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:

ZFPM2-AS1, a novel lncRNA, attenuates the p53 pathway and promotes gastric carcinogenesis by stabilizing MIF

Oncogene volume 37, pages 5982–5996 (2018)Cite this article

Subjects

A Correction to this article was published on 14 August 2018

This article has been updated

Abstract

Long non-coding RNAs (lncRNAs) are implicated to be involved in the pathogenesis of many cancers. Herein we report on our discovery of a novel lncRNA, ZFPM2 antisense RNA 1 (ZFPM2-AS1), and its critical role in gastric carcinogenesis. ZFPM2-AS1 expression in gastric cancer specimens was analyzed using Gene Expression Omnibus data set and validated in 73 paired gastric tumor and normal adjacent gastric tissue specimens using qRT-PCR. The effect of ZFPM2-AS1 expression on proliferation and apoptosis in gastric cancer cells was assessed by altering its expression in vitro and in vivo. Mechanistic investigation was carried out using cell and molecular biological approaches. ZFPM2-AS1 expression was higher in gastric tumors than in normal gastric tissue. Also, increased ZFPM2-AS1 expression in gastric cancer specimens was associated with tumor size, depth of tumor invasion, differentiation grade, and TNM stage. High ZFPM2-AS1 expression predicted markedly reduced overall and disease-free survival in gastric cancer patients. Functional experiments demonstrated that ZFPM2-AS1 expression promoted proliferation and suppressed apoptosis of gastric cancer cells in vitro and promoted tumor growth in vivo. This effect is associated with attenuated nuclear translocation of p53. Mechanistic experiments demonstrated that tumor-activated ZFPM2-AS1 could bind to and protect the degradation of macrophage migration inhibitory factor (MIF), a potent destabilizer of p53. Knockdown of MIF expression diminished ZFPM2-AS1’s impact on p53 expression in gastric cancer cells. Our findings demonstrated that ZFPM2-AS1 regulates gastric cancer progression and revealed a novel ZFPM2-AS1/MIF/p53 signaling axis, shedding light on the molecular mechanisms underlying the tumorigenicity of certain malignant gastric cells.

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
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Change history

  • 14 August 2018

    Since the online publication of the above article, the authors have noted errors in the affiliations. The authors apologise for any inconvenience caused by this error. The html and online pdf versions have now been rectified and carry the corrected paper.

References

  1. Sugano K. Screening of gastric cancer in Asia. Best Pract Res Clin Gastroenterol. 2015;29:895–905.

    Article  Google Scholar 

  2. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63:11–30.

    Article  Google Scholar 

  3. Lin Y, Ueda J, Kikuchi S, Totsuka Y, Wei WQ, Qiao YL, et al. Comparative epidemiology of gastric cancer between Japan and China. World J Gastroenterol. 2011;17:4421–8.

    Article  Google Scholar 

  4. Tan P, Yeoh KG. Genetics and molecular pathogenesis of gastric adenocarcinoma. Gastroenterology. 2015;149:1153–62.e3.

    Article  CAS  Google Scholar 

  5. The Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014;513:202–9.

  6. Fatica A, Bozzoni I. Long non-coding RNAs: new players in cell differentiation and development. Nat Rev Genet. 2014;15:7–21.

    Article  CAS  Google Scholar 

  7. Ulitsky I, Bartel DP. lincRNAs: genomics, evolution, and mechanisms. Cell. 2013;154:26–46.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  10. Katayama S, Tomaru Y, Kasukawa T, Waki K, Nakanishi M, Nakamura M, et al. Antisense transcription in the mammalian transcriptome. Science. 2005;309:1564–6.

    Article  Google Scholar 

  11. Wight M, Werner A. The functions of natural antisense transcripts. Essays Biochem. 2013;54:91–101.

    Article  CAS  Google Scholar 

  12. Werner A. Biological functions of natural antisense transcripts. BMC Biol. 2013;11:31.

    Article  CAS  Google Scholar 

  13. Villegas VE, Zaphiropoulos PG. Neighboring gene regulation by antisense long non-coding RNAs. Int J Mol Sci. 2015;16:3251–66.

