This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Li, X. Articles by Schirmacher, P. Search for Related Content PubMed PubMed Citation Articles by Li, X. Articles by Schirmacher, P.

Disrupted IGF2 Promoter Control by Silencing of Promoter P1 in Human Hepatocellular Carcinoma¹

Laboratory for Molecular Development and Tumor Biology, Experimental Alcohol and Drug Addiction Research Section, Department of Clinical Neuroscience, Karolinska Hospital, L8, S-171 76, Stockholm, Sweden [X. L., C. E., T. J. E.]; Institute of Pathology, University Hospital, Langenbeckstrasse 1, D-55101 Mainz Germany [Z. N., M. O., H. P. D., P. S.]; Department of Pathology, Uppsala University Hospital, S-751 85 Uppsala, Sweden [E. L., H. N.]; Pathologisches Institut der Universität, Im Neuheimer Feld 220, D-69120 Heidelberg, Germany [W. J. H.]; and Abteilung Gastroenterologie und Hepatologie, Medizinische Hochschule Hannover, Konstanty-Gutschow Strasse 8, D-30625 Hannover, Germany [C. T.]

Previous investigations have supported or indicated a stimulatory role of the insulin-like growth factor II gene (IGF2) in hepatocarcinogenesis. We have studied the transcript levels, promoter usage, and imprinting status of the IGF2 gene and its relationship to H19 in human hepatocellular carcinomas (HCCs) and liver tumor cell lines. The activity of the IGF2 promoter P1 was lost in about 70% of the cases (18 of 25). This is the most prominent abnormality regarding the IGF2 regulation in this study. Total IGF2 as well as promoter P3 transcription were up-regulated in a small group of the tumors. Twenty genetically informative cases were obtained from 26 cases, thus excluding the probability of loss of heterozygosity of the IGF2 gene. Among these, nine showed abnormal monoallelic expression of IGF2. One HCC and one HCC cell line proved loss of functional imprinting of IGF2. H19 and IGF2 were regulated in parallel, and expression levels were variable. Taken together, the disruption of the IGF2 promoter regulation, particularly the loss of P1 activity, is a common feature of human HCCs. The loss of P1 activity explains the frequent loss of biallelic IGF2 expression and may potentially be used as a diagnostic or monitoring marker for human HCC.

¹ This work was supported by grants from the Swedish Cancer Foundation, the Children's Cancer Foundation of Sweden, and the Swedish Natural Science Research Council (to T. J. E.). Part of the study has been supported by Grant A1 of the Sonderforschungsbereich 519 (to P. S.) and by a grant from the Stiftung Rheinland-Pfalz für Innovation (to H. P. D. and P. S.). Z. N. was a fellow of the DAAD.

² To whom requests for reprints should be addressed. E-mail: Tomas.Ekstrom@cmm.ki.se.

Received 10/30/96. Accepted 3/21/97.

This article has been cited by other articles:

				S. H. Tang, D. H. Yang, W. Huang, H. K. Zhou, X. H. Lu, and G. Ye Hypomethylated P4 Promoter Induces Expression of the Insulin-Like Growth Factor-II Gene in Hepatocellular Carcinoma in a Chinese Population. Clin. Cancer Res., July 15, 2006; 12(14): 4171 - 4177. [Abstract] [Full Text] [PDF]

				K. Breuhahn, S. Vreden, R. Haddad, S. Beckebaum, D. Stippel, P. Flemming, T. Nussbaum, W. H. Caselmann, B. B. Haab, and P. Schirmacher Molecular Profiling of Human Hepatocellular Carcinoma Defines Mutually Exclusive Interferon Regulation and Insulin-Like Growth Factor II Overexpression Cancer Res., September 1, 2004; 64(17): 6058 - 6064. [Abstract] [Full Text] [PDF]

				J-G Scharf, F Dombrowski, and G Ramadori The IGF axis and hepatocarcinogenesis Mol. Pathol., June 1, 2001; 54(3): 138 - 144. [Abstract] [Full Text]

				H. Yu and T. Rohan Role of the Insulin-Like Growth Factor Family in Cancer Development and Progression J Natl Cancer Inst, September 20, 2000; 92(18): 1472 - 1489. [Abstract] [Full Text] [PDF]

				J. Paquette, N. Giannoukakis, C. Polychronakos, P. Vafiadis, and C. Deal The INS 5' Variable Number of Tandem Repeats Is Associated with IGF2 Expression in Humans J. Biol. Chem., June 5, 1998; 273(23): 14158 - 14164. [Abstract] [Full Text] [PDF]