Imprinted genes in liver carcinogenesis

Abstract

Each cell contains both maternal and paternal copies of all genes except those that reside on the sex chromosomes. However, because of a phenomenon termed genomic imprinting, not all genes are biallelically expressed. Imprinted genes play an important role in embryogenesis and re‐cently have also been shown to be mechanistically involved in carcinogenesis. The growing list of im‐printed genes implicated in tumor formation in‐cludes both a growth factor gene, insulin‐like growth factor 2 (IGF2), and a receptor gene, mannose 6‐ phosphate/insulin‐like growth factor 2 receptor (M6P/IGF2R). Elevated expression of IGF2 is often found in tumors, and loss of imprinting is one mechanism by which its expression is deregulated. The M6P/IGF2R functions in the inactivation of the mitogen IGF2 and in the activation of the growth inhibitor, transforming growth factor beta. Recently, a high frequency of loss of heterozygosity with concomitant mutations in the remaining allele has been shown to occur at the M6P/IGF2R locus (i.e., 6q26‐q27) in both human liver and breast tumors, suggesting that this gene functions as a tumor suppressor. Expression of the M6P/IGF2R gene is biallelic in most humans but is monoallelic in mice. This species difference in M6P/IGF2R gene imprinting provides one plausible explanation for the enhanced sensitivity of mice to tumor formation. Furthermore, these findings suggest that species differences in the imprinted status of genes mechanistically involved in tumor formation should be factored into human carcinogenesis risk assessment models when extrapolating results from mice to humans.—De Souza, A. T., Yamada, T., Mills, J. J., Jirtle, R. L. Imprinted genes in liver carcinogenesis. FASEB J. 11, 60‐67 (1997)

Loss of the gene encoding mannose 6-phosphate/insulin-like growth factor II receptor is an early event in liver carcinogenesis

“…These results may also have an impact on human carcinogen risk assessment based upon rodent studies, because M6P͞IGF2R is genomically imprinted in mice (i.e., monoallelic expression) but not in most humans (i.e., biallelic expression) (for review see ref. 32). Inactivation of M6P͞IGF2R would require two genetic events in humans but only one in mice.…”

Loss of heterozygosity of M6P/IGF2R gene is an early event in the development of prostate cancer

“…[2][3][4] It is inactivated early in the development of a number of cancers, including those in the liver, breast and lung. [3][4][5][6][7][8] M6P/IGF2R mutation furthermore predicts for poor therapeutic outcome. 9 Thus, the M6P/IGF2R gene encodes for a receptor that functions normally to suppress tumor formation.…”

“…The M6P/IGF2R gene is located at 6q26, a chromosomal location commonly deleted in cancer. 3,[5][6][7][8] It encodes for a multifunctional receptor required for the intracellular trafficking of lysosomal enzymes to the lysosomes, and the extracellular activation of the growth inhibitor, transforming growth factor b1 (TGFb1), and the degradation of the mitogen, IGF2. 2,10 Evidence suggests, however, that the M6P/IGF2R is not involved in cell signaling by IGF2.…”

Analysis of the IGF Axis in Preneoplastic Hepatic Foci and Hepatocellular Neoplasms Developing after Low-Number Pancreatic Islet Transplantation into the Livers of Streptozotocin Diabetic Rats

“…During this process, a crucial role has been attributed to the IGF-I receptor (IGF-IR); IGF-IR has been shown to mediate mitogenic signals, to be protective from a variety of apoptotic injuries, and to be necessary for the transformation of certain types of cells (Baserga, 1999;LeRoith et al, 1995b). The IGF-II/mannose 6-phosphate receptor (IGF-II/M6PR), however, is thought to be a tumor suppressor gene (De Souza et al, 1997), because it is involved in transport of lysosomal enzymes; in binding, internalization, and degradation of IGF-II; and in activation of the mito-inhibitory transforming growth factor-␤ (TGF-␤) (Braulke, 1999).…”