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:

Therapy of human pancreatic carcinoma based on suppression of HMGA1 protein synthesis in preclinical models

Cancer Gene Therapy volume 11, pages 633–641 (2004)Cite this article

Abstract

Pancreatic carcinoma is one of the most aggressive tumors, and, being refractory to conventional therapies, is an excellent target for new therapeutic approaches. Based on our previous finding of high HMGA1 expression in pancreatic cancer cells compared to normal pancreatic tissue, we evaluated whether suppression of HMGA1 protein expression could be a treatment option for patients affected by pancreatic cancer. Here we report that HMGA1 proteins are overexpressed in pancreatic carcinoma cell lines, and their downregulation through an adenovirus carrying the HMGA1 gene in an antisense orientation (Ad Yas-GFP) results in the death of three human pancreatic carcinoma cell lines (PANC1, Hs766T and PSN1). Pretreatment of PANC1 and PSN1 cells with Ad Yas-GFP suppressed and reduced, respectively, their ability to form xenograft tumors in nude mice. To further verify the role of HMGA1 in pancreatic tumorigenesis, we used a HMGA1 antisense phosphorothioate oligodeoxynucleotide (ODN); its addition induced a decrease in HMGA1 protein levels and a significant reduction of the proliferation rate of PANC1-, Hs766T- and PSN1-treated cells. Therefore, suppression of HMGA1 protein synthesis by an HMGA1 antisense approach seems to be a feasible treatment strategy in pancreatic carcinomas.

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
Figure 7
Figure 8

Similar content being viewed by others

References

  1. Warshaw AL, Fernandez-del Castillo C . Pancreatic carcinoma. N Engl J Med. 1992;326:455–465.

    Article  CAS  PubMed  Google Scholar 

  2. Yeo CJ, Cameron JL, Lillemoe KD, et al. Pancreaticoduodenectomy for cancer of the head of the pancreas. 201 patients. Ann Surg. 1995;221:721–731 discussion 731–733.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Landis SH, Murray T, Bolden S, Wingo PA . Cancer statistics, 1999. CA Cancer J Clin. 1999;49:8–31.

    CAS  PubMed  Google Scholar 

  4. Johnson KR, Lehn DA, Elton TS, Barr PJ, Reeves R . Complete murine cDNA sequence, genomic structure, and tissue expression of the high mobility group protein HMG-I(Y). J Biol Chem. 1988;263:18338–18342.

    CAS  PubMed  Google Scholar 

  5. Johnson KR, Lehn DA, Reeves R . Alternative processing of mRNAs encoding mammalian chromosomal high-mobility-group proteins HMG-I and HMG-Y. Mol Cell Biol. 1989;9:2114–2123.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Manfioletti G, Giancotti V, Bandiera A, et al. cDNA cloning of the HMGI-C phosphoprotein, a nuclear protein associated with neoplastic and undifferentiated phenotypes. Nucleic Acids Res. 1991;19:6793–6797.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Grosschedl R, Giese K, Pagel J . HMG domain proteins: architectural elements in the assembly of nucleoprotein structures. Trends Genet. 1994;10:94–100.

    Article  CAS  PubMed  Google Scholar 

  8. Lovell-Badge R . Developmental genetics. Living with bad architecture. Nature. 1995;376:725–726.

    Article  CAS  PubMed  Google Scholar 

  9. Bustin M, Reeves R . High-mobility-group chromosomal proteins: architectural components that facilitate chromatin function. Prog Nucleic Acid Res Mol Biol. 1996;54:35–100.

    Article  CAS  PubMed  Google Scholar 

  10. Zhou X, Benson KF, Ashar HR, Chada K . Mutation responsible for the mouse pygmy phenotype in the developmentally regulated factor HMGI-C. Nature. 1995;376:771–774.

    Article  CAS  PubMed  Google Scholar 

  11. Chiappetta G, Avantaggiato V, Visconti R, et al. High level expression of the HMGI (Y) gene during embryonic development. Oncogene. 1996;13:2439–2446.

    CAS  PubMed  Google Scholar 

  12. Chiappetta G, Bandiera A, Berlingieri MT, et al. The expression of the high mobility group HMGI (Y) proteins correlates with the malignant phenotype of human thyroid neoplasias. Oncogene. 1995;10:1307–1314.

    CAS  PubMed  Google Scholar 

  13. Tamimi Y, van der Poel HG, Karthaus HF, Debruyne FM, Schalken JA . A retrospective study of high mobility group protein I(Y) as progression marker for prostate cancer determined by in situ hybridization. Br J Cancer. 1996;74:573–578.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Fedele M, Bandiera A, Chiappetta G, et al. Human colorectal carcinomas express high levels of high mobility group HMGI(Y) proteins. Cancer Res. 1996;56:1896–1901.

