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.

  • Original Article
  • Published:

Epithelial splicing regulatory protein 1 is a favorable prognostic factor in pancreatic cancer that attenuates pancreatic metastases

Oncogene volume 33, pages 4485–4495 (2014)Cite this article

Subjects

Abstract

Epithelial splicing regulatory protein 1 (ESRP1) binds the FGFR-2 auxiliary cis-element ISE/ISS-3, located in the intron between exon IIIb and IIIc, and primarily promotes FGFR-2 IIIb expression. Here we assessed the role of ESRP1 in pancreatic ductal adenocarcinoma (PDAC). Immunohistochemical analysis was performed using anti-ESRP1, FGFR-2 IIIb and FGFR-2 IIIc antibodies in 123 PDAC cases. ESRP1 expression vector and small interference RNA (siRNA) targeting ESRP1 were transfected into human PDAC cells, and cell growth, migration and invasion were analyzed. In vivo heterotopic and orthotopic implantations using ESRP1 overexpression clones were performed and effects on pancreatic tumor volumes and hepatic and pulmonary metastases determined. ESRP1 immunoreactivity was strong in the nuclei of cancer cells in well-to-moderately differentiated PDACs but weak in poorly differentiated cancers. Well-to-moderately differentiated cancers also exhibited high FGFR-2 IIIb and low FGFR-2 IIIc expression, whereas this ratio was reversed in the poorly differentiated cancers. Increased ESRP1 expression was associated with longer survival in comparison with low ESRP1 expression, and PANC-1 cells engineered to express ESRP1 exhibited increased FGFR-2 IIIb expression and decreased migration and invasion in vitro, whereas ESRP1 siRNA-transfected KLM-1 cells exhibited increased FGFR-2 IIIc expression and increased cell growth, migration and invasion. In vivo, ESRP1-overexpressing clones formed significantly fewer liver metastases as compared with control clones. ESRP1 regulates the expression pattern of FGFR-2 isoforms, attenuates cell growth, migration, invasion and metastasis, and is a favorable prognostic factor in PDAC. Therefore, devising mechanisms to upregulate ESRP1 may exert a beneficial therapeutic effect in PDAC.

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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Siegel R, Naishadham D, Jemal A . Cancer statistics, 2012. CA Cancer J Clin 2012; 62: 10–29.

    Article  Google Scholar 

  2. Cho K, Ishiwata T, Uchida E, Nakazawa N, Korc M, Naito Z et al. Enhanced expression of keratinocyte growth factor and its receptor correlates with venous invasion in pancreatic cancer. Am J Pathol 2007; 170: 1964–1974.

    Article  CAS  Google Scholar 

  3. Ishiwata T, Friess H, Buchler MW, Lopez ME, Korc M . Characterization of keratinocyte growth factor and receptor expression in human pancreatic cancer. Am J Pathol 1998; 153: 213–222.

    Article  CAS  Google Scholar 

  4. Dionne CA, Crumley G, Bellot F, Kaplow JM, Searfoss G, Ruta M et al. Cloning and expression of two distinct high-affinity receptors cross-reacting with acidic and basic fibroblast growth factors. EMBO J 1990; 9: 2685–2692.

    Article  CAS  Google Scholar 

  5. Miki T, Fleming TP, Bottaro DP, Rubin JS, Ron D, Aaronson SA . Expression cDNA cloning of the KGF receptor by creation of a transforming autocrine loop. Science 1991; 251: 72–75.

    Article  CAS  Google Scholar 

  6. Savagner P, Valles AM, Jouanneau J, Yamada KM, Thiery JP . Alternative splicing in fibroblast growth factor receptor 2 is associated with induced epithelial-mesenchymal transition in rat bladder carcinoma cells. Mol Biol Cell 1994; 5: 851–862.

    Article  CAS  Google Scholar 

  7. Katoh M . FGFR2 abnormalities underlie a spectrum of bone, skin, and cancer pathologies. J Invest Dermatol 2009; 129: 1861–1867.

