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

Imagen de Pablo Vivas-Mejia
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TítuloTherapeutic targeting of Id2 reduces growth of human colorectal carcinoma in the murine liver.
Publication TypeJournal Article
Year of Publication2008
AutoresGray, MJ, Dallas, NA, Van Buren, G, Xia, L, Yang, AD, Somcio, RJ, Gaur, P, Mangala, LS, Vivas-Mejia, P, Fan, F, Sanguino, AM, Gallick, GE, Lopez-Berestein, G, Sood, AK, Ellis, LM
JournalOncogene
Volume27
Issue57
Pagination7192-200
Date Published2008 Dec 4
ISSN1476-5594
Palabras claveAdenocarcinoma, Animals, Apoptosis, Autoradiography, Blotting, Western, Cell Line, Tumor, Cell Proliferation, Colorectal Neoplasms, Flow Cytometry, Humans, Immunohistochemistry, Immunoprecipitation, Inhibitor of Differentiation Protein 2, Liver Neoplasms, Mice, RNA, Small Interfering, Signal Transduction, Up-Regulation, Xenograft Model Antitumor Assays
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.

DOI10.1038/onc.2008.356
Alternate JournalOncogene
PubMed ID18806828
PubMed Central IDPMC3199128
Grant List5T32 CA09599 / CA / NCI NIH HHS / United States