    CAS  PubMed  Google Scholar 

  15. Chiappetta G, Tallini G, De Biasio MC, et al. Detection of high mobility group I HMGI(Y) protein in the diagnosis of thyroid tumors: HMGI(Y) expression represents a potential diagnostic indicator of carcinoma. Cancer Res. 1998;58:4193–4198.

    CAS  PubMed  Google Scholar 

  16. Bandiera A, Bonifacio D, Manfioletti G, et al. Expression of HMGI(Y) proteins in squamous intraepithelial and invasive lesions of the uterine cervix. Cancer Res. 1998;58:426–431.

    CAS  PubMed  Google Scholar 

  17. Abe N, Watanabe T, Sugiyama M, et al. Determination of high mobility group I(Y) expression level in colorectal neoplasias: a potential diagnostic marker. Cancer Res. 1999;59:1169–1174.

    CAS  PubMed  Google Scholar 

  18. Abe N, Watanabe T, Masaki T, et al. Pancreatic duct cell carcinomas express high levels of high mobility group I(Y) proteins. Cancer Res. 2000;60:3117–3122.

    CAS  PubMed  Google Scholar 

  19. Chiappetta G, Manfioletti G, Pentimalli F, et al. High mobility group HMGI(Y) protein expression in human colorectal hyperplastic and neoplastic diseases. Int J Cancer. 2001;91:147–151.

    Article  CAS  PubMed  Google Scholar 

  20. Berlingieri MT, Manfioletti G, Santoro M, et al. Inhibition of HMGI-C protein synthesis suppresses retrovirally induced neoplastic transformation of rat thyroid cells. Mol Cell Biol. 1995;15:1545–1553.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Berlingieri MT, Pierantoni GM, Giancotti V, Santoro M, Fusco A . Thyroid cell transformation requires the expression of the HMGA1 proteins. Oncogene. 2002;21:2971–2980.

    Article  CAS  PubMed  Google Scholar 

  22. Wood LJ, Maher JF, Bunton TE, Resar LM . The oncogenic properties of the HMG-I gene family. Cancer Res. 2000;60:4256–4261.

    CAS  PubMed  Google Scholar 

  23. Baldassarre G, Fedele M, Battista S, et al. Onset of natural killer cell lymphomas in transgenic mice carrying a truncated HMGI-C gene by the chronic stimulation of the IL-2 and IL-15 pathway. Proc Natl Acad Sci USA. 2001;98:7970–7975.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Fedele M, Battista S, Kenyon L, et al. Overexpression of the HMGA2 gene in transgenic mice leads to the onset of pituitary adenomas. Oncogene. 2002;21:3190–3198.

    Article  CAS  PubMed  Google Scholar 

  25. Scala S, Portella G, Fedele M, Chiappetta G, Fusco A . Adenovirus-mediated suppression of HMGI(Y) protein synthesis as potential therapy of human malignant neoplasias. Proc Natl Acad Sci USA. 2000;97:4256–4261.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Milner AE, Levens JM, Gregory CD . Flow cytometric methods of analyzing apoptotic cells. Methods Mol Biol. 1998;80:347–354.

    Article  CAS  PubMed  Google Scholar 

  27. Pellegata NS, Sessa F, Renault B, et al. K-ras and p53 gene mutations in pancreatic cancer: ductal and nonductal tumors progress through different genetic lesions. Cancer Res. 1994;54:1556–1560.

    CAS  PubMed  Google Scholar 

  28. Redston MS, Caldas C, Seymour AB, et al. p53 mutations in pancreatic carcinoma and evidence of common involvement of homocopolymer tracts in DNA microdeletions. Cancer Res. 1994;54:3025–3033.

    CAS  PubMed  Google Scholar 

  29. Rosenberg L . Pancreatic cancer: a review of emerging therapies. Drugs. 2000;59:1071–1089.

    Article  CAS  PubMed  Google Scholar 

  30. Schwarte-Waldhoff I, Volpert OV, Bouck NP, et al. Smad4/DPC4-mediated tumor suppression through suppression of angiogenesis. Proc Natl Acad Sci USA. 2000;97:9624–9629.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Jaffee EM, Hruban RH, Canto M, Kern SE . Focus on pancreas cancer. Cancer Cell. 2002;2:25–28.

    Article  CAS  PubMed  Google Scholar 

  32. Hao D, Rowinsky EK . Inhibiting signal transduction: recent advances in the development of receptor tyrosine kinase and Ras inhibitors. Cancer Invest. 2002;20:387–404.

    Article  CAS  PubMed  Google Scholar 

  33. Bouvet M, Bold RJ, Lee J, et al. Adenovirus-mediated wild-type p53 tumor suppressor gene therapy induces apoptosis and suppresses growth of human pancreatic cancer. Ann Surg Oncol. 1998;5:681–688.

    Article  CAS  PubMed  Google Scholar 

  34. Ghaneh P, Greenhalf W, Humphreys M, et al. Adenovirus-mediated transfer of p53 and p16(INK4a) results in pancreatic cancer regression in vitro and in vivo. Gene Therapy. 2001;8:199–208.

