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PRDM14 promotes malignant phenotype and correlates with poor prognosis in colorectal cancer

  • H. IgarashiEmail author
  • H. Taniguchi
  • K. Nosho
  • K. Ishigami
  • H. Koide
  • K. Mitsuhashi
  • K. Okita
  • I. Takemasa
  • K. Imai
  • H. Nakase
Research Article
  • 45 Downloads

Abstract

Background

Emerging evidence suggests that stemness in cancer cells is a cause of drug resistance or metastasis and is an important therapeutic target. PR [positive regulatory domain I-binding factor 1 (PRDI-BF1) and retinoblastoma protein-interacting zinc finger gene (RIZ1)] domain containing 14 (PRDM14), that regulates pluripotency in primordial germ cell, has reported the overexpression and function of stemness in various malignancies, suggesting it as the possible therapeutic target. However, to our knowledge, there have been no reports on the expression and function of PRDM14 in colorectal cancer (CRC). Therefore, we investigated the expression and the role of PRDM14 in CRC.

Methods

We performed immunohistochemistry evaluations and assessed PRDM14 expression on 414 primary CRC specimens. Colon cancer cell lines were subjected to functional and stemness assays in vitro and in vivo.

Results

We found that PRDM14 positive staining exhibited heterogeneity in the CRC primary tumor, especially at the tumor invasion front. The aberrant expression of PRDM14 at the invasion front was associated with lymph node metastasis and disease stage in patients with CRC. Furthermore, the multivariate analysis revealed high PRDM14 expression as an independent prognostic factor in the patients with Stage III CRC. Overexpression of PRDM14 enhanced the invasive, drug-resistant and stem-like properties in colon cancer cells in vitro and tumorigenicity in vivo.

Conclusion

Our findings suggest that PRDM14 is involved in progression and chemoresistance of CRC, and is a potential prognostic biomarker and therapeutic target in the CRC patients.

Keywords

Cancer stem cell Colorectal cancer Chemoresistance PRDM14 

Abbreviations

ALDH

Aldehyde dehydrogenase

CI

Confidence interval

CRC

Colorectal cancer

ESC

Embryonic stem cell

FFPE

Formalin-fixed, paraffin-embedded

HR

Hazard ratio

IHC

Immunohistochemistry

PGC

Primordial germ cell

PRDM14

Positive regulatory domain I-binding factor 1 and retinoblastoma protein-interacting zinc finger gene 1 domain containing 14

qRT-PCR

Quantitative reverse transcription PCR

SD

Standard deviation

TIF

Tumor invasion front

Notes

Acknowledgements

We thank the pathology departments of Sapporo Medical University Hospital and Keiyukai Sapporo Hospital for providing the tissue specimens. Writing assistance: the authors would like to thank Enago (https://www.enago.jp) for English language review.

Author contributions

Study concept and design: HI, HT. Data acquisition: HI, KI1, HK, KM, KO, IT. Data analysis and interpretation: HI, HT, KN. Drafting of the manuscript: HI, KI1, HK, KM. Critical revision of the manuscript for important intellectual content: HT, KN, KO, IT, KI2, HN. Statistical analysis: HI. Final approval of manuscript: all authors.

Funding

This work was supported by the Japan Society for the Promotion of Science (JSPS) Grant-in-Aid for Scientific Research (Grant number 26860515 to H. I.), Takeda Science Foundation (to H. I.), Daiwa Securities Health Foundation (to H. I.), JSPS Grant-in-Aid for Scientific Research (Grant number 16K07145 to K. N.), and Japan Agency for Medical Research and Development (Grant number 16Ack0106108h0003 to H. T.). The funding bodies had no involvement in the design of the study, collection, analysis, and interpretation of data and in writing the manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethics approval

This study was approved by the institutional review board of Sapporo Medical University Clinical trial center (reference number: 23-16), and was in accordance with the World Medical Association’s Declaration of Helsinki (1964, and its later amendments). All the animal studies were performed under the supervision of the Committee for Animal Research Center of Sapporo Medical University and in accordance with protocols approved by the Institutional Animal Care and Use Committee (reference number: 18-071).

