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

Oncogene volume 27, pages 7192–7200 (2008)Cite this article

A Correction to this article was published on 30 April 2020

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.

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Abbreviations

CRC:

colorectal carcinoma

Id2:

inhibitor of DNA-bind-2

Rb:

Retinoblastoma protein

shRNA:

short hairpin RNA

siRNA:

small interfering RNA

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Acknowledgements

We thank Rita Hernandez (Department of Surgical Oncology) and Christine Wogan (Department of Scientific Publications) for manuscript editing and preparation. Supported by NIH-5 T32 CA09599 (GVB, NAD, ADY and PG), Program Project Development Grant from the Ovarian Cancer Research Fund, Inc. (AKS), the Zarrow Foundation (AKS) and William C Liedtke, Jr Chair in Cancer Research (LME).

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Authors and Affiliations

  1. Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    M J Gray, N A Dallas, G Van Buren, A D Yang, P Gaur & L M Ellis

  2. Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    L Xia, R J Somcio, F Fan, G E Gallick, A K Sood & L M Ellis

  3. Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    L S Mangala & A K Sood

  4. Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    P E Vivas-Mejia, A M Sanguino & G Lopez-Berestein

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  1. M J Gray
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  3. G Van Buren
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  4. L Xia
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  15. L M Ellis
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Correspondence to M J Gray or L M Ellis.

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Gray, M., Dallas, N., Van Buren, G. et al. Therapeutic targeting of Id2 reduces growth of human colorectal carcinoma in the murine liver. Oncogene 27, 7192–7200 (2008). https://doi.org/10.1038/onc.2008.356

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  • DOI: https://doi.org/10.1038/onc.2008.356

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