    Article  CAS  PubMed  Google Scholar 

  35. Joshi US, Dergham ST, Chen YQ, et al. Inhibition of pancreatic tumor cell growth in culture by p21WAF1 recombinant adenovirus. Pancreas. 1998;16:107–113.

    Article  CAS  PubMed  Google Scholar 

  36. Dumon KR, Ishii H, Vecchione A, et al. Fragile histidine triad expression delays tumor development and induces apoptosis in human pancreatic cancer. Cancer Res. 2001;15:4827–4836.

    Google Scholar 

  37. Takeuchi M, Shichinohe T, Senmaru N, et al. The dominant negative H-ras mutant, N116Y, suppresses growth of metastatic human pancreatic cancer cells in the liver of nude mice. Gene Therapy. 2000;7:518–526.

    Article  CAS  PubMed  Google Scholar 

  38. Bardeesy N, DePinho RA . Pancreatic cancer biology and genetics. Nat Rev Cancer. 2002;2:897–909.

    Article  CAS  PubMed  Google Scholar 

  39. Laheru D, Biedrzycki B, Jaffee EM . Immunologic approaches to the management of pancreatic cancer. Cancer J. 2001;7:324–337.

    CAS  PubMed  Google Scholar 

  40. Mulvihill S, Warren R, Venook A, et al. Safety and feasibility of injection with an E1B-55 kDa gene-deleted, replication-selective adenovirus (ONYX-015) into primary carcinomas of the pancreas: a phase I trial. Gene Therapy. 2001;8:308–315.

    Article  CAS  PubMed  Google Scholar 

  41. Rodicker F, Stiewe T, Zimmermann S, Putzer BM . Therapeutic efficacy of E2F1 in pancreatic cancer correlates with TP73 induction. Cancer Res. 2001;61:7052–7055.

    CAS  PubMed  Google Scholar 

  42. Stark GR, Kerr IM, Williams BR, Silverman RH, Schreiber RD . How cells respond to interferons. Annu Rev Biochem. 1998;67:227–264.

    Article  CAS  PubMed  Google Scholar 

  43. Elbashir SM, Harborth J, Lendeckel W, et al. Duplexes of 21-nucleotide RNAs mediate RNA interference in mammalian cell culture. Nature. 2001;411:494–498.

    Article  CAS  PubMed  Google Scholar 

  44. Caplen NJ, Parrish S, Imani F, Fire A, Morgan RA . Specific inhibition of gene expression by small double-stranded RNAs in invertebrate and vertebrate systems. Proc Natl Acad Sci USA. 2001;98:9742–9747.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Bitko V, Barik S . Phenotypic silencing of cytoplasmic genes using sequence-specific double-stranded short interfering RNA and its application in the reverse genetics of wild type negative-strand RNA viruses. BMC Microbiol. 2001;1:34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This study was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC), by the Programma Italia-USA sulla Terapia dei Tumori coordinated by Professor Cesare Peschle, Progetto Finalizzato “Biotecnologie” of Consiglio Nazionale delle Ricerche, Progetto “5%” of the Consiglio Nazionale delle Ricerche, and the MURST Project “Terapie antineoplastiche innovative”. We are indebted to Jean Gilder for editing the text and we are also grateful to David Fineman for his friendly support to our group.

Author information

Authors and Affiliations

  1. Dipartimento di Biologia e Patologia Cellulare e Molecolare, c/o Centro di Endocrinologia ed Oncologia Sperimentale del CNR, Università di Napoli “Federico II”, Naples, Italy

    Francesco Trapasso, Francesca Pentimalli, Giuseppe Viglietto & Alfredo Fusco

  2. Kimmel Cancer Center, Jefferson Medical College, Philadelphia, Pennsylvania, USA

    Francesco Trapasso, Manuela Sarti, Rossano Cesari, Sai Yendamuri, Kristoffel R Dumon, Rami I Aqeilan, Luisa Infante, Hansjuerg Alder & Carlo M Croce

  3. First Department of Surgery, Department of Clinical Pathology, Kyorin University School of Medicine, Mitaka City, Tokyo, Japan

    Nobutsugu Abe & Takashi Watanabe

Authors
  1. Francesco Trapasso
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Manuela Sarti
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rossano Cesari
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sai Yendamuri
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kristoffel R Dumon
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rami I Aqeilan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Francesca Pentimalli
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Luisa Infante
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hansjuerg Alder
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Nobutsugu Abe
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Takashi Watanabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Giuseppe Viglietto
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Carlo M Croce
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Alfredo Fusco
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alfredo Fusco.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Trapasso, F., Sarti, M., Cesari, R. et al. Therapy of human pancreatic carcinoma based on suppression of HMGA1 protein synthesis in preclinical models. Cancer Gene Ther 11, 633–641 (2004). https://doi.org/10.1038/sj.cgt.7700745

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.cgt.7700745

Keywords

This article is cited by

Search

Advanced search

Quick links