2014;111:2131–41.

  11. 11.

    Li L, Chen H, Gao Y, Wang YW, Zhang GQ, Pan SH, et al. Long noncoding RNA MALAT1 promotes aggressive pancreatic cancer proliferation and metastasis via the stimulation of autophagy. Mol Cancer Ther. 2016;15:2232–43.

  12. 12.

    Li X, Deng SJ, Zhu S, Jin Y, Cui SP, Chen JY, et al. Hypoxia-induced lncRNA-NUTF2P3-001 contributes to tumorigenesis of pancreatic cancer by derepressing the miR-3923/KRAS pathway. Oncotarget. 2016;7:6000–14.

  13. 13.

    Kang S, Lee TA, Ra EA, Lee E, Hj C, Lee S, et al. Differential control of interleukin-6 mRNA levels by cellular distribution of YB-1. PLoS ONE. 2014;9:e112754.

  14. 14.

    Evdokimova V, Ovchinnikov LP, Sorensen PH. Y-box binding protein 1: providing a new angle on translational regulation. Cell Cycle. 2006;5:1143–7.

  15. 15.

    Zhou KR, Liu S, Sun WJ, Zheng LL, Zhou H, Yang JH, et al. ChIPBase v2.0: decoding transcriptional regulatory networks of non-coding RNAs and protein-coding genes from ChIP-seq data. Nucleic Acids Res. 2017;45:D43–D50.

  16. 16.

    Mccarty G, Loeb DM. Hypoxia-sensitive epigenetic regulation of an antisense-oriented lncRNA controls WT1 expression in myeloid leukemia cells. PLoS ONE. 2015;10:e0119837.

  17. 17.

    Aghdassi A, Sendler M, Guenther A, Mayerle J, Behn CO, Heidecke CD, et al. Recruitment of histone deacetylases HDAC1 and HDAC2 by the transcriptional repressor ZEB1 downregulates E-cadherin expression in pancreatic cancer. Gut. 2012;61:439–48.

  18. 18.

    Krebs AM, Mitschke J, Lasierra LM, Schmalhofer O, Boerries M, Busch H, et al. The EMT-activator Zeb1 is a key factor for cell plasticity and promotes metastasis in pancreatic cancer. Nat Cell Biol. 2017;19:518–29.

  19. 19.

    Arumugam T, Ramachandran V, Fournier KF, Wang H, Marquis L, Abbruzzese JL, et al. Epithelial to mesenchymal transition contributes to drug resistance in pancreatic cancer. Cancer Res. 2009;69:5820–8.

  20. 20.

    Yuan J-h, Yang F, Wang F, Ma J-z, Guo Y-j, Tao Q-f, et al. A long noncoding RNA activated by TGF-β promotes the invasion-metastasis cascade in hepatocellular carcinoma. Cancer Cell. 2014;25:666–81.

  21. 21.

    Zhan HX, Wang Y, Li C, Xu JW, Zhou B, Zhu JK, et al. LincRNA-ROR promotes invasion, metastasis and tumor growth in pancreatic cancer through activating ZEB1 pathway. Cancer Lett. 2016;374:261–71.

  22. 22.

    Evdokimova V, Tognon C, Ng T, Sorensen PHB. Reduced proliferation and enhanced migration: two sides of the same coin? Molecular mechanisms of metastatic progression by YB-1. Cell Cycle. 2009;8:2901–6.

  23. 23.

    Kohno K, Izumi H, Uchiumi T, Ashizuka M, Kuwano M. The pleiotropic functions of the Y-box-binding protein, YB-1. Bioessays News Rev Mol Cell Dev Biol. 2003;25:691–8.

  24. 24.

    Astanehe A, Finkbeiner MR, Hojabrpour P, To K, Fotovati A, Shadeo A, et al. The transcriptional induction of PIK3CA in tumor cells is dependent on the oncoprotein Y-box binding protein-1. Oncogene. 2009;28:2406–18.

  25. 25.

    Evdokimova V, Tognon C, Ng T, Ruzanov P, Melnyk N, Fink D, et al. Translational activation of snail1 and other developmentally regulated transcription factors by YB-1 promotes an epithelial-mesenchymal transition. Cancer Cell. 2009;15:402–15.

  26. 26.

    Hani C, Johannes S, Spyros O, Carme C, Steffen G, Harris AL, et al. Extensive regulation of the non-coding transcriptome by hypoxia: role of HIF in releasing paused RNApol2. EMBO Rep. 2014;15:70–76.

  27. 27.

    Wang Y, Liu X, Zhang H, Sun L, Zhou Y, Jin H, et al. Hypoxia-inducible lncRNA-AK058003 promotes gastric cancer metastasis by targeting γ-Synuclein 1 2. Neoplasia. 2014;16:1094–106.

