Therapeutic targeting of Id2 reduces growth of human colorectal carcinoma in the murine liver

M. J. Gray, N. A. Dallas, G. Van Buren, L. Xia, A. D. Yang, R. J. Somcio, P. Gaur, L. S. Mangala, P. E. Vivas-Mejia, F. Fan, A. M. Sanguino, G. E. Gallick, G. Lopez-Berestein, A. K. Sood, L. M. Ellis

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

During development inhibitor of DNA-bind-2 (Id2) regulates proliferation and differentiation. Id2 expression has been detected in cancer cells, yet its cellular function and validity as a therapeutic target remains largely unknown. Immunohistochemical analysis of colorectal cancer (CRC) specimens revealed that Id2 was undetectable in normal colonic mucosa, but occurs in 40% of primary tumors and in most CRC liver metastases (P<0.0001). Additionally, Id2 was expressed in all CRC cell lines assayed. CRC cells with reduced Id2 expression demonstrated reduced proliferation. Analysis of CRC cell cycle regulatory proteins showed that reducing Id2 levels reduces cyclin D1 levels and increased p21 levels. Reduction of Id2 expression also enhanced tumor cell apoptosis, increasing levels of the pro-apoptotic protein Bim/Bod, and cleavage of caspase-7 and poly (ADP-ribose) polymerase. In vivo studies show tumors derived from cells with decreased Id2 levels formed smaller tumors with fewer metastases compared with tumors with normal levels (P<0.05). Furthermore, intraperitoneal administration of Id2 small interfering RNA (siRNA) conjugated with the neutral liposome 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine decreased tumor burden in mice compared with control treatment (P=0.006). We conclude that Id2 is upregulated in CRC, and is important in promoting cell survival. In vivo targeting of Id2 by siRNA establishes that it is a valid therapeutic target where its expression occurs.

Original languageEnglish (US)
Pages (from-to)7192-7200
Number of pages9
JournalOncogene
Volume27
Issue number57
DOIs
StatePublished - Dec 4 2008
Externally publishedYes

Fingerprint

Colorectal Neoplasms
Liver
DNA
Growth
Therapeutics
Neoplasms
Small Interfering RNA
Neoplasm Metastasis
Caspase 7
Cell Cycle Proteins
Apoptosis Regulatory Proteins
Poly(ADP-ribose) Polymerases
Cyclin D1
Liver Neoplasms
Tumor Burden
Phosphatidylcholines
Liposomes
Cell Survival
Mucous Membrane
Apoptosis

Keywords

  • Colorectal carcinoma
  • Id2
  • Inhibitor of DNA-binding
  • Metastasis, siRNA

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Gray, M. J., Dallas, N. A., Van Buren, G., Xia, L., Yang, A. D., Somcio, R. J., ... Ellis, L. M. (2008). Therapeutic targeting of Id2 reduces growth of human colorectal carcinoma in the murine liver. Oncogene, 27(57), 7192-7200. https://doi.org/10.1038/onc.2008.356

Therapeutic targeting of Id2 reduces growth of human colorectal carcinoma in the murine liver. / Gray, M. J.; Dallas, N. A.; Van Buren, G.; Xia, L.; Yang, A. D.; Somcio, R. J.; Gaur, P.; Mangala, L. S.; Vivas-Mejia, P. E.; Fan, F.; Sanguino, A. M.; Gallick, G. E.; Lopez-Berestein, G.; Sood, A. K.; Ellis, L. M.

In: Oncogene, Vol. 27, No. 57, 04.12.2008, p. 7192-7200.

Research output: Contribution to journalArticle

Gray, MJ, Dallas, NA, Van Buren, G, Xia, L, Yang, AD, Somcio, RJ, Gaur, P, Mangala, LS, Vivas-Mejia, PE, Fan, F, Sanguino, AM, Gallick, GE, Lopez-Berestein, G, Sood, AK & Ellis, LM 2008, 'Therapeutic targeting of Id2 reduces growth of human colorectal carcinoma in the murine liver', Oncogene, vol. 27, no. 57, pp. 7192-7200. https://doi.org/10.1038/onc.2008.356
Gray MJ, Dallas NA, Van Buren G, Xia L, Yang AD, Somcio RJ et al. Therapeutic targeting of Id2 reduces growth of human colorectal carcinoma in the murine liver. Oncogene. 2008 Dec 4;27(57):7192-7200. https://doi.org/10.1038/onc.2008.356
Gray, M. J. ; Dallas, N. A. ; Van Buren, G. ; Xia, L. ; Yang, A. D. ; Somcio, R. J. ; Gaur, P. ; Mangala, L. S. ; Vivas-Mejia, P. E. ; Fan, F. ; Sanguino, A. M. ; Gallick, G. E. ; Lopez-Berestein, G. ; Sood, A. K. ; Ellis, L. M. / Therapeutic targeting of Id2 reduces growth of human colorectal carcinoma in the murine liver. In: Oncogene. 2008 ; Vol. 27, No. 57. pp. 7192-7200.
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