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

12094_2019_2239_MOESM1_ESM.doc (383 kb)
Supplementary file1 (DOC 383 kb)

References

  1. 1.
    Fitzmaurice C, Allen C, Barber RM, Barregard L, Bhutta ZA, Brenner H, et al. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015: a systematic analysis for the global burden of disease study. JAMA Oncol. 2017;3(4):524–48.  https://doi.org/10.1001/jamaoncol.2016.5688.CrossRefPubMedGoogle Scholar
  2. 2.
    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA. 2018;68(1):7–30.  https://doi.org/10.3322/caac.21442.CrossRefPubMedGoogle Scholar
  3. 3.
    Ferlay J, Colombet M, Soerjomataram I, Mathers C, Parkin DM, Pineros M, et al. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int J Cancer. 2019;144(8):1941–53.  https://doi.org/10.1002/ijc.31937.CrossRefPubMedGoogle Scholar
  4. 4.
    Meacham CE, Morrison SJ. Tumour heterogeneity and cancer cell plasticity. Nature. 2013;501(7467):328–37.  https://doi.org/10.1038/nature12624.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Visvader JE, Lindeman GJ. Cancer stem cells: current status and evolving complexities. Cell Stem Cell. 2012;10(6):717–28.  https://doi.org/10.1016/j.stem.2012.05.007.CrossRefPubMedGoogle Scholar
  6. 6.
    Maccalli C, De Maria R. Cancer stem cells: perspectives for therapeutic targeting. CII. 2015;64(1):91–7.  https://doi.org/10.1007/s00262-014-1592-1.CrossRefPubMedGoogle Scholar
  7. 7.
    Nakaki F, Saitou M. PRDM14: a unique regulator for pluripotency and epigenetic reprogramming. Trends Biochem Sci. 2014;39(6):289–98.  https://doi.org/10.1016/j.tibs.2014.04.003.CrossRefPubMedGoogle Scholar
  8. 8.
    Chia NY, Chan YS, Feng B, Lu X, Orlov YL, Moreau D, et al. A genome-wide RNAi screen reveals determinants of human embryonic stem cell identity. Nature. 2010;468(7321):316–20.  https://doi.org/10.1038/nature09531.CrossRefPubMedGoogle Scholar
  9. 9.
    Tsuneyoshi N, Sumi T, Onda H, Nojima H, Nakatsuji N, Suemori H. PRDM14 suppresses expression of differentiation marker genes in human embryonic stem cells. Biochem Biophys Res Commun. 2008;367(4):899–905.  https://doi.org/10.1016/j.bbrc.2007.12.189.CrossRefPubMedGoogle Scholar
  10. 10.
    Yamaji M, Seki Y, Kurimoto K, Yabuta Y, Yuasa M, Shigeta M, et al. Critical function of Prdm14 for the establishment of the germ cell lineage in mice. Nat Genet. 2008;40(8):1016–22.  https://doi.org/10.1038/ng.186.CrossRefPubMedGoogle Scholar
  11. 11.
    Moriya C, Taniguchi H, Miyata K, Nishiyama N, Kataoka K, Imai K. Inhibition of PRDM14 expression in pancreatic cancer suppresses cancer stem-like properties and liver metastasis in mice. Carcinogenesis. 2017;38(6):638–48.  https://doi.org/10.1093/carcin/bgx040.CrossRefPubMedGoogle Scholar
  12. 12.
    Nishikawa N, Toyota M, Suzuki H, Honma T, Fujikane T, Ohmura T, et al. Gene amplification and overexpression of PRDM14 in breast cancers. Can Res. 2007;67(20):9649–57.  https://doi.org/10.1158/0008-5472.CAN-06-4111.CrossRefGoogle Scholar
  13. 13.
    Terashima K, Yu A, Chow W-YT, Hsu W-cJ, Chen P, Wong S, et al. Genome-wide analysis of DNA copy number alterations and loss of heterozygosity in intracranial germ cell tumors. Pediatr Blood Cancer. 2014;61(4):593–600.  https://doi.org/10.1002/pbc.24833.CrossRefPubMedGoogle Scholar
  14. 14.
    Weiser KC, Liu B, Hansen GM, Skapura D, Hentges KE, Yarlagadda S, et al. Retroviral insertions in the VISION database identify molecular pathways in mouse lymphoid leukemia and lymphoma. Mamm Genome. 2007;18(10):709–22.  https://doi.org/10.1007/s00335-007-9060-2.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Zhang T, Meng L, Dong W, Shen H, Zhang S, Liu Q, et al. High expression of PRDM14 correlates with cell differentiation and is a novel prognostic marker in resected non-small cell lung cancer. Med Oncol. 2013;30(3):605.  https://doi.org/10.1007/s12032-013-0605-9.CrossRefPubMedGoogle Scholar
