Variability in the expression of polycomb proteins in different normal and tumoral tissues. A pilot study using tissue microarrays

Abstract

In spite of the known function of polycomb group (PcG) genes in stem cell self-renewal, control of cellular proliferation and differentiation, its role in cancer pathogenesis is still poorly understood. We studied the expression by immunohistochemistry of several PcG-maintenance complex proteins (RING1, RNF2, BMI1, MEL18, HPH1 and RYBP) in nontumoral (154 samples) and tumoral (550 samples) human tissues using Tissue Microarrays. For selected genes (BMI1 and RING1) FISH analysis has been also carried out. PcG proteins had a tissue-and cell-type-specific expression pattern. Some of them were highly selectively expressed, such as HPH1, which was detected in germ cells in testis, pituitary and parathyroid glands and Langerhans islets, and RYBP, which was found in placenta, umbilical cord and thyroid gland. By contrast, RING1 was ubiquitously expressed in every normal tissue analyzed. Changes in expression associated with tumoral transformation have been found for BMI1 and RNF2, which exhibited increased expression in a large series of tumors, including gastrointestinal tumors, pituitary and parathyroid adenomas, and lymphomas, compared with their expression in normal-cell counterparts. The high level of expression of BMI1 protein observed in mantle-cell lymphomas and pituitary adenomas is associated in some cases with amplification of BMI1 locus. These findings imply that upregulation of BMI1 may constitute a malignancy marker in different types of cancer, mainly in lymphoid and endocrine tumors. RING1 was lost in a group of renal-cell carcinomas and testicular germ-cell tumors. Lastly, RYBP is anomalously expressed in Hodgkin's lymphomas and oligodendrogliomas, among others tumors. A significant finding of the study is the identification of unique PcG profiles for some tumors, such as testicular germ-cell tumors, which have high levels of HPH1 expression and loss of RING1 and/ or BMI1; pituitary adenomas, which expressed every PcG protein analyzed; and clear-cell renal-cell carcinoma, which was the only tumor other than testicular germ-cell tumors that did not express RING1.

RNF2/Ring1b negatively regulates p53 expression in selective cancer cell types to promote tumor development

“…The significance of the degradation of mutant p53 through Rnf2 remains unknown. Previous studies have shown that the increased expression of Bmi1 and Rnf2 are associated with tumor cell transformation in a number of tumors (27,40). Our results indicate that Rnf2 is required for tumor progression in a p53-dependent manner.…”

“…Previous studies have indicated that Rnf2 expression is increased in a large variety of tumors (27). As a first step to characterize the molecular mechanisms of Rnf2 in tumor formation, we attempted to identify the binding partners of this protein.…”

“…Rnf2 shows increased expression in a high percentage of various tumors compared with normal tissue counterparts (27). Because we identified Rnf2 as a direct negative regulator of p53, we postulated that Rnf2 might act as an oncoprotein in specific tissue types to antagonize p53 functions and to promote tumor formation.…”

“…Protein structure analysis revealed that within the PRC1 complex, Bmi1 and RNF2 heterodimerize via their N-terminal RING domains to form an active E3 ubiquitin ligase (24)(25)(26). The overexpression of Rnf2 has also been documented in clinical gastrointestinal tumors and lymphomas (27). Despite these findings, the mechanisms of Rnf2 in tumor formation remain poorly understood.…”

Classical Hodgkin's lymphoma shows epigenetic features of abortive plasma cell differentiation

“…Strikingly, several of these genes, such as ATF3, JUN, IRF4, ID2, FSCN1, CCR7 and RYBP have already been recognized by previous completely independent studies and modifications of these genes are suggested to play a role in the pathogenesis of cHL. 20,[42][43][44][45] Our special attention was attracted by the Ring1 and YY1 binding protein (RYBP) due to its importance as an interacting partner for the Polycomb group protein Ring1A. 46 Polycomb group (PcG) proteins act as transcriptional repressors by means of histone modification and are involved in the regulation of organogenesis and cell lineage fidelity.…”