    Article  CAS  Google Scholar 

  14. Huang B, Song JH, Cheng Y, Abraham JM, Ibrahim S, Sun Z, et al. Long non-coding antisense RNA KRT7-AS is activated in gastric cancers and supports cancer cell progression by increasing KRT7 expression. Oncogene. 2016;35:4927–36.

    Article  CAS  Google Scholar 

  15. Fukaya R, Ohta S, Yaguchi T, Matsuzaki Y, Sugihara E, Okano H, et al. MIF maintains the tumorigenic capacity of brain tumor-initiating cells by directly inhibiting p53. Cancer Res. 2016;76:2813–23.

    Article  CAS  Google Scholar 

  16. Shun CT, Lin JT, Huang SP, Lin MT, Wu MS. Expression of macrophage migration inhibitory factor is associated with enhanced angiogenesis and advanced stage in gastric carcinomas. World J Gastroenterol. 2005;11:3767–71.

    Article  CAS  Google Scholar 

  17. Sun B, Nishihira J, Suzuki M, Fukushima N, Ishibashi T, Kondo M, et al. Induction of macrophage migration inhibitory factor by lysophosphatidic acid: relevance to tumor growth and angiogenesis. Int J Mol Med. 2003;12:633–41.

    CAS  PubMed  Google Scholar 

  18. Cotter TG. Apoptosis and cancer: the genesis of a research field. Nat Rev Cancer. 2009;9:501–7.

    Article  CAS  Google Scholar 

  19. Lopez-Saez JF, de la Torre C, Pincheira J, Gimenez-Martin G. Cell proliferation and cancer. Histol Histopathol. 1998;13:1197–214.

    CAS  PubMed  Google Scholar 

  20. Pardal R, Molofsky AV, He S, Morrison SJ. Stem cell self-renewal and cancer cell proliferation are regulated by common networks that balance the activation of proto-oncogenes and tumor suppressors. Cold Spring Harb Symp Quant Biol. 2005;70:177–85.

    Article  CAS  Google Scholar 

  21. Schulz R, Marchenko ND, Holembowski L, Fingerle-Rowson G, Pesic M, Zender L, et al. Inhibiting the HSP90 chaperone destabilizes macrophage migration inhibitory factor and thereby inhibits breast tumor progression. J Exp Med. 2012;209:275–89.

    Article  CAS  Google Scholar 

  22. Mitchell RA, Liao H, Chesney J, Fingerle-Rowson G, Baugh J, David J, et al. Macrophage migration inhibitory factor (MIF) sustains macrophage proinflammatory function by inhibiting p53: regulatory role in the innate immune response. Proc Natl Acad Sci USA. 2002;99:345–50.

    Article  CAS  Google Scholar 

  23. Beermann J, Piccoli MT, Viereck J, Thum T. Non-coding RNAs in development and disease: background, mechanisms, and therapeutic approaches. Physiol Rev. 2016;96:1297–325.

    Article  CAS  Google Scholar 

  24. Fu M, Zou C, Pan L, Liang W, Qian H, Xu W, et al. Long noncoding RNAs in digestive system cancers: functional roles, molecular mechanisms, and clinical implications (review). Oncol Rep. 2016;36:1207–18.

    Article  CAS  Google Scholar 

  25. Li T, Mo X, Fu L, Xiao B, Guo J. Molecular mechanisms of long noncoding RNAs on gastric cancer. Oncotarget. 2016;7:8601–12.

    PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  Google Scholar 

  27. Zhang CL, Zhu KP, Ma XL. Antisense lncRNA FOXC2-AS1 promotes doxorubicin resistance in osteosarcoma by increasing the expression of FOXC2. Cancer Lett. 2017;396:66–75.

    Article  CAS  Google Scholar 

  28. Amit-Avraham I, Pozner G, Eshar S, Fastman Y, Kolevzon N, Yavin E, et al. Antisense long noncoding RNAs regulate var gene activation in the malaria parasite Plasmodium falciparum. Proc Natl Acad Sci USA. 2015;112:E982–91.