  16. 16.
    Bi HX, Shi HB, Zhang T, Cui G. PRDM14 promotes the migration of human non-small cell lung cancer through extracellular matrix degradation in vitro. Chin Med J. 2015;128(3):373–7.  https://doi.org/10.4103/0366-6999.150109.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Carofino BL, Ayanga B, Justice MJ. A mouse model for inducible overexpression of Prdm14 results in rapid-onset and highly penetrant T-cell acute lymphoblastic leukemia (T-ALL). Dis Mod Mech. 2013;6(6):1494–506.  https://doi.org/10.1242/dmm.012575.CrossRefGoogle Scholar
  18. 18.
    Dettman EJ, Simko SJ, Ayanga B, Carofino BL, Margolin JF, Morse HC 3rd, et al. Prdm14 initiates lymphoblastic leukemia after expanding a population of cells resembling common lymphoid progenitors. Oncogene. 2011;30(25):2859–73.  https://doi.org/10.1038/onc.2011.12.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Taniguchi H, Hoshino D, Moriya C, Zembutsu H, Nishiyama N, Yamamoto H, et al. Silencing PRDM14 expression by an innovative RNAi therapy inhibits stemness, tumorigenicity, and metastasis of breast cancer. Oncotarget. 2017;8(29):46856–74.  https://doi.org/10.18632/oncotarget.16776.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Nosho K, Kure S, Irahara N, Shima K, Baba Y, Spiegelman D, et al. A prospective cohort study shows unique epigenetic, genetic, and prognostic features of synchronous colorectal cancers. Gastroenterology. 2009;137(5):1609–20.  https://doi.org/10.1053/j.gastro.2009.08.002(e1–3).CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Iwagami S, Baba Y, Watanabe M, Shigaki H, Miyake K, Ishimoto T, et al. LINE-1 hypomethylation is associated with a poor prognosis among patients with curatively resected esophageal squamous cell carcinoma. Ann Surg. 2013;257(3):449–55.  https://doi.org/10.1097/SLA.0b013e31826d8602.CrossRefPubMedGoogle Scholar
  22. 22.
    Ashktorab H, Shakoori A, Zarnogi S, Sun X, Varma S, Lee E, et al. Reduced representation bisulfite sequencing determination of distinctive DNA hypermethylated genes in the progression to colon cancer in African Americans. Gastroenterol Res Pract. 2016;2016:1–8.  https://doi.org/10.1155/2016/2102674.CrossRefGoogle Scholar
  23. 23.
    Haraguchi N, Ohara N, Koseki J, Takahashi H, Nishimura J, Hata T, et al. High expression of ADAMTS5 is a potent marker for lymphatic invasion and lymph node metastasis in colorectal cancer. Mol Clin Oncol. 2017;6(1):130–4.  https://doi.org/10.3892/mco.2016.1088.CrossRefPubMedGoogle Scholar
  24. 24.
    Huang L, Wang X, Wen C, Yang X, Song M, Chen J, et al. Hsa-miR-19a is associated with lymph metastasis and mediates the TNF-alpha induced epithelial-to-mesenchymal transition in colorectal cancer. Sci Rep. 2015;5:13350.  https://doi.org/10.1038/srep13350.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Zheng Y, Song D, Xiao K, Yang C, Ding Y, Deng W, et al. LncRNA GAS5 contributes to lymphatic metastasis in colorectal cancer. Oncotarget. 2016;7(50):83727–34.  https://doi.org/10.18632/oncotarget.13384.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Baltaci E, Karaman E, Dalay N, Buyru N. Analysis of gene copy number changes in head and neck cancer. Clin Otolaryngol. 2018;43(4):1004–9.  https://doi.org/10.1111/coa.12686.CrossRefPubMedGoogle Scholar
  27. 27.
    Baykara O, Bakir B, Buyru N, Kaynak K, Dalay N. Amplification of chromosome 8 genes in lung cancer. J Cancer. 2015;6(3):270–5.  https://doi.org/10.7150/jca.10638.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Moelans CB, de Weger RA, Monsuur HN, Vijzelaar R, van Diest PJ. Molecular profiling of invasive breast cancer by multiplex ligation-dependent probe amplification-based copy number analysis of tumor suppressor and oncogenes. Mod Pathol. 2010;23(7):1029–39.  https://doi.org/10.1038/modpathol.2010.84.CrossRefPubMedGoogle Scholar