  28. 28.

    Gómezmaldonado L, Tiana M, Roche O, Pradocabrero A, Jensen L, Fernandezbarral A, et al. EFNA3 long noncoding RNAs induced by hypoxia promote metastatic dissemination. Oncogene. 2015;34:2609–20.

  29. 29.

    Xu X, Tan X, Tampe B, Sanchez E, Zeisberg M, Zeisberg EM. Snail is a direct target of hypoxia-inducible factor 1α (HIF1α) in hypoxia-induced endothelial to mesenchymal transition of human coronary endothelial cells. J Biol Chem. 2015;290:16653–64.

  30. 30.

    Zhang L, Huang G, Li X, Zhang Y, Jiang Y, Shen J, et al. Hypoxia induces epithelial-mesenchymal transition via activation of SNAI1 by hypoxia-inducible factor-1α in hepatocellular carcinoma. BMC Cancer. 2013;13:108.

  31. 31.

    Zhu Y, Tan J, Xie H, Wang J, Meng X, Wang R. HIF-1α regulates EMT via the snail and β-catenin pathways in paraquat poisoning-induced early pulmonary fibrosis. J Cell Mol Med. 2016;20:688–97.

  32. 32.

    Chou CC, Chuang HC, Salunke SB, Kulp SK, Chen CS. A novel HIF-1α-integrin-linked kinase regulatory loop that facilitates hypoxia-induced HIF-1α expression and epithelial-mesenchymal transition in cancer cells. Oncotarget. 2015;6:8271–85.

  33. 33.

    Zhang W, Shi X, Peng Y, Wu M, Zhang P, Xie R, et al. HIF-1α promotes epithelial-mesenchymal transition and metastasis through direct regulation of ZEB1 in colorectal cancer. PLoS ONE. 2015;10:e0129603.

  34. 34.

    Salnikov AV, Liu L, Platen M, Gladkich J, Salnikova O, Ryschich E, et al. Hypoxia induces EMT in low and highly aggressive pancreatic tumor cells but only cells with cancer stem cell characteristics acquire pronounced migratory potential. PLoS ONE. 2012;7:e46391.

  35. 35.

    Lei J, Ma J, Ma Q, Li X, Liu H, Xu Q, et al. Hedgehog signaling regulates hypoxia induced epithelial to mesenchymal transition and invasion in pancreatic cancer cells via a ligand-independent manner. Mol Cancer. 2013;12:66

  36. 36.

    Polyak K, Weinberg RA. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer. 2009;9:265–73.

  37. 37.

    Deng S, Li X, Niu Y, Zhu S, Jin Y, Deng S, et al. MiR-652 inhibits acidic microenvironment-induced epithelial-mesenchymal transition of pancreatic cancer cells by targeting ZEB1. Oncotarget. 2015;6:39661–75.

  38. 38.

    Krzywinski M, Altman N. Points of significance: power and sample size. Nat Methods. 2013;10:1139–40.

Download references

Acknowledgements

This study was supported from the National Science Foundation Committee (NSFC) of China (Grant number: 81372666 and 81672406 to Gang Zhao; No. 81502076 to Shi-chang Deng)

Author information

Author notes

  1. These authors contributed equally: Shi-jiang Deng, Heng-yu Chen, Zeng Ye.

Affiliations

  1. Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China

    • Shi-jiang Deng
    • , Heng-yu Chen
    • , Zeng Ye
    • , Shi-chang Deng
    • , Shuai Zhu
    • , Zhu Zeng
    • , Chi He
    • , Ming-liang Liu
    • , Kang Huang
    • , Jian-xin Zhong
    • , Feng-yu Xu
    • , Qiang Li
    • , Yang Liu
    • , Chun-you Wang
    •  & Gang Zhao

Authors

  1. Search for Shi-jiang Deng in:

  2. Search for Heng-yu Chen in:

  3. Search for Zeng Ye in:

  4. Search for Shi-chang Deng in:

  5. Search for Shuai Zhu in:

  6. Search for Zhu Zeng in:

  7. Search for Chi He in:

  8. Search for Ming-liang Liu in:

  9. Search for Kang Huang in:

  10. Search for Jian-xin Zhong in:

  11. Search for Feng-yu Xu in:

  12. Search for Qiang Li in:

  13. Search for Yang Liu in:

  14. Search for Chun-you Wang in:

  15. Search for Gang Zhao in:

Conflict of interest

The authors declare that they have no conflict of interest.

Corresponding author

Correspondence to Gang Zhao.

Electronic supplementary material

About this article

Publication history

Received

Revised

Accepted

Published

Issue Date

DOI

https://doi.org/10.1038/s41388-018-0382-1