    Article  CAS  Google Scholar 

  29. Wei N, Wang Y, Xu RX, Wang GQ, Xiong Y, Yu TY, et al. PU.1 antisense lncRNA against its mRNA translation promotes adipogenesis in porcine preadipocytes. Anim Genet. 2015;46:133–40.

    Article  CAS  Google Scholar 

  30. Conroy H, Mawhinney L, Donnelly SC. Inflammation and cancer: macrophage migration inhibitory factor (MIF)--the potential missing link. QJM. 2010;103:831–6.

    Article  CAS  Google Scholar 

  31. He XX, Yang J, Ding YW, Liu W, Shen QY, Xia HH. Increased epithelial and serum expression of macrophage migration inhibitory factor (MIF) in gastric cancer: potential role of MIF in gastric carcinogenesis. Gut. 2006;55:797–802.

    Article  CAS  Google Scholar 

  32. Yang S, He P, Wang J, Schetter A, Tang W, Funamizu N, et al. A novel MIF signaling pathway drives the malignant character of pancreatic cancer by targeting NR3C2. Cancer Res. 2016;76:3838–50.

    Article  CAS  Google Scholar 

  33. Schulz R, Streller F, Scheel AH, Ruschoff J, Reinert MC, Dobbelstein M, et al. HER2/ErbB2 activates HSF1 and thereby controls HSP90 clients including MIF in HER2-overexpressing breast cancer. Cell Death Dis. 2014;5:e980.

    Article  CAS  Google Scholar 

  34. Dessein AF, Stechly L, Jonckheere N, Dumont P, Monte D, Leteurtre E, et al. Autocrine induction of invasive and metastatic phenotypes by the MIF-CXCR4 axis in drug-resistant human colon cancer cells. Cancer Res. 2010;70:4644–54.

    Article  CAS  Google Scholar 

  35. Larsen M, Tazzyman S, Lund EL, Junker N, Lewis CE, Kristjansen PE, et al. Hypoxia-induced secretion of macrophage migration-inhibitory factor from MCF-7 breast cancer cells is regulated in a hypoxia-inducible factor-independent manner. Cancer Lett. 2008;265:239–49.

    Article  CAS  Google Scholar 

  36. Oda S, Oda T, Nishi K, Takabuchi S, Wakamatsu T, Tanaka T, et al. Macrophage migration inhibitory factor activates hypoxia-inducible factor in a p53-dependent manner. PLoS ONE. 2008;3:e2215.

    Article  Google Scholar 

  37. Winner M, Koong AC, Rendon BE, Zundel W, Mitchell RA. Amplification of tumor hypoxic responses by macrophage migration inhibitory factor-dependent hypoxia-inducible factor stabilization. Cancer Res. 2007;67:186–93.

    Article  CAS  Google Scholar 

  38. Rinn JL, Chang HY. Genome regulation by long noncoding RNAs. Annu Rev Biochem. 2012;81:145–66.

    Article  CAS  Google Scholar 

  39. Shi X, Sun M, Wu Y, Yao Y, Liu H, Wu G, et al. Post-transcriptional regulation of long noncoding RNAs in cancer. Tumour Biol. 2015;36:503–13.

    Article  CAS  Google Scholar 

  40. Brock SE, Rendon BE, Xin D, Yaddanapudi K, Mitchell RA. MIF family members cooperatively inhibit p53 expression and activity. PLoS ONE. 2014;9:e99795.

    Article  Google Scholar 

  41. Salminen A, Kaarniranta K. Control of p53 and NF-kappaB signaling by WIP1 and MIF: role in cellular senescence and organismal aging. Cell Signal. 2011;23:747–52.

    Article  CAS  Google Scholar 

  42. Jung H, Seong HA, Ha H. Direct interaction between NM23-H1 and macrophage migration inhibitory factor (MIF) is critical for alleviation of MIF-mediated suppression of p53 activity. J Biol Chem. 2008;283:32669–79.

    Article  CAS  Google Scholar 

  43. Jung H, Seong HA, Ha H. Critical role of cysteine residue 81 of macrophage migration inhibitory factor (MIF) in MIF-induced inhibition of p53 activity. J Biol Chem. 2008;283:20383–96.