  29. 29.
    Cancer Genome Atlas N. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487(7407):330–7.  https://doi.org/10.1038/nature11252.CrossRefGoogle Scholar
  30. 30.
    Nandy SB, Orozco A, Lopez-Valdez R, Roberts R, Subramani R, Arumugam A, et al. Glucose insult elicits hyperactivation of cancer stem cells through miR-424-cdc42-prdm14 signalling axis. Br J Cancer. 2017;117(11):1665–75.  https://doi.org/10.1038/bjc.2017.335.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Brabletz T, Jung A, Reu S, Porzner M, Hlubek F, Kunz-Schughart LA, et al. Variable beta-catenin expression in colorectal cancers indicates tumor progression driven by the tumor environment. Proc Natl Acad Sci USA. 2001;98(18):10356–61.  https://doi.org/10.1073/pnas.171610498.CrossRefPubMedGoogle Scholar
  32. 32.
    Brabletz T, Jung A, Hermann K, Gunther K, Hohenberger W, Kirchner T. Nuclear overexpression of the oncoprotein beta-catenin in colorectal cancer is localized predominantly at the invasion front. Pathol Res Pract. 1998;194(10):701–4.CrossRefGoogle Scholar
  33. 33.
    Hlubek F, Brabletz T, Budczies J, Pfeiffer S, Jung A, Kirchner T. Heterogeneous expression of Wnt/beta-catenin target genes within colorectal cancer. Int J Cancer. 2007;121(9):1941–8.  https://doi.org/10.1002/ijc.22916.CrossRefPubMedGoogle Scholar
  34. 34.
    Kahlert C, Lahes S, Radhakrishnan P, Dutta S, Mogler C, Herpel E, et al. Overexpression of ZEB2 at the invasion front of colorectal cancer is an independent prognostic marker and regulates tumor invasion in vitro. Clin Cancer Res. 2011;17(24):7654–63.  https://doi.org/10.1158/1078-0432.CCR-10-2816.CrossRefPubMedGoogle Scholar
  35. 35.
    Le NH, Franken P, Fodde R. Tumour-stroma interactions in colorectal cancer: converging on beta-catenin activation and cancer stemness. Br J Cancer. 2008;98(12):1886–933.  https://doi.org/10.1038/sj.bjc.6604401.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Nemolato S, Restivo A, Cabras T, Coni P, Zorcolo L, Orru G, et al. Thymosin beta 4 in colorectal cancer is localized predominantly at the invasion front in tumor cells undergoing epithelial mesenchymal transition. Cancer Biol Ther. 2012;13(4):191–7.  https://doi.org/10.4161/cbt.13.4.18691.CrossRefPubMedGoogle Scholar
  37. 37.
    Ougolkov AV, Yamashita K, Mai M, Minamoto T. Oncogenic β-catenin and MMP-7 (matrilysin) cosegregate in late-stage clinical colon cancer. Gastroenterology. 2002;122(1):60–71.  https://doi.org/10.1053/gast.2002.30306.CrossRefPubMedGoogle Scholar
  38. 38.
    Vignjevic D, Schoumacher M, Gavert N, Janssen KP, Jih G, Lae M, et al. Fascin, a novel target of beta-catenin-TCF signaling, is expressed at the invasive front of human colon cancer. Can Res. 2007;67(14):6844–53.  https://doi.org/10.1158/0008-5472.CAN-07-0929.CrossRefGoogle Scholar
  39. 39.
    Guinney J, Dienstmann R, Wang X, de Reynies A, Schlicker A, Soneson C, et al. The consensus molecular subtypes of colorectal cancer. Nat Med. 2015;21(11):1350–6.  https://doi.org/10.1038/nm.3967.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Federación de Sociedades Españolas de Oncología (FESEO) 2019

Authors and Affiliations

  1. 1.Department of Gastroenterology and HepatologySapporo Medical University School of MedicineSapporoJapan
  2. 2.The Center for Antibody and Vaccine Therapy, Research Hospital, The Institute of Medical ScienceThe University of TokyoTokyoJapan
  3. 3.Department of Surgery, Surgical Oncology and ScienceSapporo Medical University School of MedicineSapporoJapan
  4. 4.The Institute of Medical ScienceThe University of TokyoTokyoJapan

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