Skip to main content

Advertisement

SpringerLink
Log in

ZNF281 Promotes Growth and Invasion of Pancreatic Cancer Cells by Activating Wnt/β-Catenin Signaling

  • Original Article
  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

Background

Zinc finger protein 281 (ZNF281) has been identified to be involved in embryonic stem cell differentiation and tissue development. Also, ZNF281 was found in various types of cancers. However, its biological functions and clinical significance in pancreatic cancer remain elusive.

Aims

To explore the role of ZNF281 in pancreatic cancer cells proliferation and invasion.

Methods

ZNF281 expression was examined in public database Oncomine and cBioPortal. The correlation between ZNF281 and clinicopathological features was measured, and Kaplan–Meier method was used to measure the overall survival and recurrence-free survival in the TCGA cohort. Ectopic expression and knockdown of ZNF281 were performed to measure the impact on cell proliferation and invasion. Western blot and immunoprecipitation were further used to identify the ZNF281 interacting proteins. Topflash luciferase assay was used to detect the Wnt/β-catenin signaling activation.

Results

ZNF281 was predominantly up-regulated in pancreatic cancer tissues and significantly associated with advanced stage. Meanwhile, the high expression of ZNF281 indicated shorter overall survival and recurrence-free survival and ZNF281 could be an independent prognostic factor of pancreatic cancer. ZNF281 promoted cell proliferation and invasion in vitro. Mechanically, ZNF281 activated Wnt/β-catenin signaling and induced the downstream gene expression by directly binding with β-catenin and decreasing the polyubiquitination.

Conclusions

ZNF281 promotes pancreatic cancer cells proliferation and invasion by interacting and up-regulating β-catenin, highlighting the role of ZNF281 in pancreatic cancer progression.

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

Similar content being viewed by others

References

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66:7–30.

    Article  PubMed  Google Scholar 

  2. Yachida S, Jones S, Bozic I, et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature. 2010;467:1114–1117.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Xia S, Feng Z, Qi X, et al. Clinical implication of Sox9 and activated Akt expression in pancreatic ductal adenocarcinoma. Med Oncol. 2015;32:358.

    Article  PubMed  Google Scholar 

  4. Wang J, Rao S, Chu J, et al. A protein interaction network for pluripotency of embryonic stem cells. Nature. 2006;444:364–368.

    Article  CAS  PubMed  Google Scholar 

  5. Wang ZX, Teh CH, Chan CM, et al. The transcription factor Zfp281 controls embryonic stem cell pluripotency by direct activation and repression of target genes. Stem Cells. 2008;26:2791–2799.

    Article  CAS  PubMed  Google Scholar 

  6. Lisowsky T, Polosa PL, Sagliano A, Roberti M, Gadaleta MN, Cantatore P. Identification of human GC-box-binding zinc finger protein, a new Kruppel-like zinc finger protein, by the yeast one-hybrid screening with a GC-rich target sequence. FEBS Lett. 1999;453:369–374.

    Article  CAS  PubMed  Google Scholar 

  7. Koch HB, Zhang R, Verdoodt B, et al. Large-scale identification of c-MYC-associated proteins using a combined TAP/MudPIT approach. Cell Cycle. 2007;6:205–217.

    Article  CAS  PubMed  Google Scholar 

  8. Brandenberger R, Wei H, Zhang S, et al. Transcriptome characterization elucidates signaling networks that control human ES cell growth and differentiation. Nat Biotechnol. 2004;22:707–716.

    Article  PubMed  Google Scholar 

  9. Seo KW, Roh KH, Bhandari DR, Park SB, Lee SK, Kang KS. ZNF281 knockdown induced osteogenic differentiation of human multipotent stem cells in vivo and in vitro. Cell Transplant. 2013;22:29–40.

    Article  PubMed  Google Scholar 

  10. Fidalgo M, Shekar PC, Ang YS, Fujiwara Y, Orkin SH, Wang J. Zfp281 functions as a transcriptional repressor for pluripotency of mouse embryonic stem cells. Stem Cells. 2011;29:1705–1716.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Fidalgo M, Huang X, Guallar D, et al. Zfp281 coordinates opposing functions of Tet1 and Tet2 in pluripotent states. Cell Stem Cell. 2016;19:355–369.