    Article  CAS  Google Scholar 

  44. Bellini MF, Cadamuro AC, Succi M, Proenca MA, Silva AE. Alterations of the TP53 gene in gastric and esophageal carcinogenesis. J Biomed Biotechnol. 2012;2012:891961

    Article  Google Scholar 

  45. Imazeki F, Omata M, Nose H, Ohto M, Isono K. p53 gene mutations in gastric and esophageal cancers. Gastroenterology. 1992;103:892–6.

    Article  CAS  Google Scholar 

  46. Gabbert HE, Muller W, Schneiders A, Meier S, Hommel G. The relationship of p53 expression to the prognosis of 418 patients with gastric carcinoma. Cancer. 1995;76:720–6.

    Article  CAS  Google Scholar 

  47. Huarte M, Guttman M, Feldser D, Garber M, Koziol MJ, Kenzelmann-Broz D, et al. A large intergenic noncoding RNA induced by p53 mediates global gene repression in the p53 response. Cell. 2010;142:409–19.

    Article  CAS  Google Scholar 

  48. Dimitrova N, Zamudio JR, Jong RM, Soukup D, Resnick R, Sarma K, et al. LincRNA-p21 activates p21 in cis to promote Polycomb target gene expression and to enforce the G1/S checkpoint. Mol Cell. 2014;54:777–90.

    Article  CAS  Google Scholar 

  49. Hung T, Wang Y, Lin MF, Koegel AK, Kotake Y, Grant GD, et al. Extensive and coordinated transcription of noncoding RNAs within cell-cycle promoters. Nat Genet. 2011;43:621–9.

    Article  CAS  Google Scholar 

  50. Tripathi V, Shen Z, Chakraborty A, Giri S, Freier SM, Wu X, et al. Long noncoding RNA MALAT1 controls cell cycle progression by regulating the expression of oncogenic transcription factor B-MYB. PLoS Genet. 2013;9:e1003368.

    Article  CAS  Google Scholar 

  51. Guo K, Cui J, Quan M, Xie D, Jia Z, Wei D, et al. The novel KLF4/MSI2 signaling pathway regulates growth and metastasis of pancreatic cancer. Clin Cancer Res. 2017;23:687–96.

    Article  CAS  Google Scholar 

  52. Kong F, Kong X, Du Y, Chen Y, Deng X, Zhu J, et al. STK33 promotes growth and progression of pancreatic cancer as a critical downstream mediator of HIF1alpha. Cancer Res. 2017;77:6851–62.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We would like to thank Don Norwood for editing the manuscript.

Funding

This work was supported by grants R01CA172233, R01CA195651, and R01CA198090 from the National Cancer Institute, National Institutes of Health (to K.X.) and grant 81772640 from the National Natural Science Foundation of China (to X.K.).

Author information

Author notes

  1. These authors contributed equally: Fanyang Kong, Xuan Deng, Xiangyu Kong.

Authors and Affiliations

  1. Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai, People’s Republic of China

    Fanyang Kong, Xiangyu Kong, Yiqi Du, Lei Li, Huiyun Zhu, Yuxin Wang & Zhaoshen Li

  2. Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

    Fanyang Kong, Xiangyu Kong, Dacheng Xie, Shivani Guha & Keping Xie

  3. Department of Laboratory Medicine, Huashan Hospital Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China

    Xuan Deng & Ming Guan

Authors
  1. Fanyang Kong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xuan Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiangyu Kong
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yiqi Du
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lei Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Huiyun Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yuxin Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Dacheng Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Shivani Guha
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Zhaoshen Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Ming Guan
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Keping Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Zhaoshen Li, Ming Guan or Keping Xie.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kong, F., Deng, X., Kong, X. et al. ZFPM2-AS1, a novel lncRNA, attenuates the p53 pathway and promotes gastric carcinogenesis by stabilizing MIF. Oncogene 37, 5982–5996 (2018). https://doi.org/10.1038/s41388-018-0387-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-018-0387-9

This article is cited by

Search

Advanced search

Quick links