    Article  CAS  Google Scholar 

  8. Baum B, Settleman J, Quinlan MP . Transitions between epithelial and mesenchymal states in development and disease. Semin Cell Dev Biol 2008; 19: 294–308.

    Article  CAS  Google Scholar 

  9. Yan G, Fukabori Y, McBride G, Nikolaropolous S, McKeehan WL . Exon switching and activation of stromal and embryonic fibroblast growth factor (FGF)-FGF receptor genes in prostate epithelial cells accompany stromal independence and malignancy. Mol Cell Biol 1993; 13: 4513–4522.

    Article  CAS  Google Scholar 

  10. Ishiwata T, Matsuda Y, Yamamoto T, Uchida E, Korc M, Naito Z . Enhanced expression of fibroblast growth factor receptor 2 IIIc promotes human pancreatic cancer cell proliferation. Am J Pathol 2012; 180: 1928–1941.

    Article  CAS  Google Scholar 

  11. Hovhannisyan RH, Carstens RP . Heterogeneous ribonucleoprotein m is a splicing regulatory protein that can enhance or silence splicing of alternatively spliced exons. J Biol Chem 2007; 282: 36265–36274.

    Article  CAS  Google Scholar 

  12. Mauger DM, Lin C, Garcia-Blanco MA . hnRNP H.and hnRNP F complex with Fox2 to silence fibroblast growth factor receptor 2 exon IIIc. Mol Cell Biol 2008; 28: 5403–5419.

    Article  CAS  Google Scholar 

  13. Warzecha CC, Sato TK, Nabet B, Hogenesch JB, Carstens RP . ESRP1 and ESRP2 are epithelial cell-type-specific regulators of FGFR2 splicing. Mol Cell 2009; 33: 591–601.

    Article  CAS  Google Scholar 

  14. Warzecha CC, Shen S, Xing Y, Carstens RP . The epithelial splicing factors ESRP1 and ESRP2 positively and negatively regulate diverse types of alternative splicing events. RNA Biol 2009; 6: 546–562.

    Article  CAS  Google Scholar 

  15. Leontieva OV, Ionov Y . RNA-binding motif protein 35A is a novel tumor suppressor for colorectal cancer. Cell Cycle 2009; 8: 490–497.

    Article  CAS  Google Scholar 

  16. Gemmill RM, Roche J, Potiron VA, Nasarre P, Mitas M, Coldren CD et al. ZEB1-responsive genes in non-small cell lung cancer. Cancer Lett 2011; 300: 66–78.

    Article  CAS  Google Scholar 

  17. Onder TT, Gupta PB, Mani SA, Yang J, Lander ES, Weinberg RA . Loss of E-cadherin promotes metastasis via multiple downstream transcriptional pathways. Cancer Res 2008; 68: 3645–3654.

    Article  CAS  Google Scholar 

  18. Shapiro IM, Cheng AW, Flytzanis NC, Balsamo M, Condeelis JS, Oktay MH et al. An EMT-driven alternative splicing program occurs in human breast cancer and modulates cellular phenotype. PLoS Genet 2011; 7: e1002218.

    Article  CAS  Google Scholar 

  19. Warzecha CC, Jiang P, Amirikian K, Dittmar KA, Lu H, Shen S et al. An ESRP-regulated splicing programme is abrogated during the epithelial-mesenchymal transition. EMBO J 2010; 29: 3286–3300.

    Article  CAS  Google Scholar 

  20. Thiery JP, Sleeman JP . Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol 2006; 7: 131–142.

    Article  CAS  Google Scholar 

  21. Hruban RH, Maitra A, Goggins M . Update on pancreatic intraepithelial neoplasia. Int J Clin Exp Pathol 2008; 1: 306–316.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Hezel AF, Kimmelman AC, Stanger BZ, Bardeesy N, Depinho RA . Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev 2006; 20: 1218–1249.

    Article  CAS  Google Scholar 

  23. Esposito I, Menicagli M, Funel N, Bergmann F, Boggi U, Mosca F et al. Inflammatory cells contribute to the generation of an angiogenic phenotype in pancreatic ductal adenocarcinoma. J Clin Pathol 2004; 57: 630–636.