    Article  CAS  PubMed  Google Scholar 

  12. Pieraccioli M, Nicolai S, Antonov A, et al. ZNF281 contributes to the DNA damage response by controlling the expression of XRCC2 and XRCC4. Oncogene. 2016;35:2592–2601.

    Article  CAS  PubMed  Google Scholar 

  13. Hahn S, Jackstadt R, Siemens H, Hunten S, Hermeking H. SNAIL and miR-34a feed-forward regulation of ZNF281/ZBP99 promotes epithelial-mesenchymal transition. EMBO J. 2013;32:3079–3095.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Lim X, Tan SH, Yu KL, Lim SB, Nusse R. Axin2 marks quiescent hair follicle bulge stem cells that are maintained by autocrine Wnt/beta-catenin signaling. Proc Natl Acad Sci USA. 2016;113:E1498–E1505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Sano M, Driscoll DR, DeJesus-Monge WE, et al. Activation of WNT/beta-Catenin Signaling Enhances Pancreatic Cancer Development and the Malignant Potential Via Up-regulation of Cyr61. Neoplasia. 2016;18:785–794.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Leung WK, He M, Chan AW, Law PT, Wong N. Wnt/beta-Catenin activates MiR-183/96/182 expression in hepatocellular carcinoma that promotes cell invasion. Cancer Lett. 2015;362:97–105.

    Article  CAS  PubMed  Google Scholar 

  17. Ninsontia C, Plaimee Phiboonchaiyanan P, Kiratipaiboon C, Chanvorachote P. Zinc suppresses stem cell properties of lung cancer cells through protein kinase C-mediated beta-catenin degradation. Am J Physiol Cell Physiol. 2017:ajpcell 00173 2016.

  18. Yuan R, Wang K, Hu J, et al. Ubiquitin-like protein FAT10 promotes the invasion and metastasis of hepatocellular carcinoma by modifying beta-catenin degradation. Cancer Res. 2014;74:5287–5300.

    Article  CAS  PubMed  Google Scholar 

  19. Xue J, Chen Y, Wu Y, et al. Tumour suppressor TRIM33 targets nuclear beta-catenin degradation. Nat Commun. 2015;6:6156.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Lee SH, Koo BS, Kim JM, et al. Wnt/beta-catenin signalling maintains self-renewal and tumourigenicity of head and neck squamous cell carcinoma stem-like cells by activating Oct4. J Pathol. 2014;234:99–107.

    Article  CAS  PubMed  Google Scholar 

  21. Edge SB, Compton CC. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol. 2010;17:1471–1474.

    Article  PubMed  Google Scholar 

  22. Li T, Lai Q, Wang S, et al. MicroRNA-224 sustains Wnt/beta-catenin signaling and promotes aggressive phenotype of colorectal cancer. J Exp Clin Cancer Research: CR. 2016;35:21.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Wang B, Ma A, Zhang L, Jin W-L, Qian Y, Xu G, et al. POH1 deubiquitylates and stabilizes E2F1 to promote tumour formation. Nat Commun. 2015;6.

  24. Hermann PC, Huber SL, Herrler T, et al. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell. 2007;1:313–323.

    Article  CAS  PubMed  Google Scholar 

  25. Badea L, Herlea V, Dima SO, Dumitrascu T, Popescu I. Combined gene expression analysis of whole-tissue and microdissected pancreatic ductal adenocarcinoma identifies genes specifically overexpressed in tumor epithelia. Hepato-gastroenterology. 2008;55:2016–2027.

    CAS  PubMed  Google Scholar 

  26. Ishikawa M, Yoshida K, Yamashita Y, et al. Experimental trial for diagnosis of pancreatic ductal carcinoma based on gene expression profiles of pancreatic ductal cells. Cancer Sci. 2005;96:387–393.

    Article  CAS  PubMed  Google Scholar 

  27. Pei H, Li L, Fridley BL, et al. FKBP51 affects cancer cell response to chemotherapy by negatively regulating Akt. Cancer Cell. 2009;16:259–266.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Iacobuzio-Donahue CA, Maitra A, Olsen M, et al. Exploration of global gene expression patterns in pancreatic adenocarcinoma using cDNA microarrays. Am J Pathol. 2003;162:1151–1162.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Buchholz M, Braun M, Heidenblut A, et al. Transcriptome analysis of microdissected pancreatic intraepithelial neoplastic lesions. Oncogene. 2005;24:6626–6636.