    Article  CAS  Google Scholar 

  24. Korc M . Role of growth factors in pancreatic cancer. Surg Oncol Clin N Am 1998; 7: 25–41.

    Article  CAS  Google Scholar 

  25. Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 2008; 321: 1801–1806.

    Article  CAS  Google Scholar 

  26. Hidalgo M . Pancreatic cancer. N Engl J Med 2010; 362: 1605–1617.

    Article  CAS  Google Scholar 

  27. Korc M, Friesel RE . The role of fibroblast growth factors in tumor growth. Curr Cancer Drug Targets 2009; 9: 639–651.

    Article  CAS  Google Scholar 

  28. Feig C, Gopinathan A, Neesse A, Chan DS, Cook N, Tuveson DA . The pancreas cancer microenvironment. Clin Cancer Res 2012; 18: 4266–4276.

    Article  CAS  Google Scholar 

  29. Joyce JA, Pollard JW . Microenvironmental regulation of metastasis. Nat Rev Cancer 2009; 9: 239–252.

    Article  CAS  Google Scholar 

  30. Grivennikov SI, Greten FR, Karin M . Immunity, inflammation, and cancer. Cell 2010; 140: 883–899.

    Article  CAS  Google Scholar 

  31. Nguyen DX, Bos PD, Massague J . Metastasis: from dissemination to organ-specific colonization. Nat Rev Cancer 2009; 9: 274–284.

    Article  CAS  Google Scholar 

  32. Di Modugno F, Iapicca P, Boudreau A, Mottolese M, Terrenato I, Perracchio L et al. Splicing program of human MENA produces a previously undescribed isoform associated with invasive, mesenchymal-like breast tumors. Proc Natl Acad Sci USA 2012; 109: 19280–19285.

    Article  CAS  Google Scholar 

  33. Pan Q, Shai O, Lee LJ, Frey BJ, Blencowe BJ . Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing. Nat Genet 2008; 40: 1413–1415.

    Article  CAS  Google Scholar 

  34. Wang ET, Sandberg R, Luo S, Khrebtukova I, Zhang L, Mayr C et al. Alternative isoform regulation in human tissue transcriptomes. Nature 2008; 456: 470–476.

    Article  CAS  Google Scholar 

  35. Johnson M, Sharma M, Henderson BR . IQGAP1 regulation and roles in cancer. Cell Signal 2009; 21: 1471–1478.

    Article  CAS  Google Scholar 

  36. Wickstrom SA, Lange A, Hess MW, Polleux J, Spatz JP, Kruger M et al. Integrin-linked kinase controls microtubule dynamics required for plasma membrane targeting of caveolae. Dev Cell 2010; 19: 574–588.

    Article  Google Scholar 

  37. Bailey KM, Liu J . Caveolin-1 up-regulation during epithelial to mesenchymal transition is mediated by focal adhesion kinase. J Biol Chem 2008; 283: 13714–13724.

    Article  CAS  Google Scholar 

  38. Yan L, Gu H, Li J, Xu M, Liu T, Shen Y et al. RKIP and 14–3-3epsilon exert an opposite effect on human gastric cancer cells SGC7901 by regulating the ERK/MAPK pathway differently. Dig Dis Sci 2013; 58: 389–396.

    Article  CAS  Google Scholar 

  39. Brown RL, Reinke LM, Damerow MS, Perez D, Chodosh LA, Yang J et al. CD44 splice isoform switching in human and mouse epithelium is essential for epithelial-mesenchymal transition and breast cancer progression. J Clin Invest 2011; 121: 1064–1074.

    Article  CAS  Google Scholar 

  40. Rhim AD, Mirek ET, Aiello NM, Maitra A, Bailey JM, McAllister F et al. EMT and dissemination precede pancreatic tumor formation. Cell 2012; 148: 349–361.

    Article  CAS  Google Scholar 

  41. Tuveson DA, Neoptolemos JP . Understanding metastasis in pancreatic cancer: a call for new clinical approaches. Cell 2012; 148: 21–23.

    Article  CAS  Google Scholar 

  42. Kawase R, Ishiwata T, Matsuda Y, Onda M, Kudo M, Takeshita T et al. Expression of fibroblast growth factor receptor 2 IIIc in human uterine cervical intraepithelial neoplasia and cervical cancer. Int J Oncol 2010; 36: 331–340.

    CAS  PubMed  Google Scholar 

  43. Matsuda Y, Yamamoto T, Kudo M, Kawahara K, Kawamoto M, Nakajima Y et al. Expression and roles of lumican in lung adenocarcinoma and squamous cell carcinoma. Int J Oncol 2008; 33: 1177–1185.

    CAS  PubMed  Google Scholar 

  44. Matsuda Y, Naito Z, Kawahara K, Nakazawa N, Korc M, Ishiwata T . Nestin is a novel target for suppressing pancreatic cancer cell migration, invasion and metastasis. Cancer Biol Ther 2011; 11: 512–523.

    Article  CAS  Google Scholar 

  45. Gorg A, Obermaier C, Boguth G, Csordas A, Diaz JJ, Madjar JJ . Very alkaline immobilized pH gradients for two-dimensional electrophoresis of ribosomal and nuclear proteins. Electrophoresis 1997; 18: 328–337.

    Article  CAS  Google Scholar 

  46. Gorg A, Obermaier C, Boguth G, Weiss W . Recent developments in two-dimensional gel electrophoresis with immobilized pH gradients: wide pH gradients up to pH 12, longer separation distances and simplified procedures. Electrophoresis 1999; 20: 712–717.

    Article  CAS  Google Scholar 

  47. Suemizu H, Monnai M, Ohnishi Y, Ito M, Tamaoki N, Nakamura M . Identification of a key molecular regulator of liver metastasis in human pancreatic carcinoma using a novel quantitative model of metastasis in NOD/SCID/gammacnull (NOG) mice. Int J Onco 2007; 31: 741–751.

    CAS  Google Scholar 

  48. Seiden-Long I, Navab R, Shih W, Li M, Chow J, Zhu CQ et al. Gab1 but not Grb2 mediates tumor progression in Met overexpressing colorectal cancer cells. Carcinogenesis 2008; 29: 647–655.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We express our appreciation to Dr Masahito Hagio for helpful discussion and Dr Tetsushi Yamamoto, Mr Yuji Yanagisawa, Ms Taeko Suzuki, Ms Yoko Kawamoto and Ms Kiyoko Kawahara (Department of Pathology, Nippon Medical School) for their excellent technical assistance. We also thank Dr Shin-ichi Tsuchiya (Division of Surgical Pathology, Nippon Medical School Hospital) for preparing tissue blocks. This work was supported by Grants-in-Aid for Scientific Research (C, No.22591531 for TI), a Grant-in-Aid for Young Scientists (A, No. 22689038 for YM) a Grant-in-Aid for Challenging Exploratory Research (No. 23650604 for YM) from the Japan Society for the Promotion of Science, and in part by NIH grant R37-CA-075059 to MK.

Author information

Authors and Affiliations

  1. Departments of Pathology and Integrative Oncological Pathology, Nippon Medical School, Tokyo, Japan

    J Ueda, Y Matsuda, K Yamahatsu, Z Naito & T Ishiwata

  2. Department of Surgery for Organ and Biological Regulation, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan

    J Ueda, K Yamahatsu & E Uchida

  3. Departments of Medicine, and Biochemistry and Molecular Biology, Indiana University School of Medicine and the Melvin and Bren Simon Cancer Center, Indianapolis, IN, USA

    M Korc

Authors
  1. J Ueda
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Y Matsuda
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. K Yamahatsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. E Uchida
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Z Naito
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M Korc
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. T Ishiwata
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to T Ishiwata.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ueda, J., Matsuda, Y., Yamahatsu, K. et al. Epithelial splicing regulatory protein 1 is a favorable prognostic factor in pancreatic cancer that attenuates pancreatic metastases. Oncogene 33, 4485–4495 (2014). https://doi.org/10.1038/onc.2013.392

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2013.392

Keywords

This article is cited by

Search

Advanced search

Quick links