    Article  CAS  PubMed  Google Scholar 

  30. Segara D, Biankin AV, Kench JG, et al. Expression of HOXB2, a retinoic acid signaling target in pancreatic cancer and pancreatic intraepithelial neoplasia. Clinical Cancer Res. 2005;11:3587–3596.

    Article  CAS  Google Scholar 

  31. Grutzmann R, Pilarsky C, Ammerpohl O, et al. Gene expression profiling of microdissected pancreatic ductal carcinomas using high-density DNA microarrays. Neoplasia. 2004;6:611–622.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6:11.

  33. Scharer CD, McCabe CD, Ali-Seyed M, Berger MF, Bulyk ML, Moreno CS. Genome-wide promoter analysis of the SOX4 transcriptional network in prostate cancer cells. Cancer Res. 2009;69:709–717.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Viticchie G, Lena AM, Latina A, et al. MiR-203 controls proliferation, migration and invasive potential of prostate cancer cell lines. Cell Cycle. 2011;10:1121–1131.

    Article  CAS  PubMed  Google Scholar 

  35. Tong X, Li L, Li X, et al. SOX10, a novel HMG-box-containing tumor suppressor, inhibits growth and metastasis of digestive cancers by suppressing the Wnt/beta-catenin pathway. Oncotarget. 2014;5:10571–10583.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Lin H, Sun LH, Han W, et al. Knockdown of OCT4 suppresses the growth and invasion of pancreatic cancer cells through inhibition of the AKT pathway. Mol Med Rep. 2014;10:1335–1342.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Soares HP, Ni Y, Kisfalvi K, Sinnett-Smith J, Rozengurt E. Different patterns of Akt and ERK feedback activation in response to rapamycin, active-site mTOR inhibitors and metformin in pancreatic cancer cells. PLoS One. 2013;8:e57289.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Mu GG, Zhang LL, Li HY, Liao Y, Yu HG. Thymoquinone Pretreatment Overcomes the Insensitivity and Potentiates the Antitumor Effect of Gemcitabine Through Abrogation of Notch1, PI3 K/Akt/mTOR Regulated Signaling Pathways in Pancreatic Cancer. Dig Dis Sci. 2015;60:1067–1080.

    Article  CAS  PubMed  Google Scholar 

  39. Liu C, Li Y, Semenov M, et al. Control of beta-catenin phosphorylation/degradation by a dual-kinase mechanism. Cell. 2002;108:837–847.

    Article  CAS  PubMed  Google Scholar 

  40. Lu R, Wu S, Zhang YG, et al. Enteric bacterial protein AvrA promotes colonic tumorigenesis and activates colonic beta-catenin signaling pathway. Oncogenesis. 2014;3:e105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

We thank Dr. Jinlong Liu at Shanghai Institutes for Biological Science, Chinese Academy of Sciences for the advising and help in the present study.

Author information

Author notes

  1. Yu Qian and Jingyi Li have been contributed equally to this work.

Authors and Affiliations

  1. Translational Medicine Research Center, Shanxi Medical University, 56#, South Xinjian Road, Taiyuan, 030001, Shanxi Province, China

    Yu Qian

  2. Department of Gastroenterology, Shanxi Provincial Cancer Hospital, Shanxi Medical University, Taiyuan, 030013, Shanxi, China

    Jingyi Li

  3. Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, Jiangsu, China

    Suhua Xia

Authors
  1. Yu Qian
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jingyi Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Suhua Xia
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yu Qian.

Ethics declarations

Conflict of interest

No potential conflicts of interest were disclosed.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Qian, Y., Li, J. & Xia, S. ZNF281 Promotes Growth and Invasion of Pancreatic Cancer Cells by Activating Wnt/β-Catenin Signaling. Dig Dis Sci 62, 2011–2020 (2017). https://doi.org/10.1007/s10620-017-4611-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-017-4611-1

Keywords

Search

Navigation