1621 Aberrant activation of Wingless-type (Wnt) signaling pathway plays a critical role in oncogenesis of various human cancers. Wnt inhibitory factor-1 (WIF-1) is a secreted antagonist of Wnt signaling and acts through direct binding to Wnt in the extracelllular space. Recently, we had reported the pivotal role of Wnt signaling in non-small cell lung cancer, mesothelioma, colorectal cancer, melanoma, and leukemia. Besides, we revealed WIF-1 silencing due to promoter hypermethylation in lung cancers. However, little is known regarding the Wnt signaling and WIF-1 expression in nasopharyngeal carcinoma (NPC). In this study, we found constitutive activation of Wnt signaling and WIF-1 silencing in three NPC cell lines. Furthermore, by utilizing methylation-specific PCR and sequence analysis, we demonstrated frequent hypermethylation of WIF-1 promoter correlates with WIF-1 silencing in NPC cell lines. Our results indicate aberrant Wnt signaling linked with WIF-1 silencing is, at least in cell lines, a common event in NPC carcinogenesis. Strategies targeting these molecules should be potentially promising in treating NPC.

Restricted accessAbstractFirst published January 2006Hypermethylation Silences Wnt Inhibitory Factor 1 in Nasopharyngeal CarcinomaE.G. Thung, J. Chou, […], L. You, Z. Xu, and D.M. Jablons+2-2View all authors and affiliationsVolume 54, Issue 1_supplhttps://doi.org/10.1177/108155890605401S28

Nasopharyngeal carcinoma (NPC) is an epithelial tumor that is endemic to southern China. Although much is known about its pathology and its association with Epstein-Barr virus infection, the molecular events that lead to the formation of the tumor are not clearly understood. Recently, it was discovered that the up-regulation of the wingless-type (Wnt) signaling pathway may contribute to the pathogenesis of NPC. Wnt inhibitory factor-1 (WIF-1) is an antagonist of Wnt; studies have shown that WIF-1 down-regulation and the subsequent up-regulation of Wnt signaling are found in several human cancers. In order to determine if the down-regulation of WIF-1 plays a role in NPC, the expression of human WIF-1 in NPC cells was first assessed using reverse transcription-PCR. The NPC cell lines used were CNE, HNE-1, and HONE-1. The methylation status of WIF-1 was then determined by sequencing and by using methylation-specific PCR on bisulfite-treated NPC DNA. We find that WIF-1 is not expressed in NPC cells and that CpG island hypermethylation is seen in the promoter region of WIF-1, suggesting that hypermethylation silences WIF-1 expression. These results indicate that the up-regulation of the Wnt pathway due to the methylation silencing of WIF-1 is part of the mechanism that leads to tumor formation in NPC. Discovering ways to either inhibit the Wnt pathway or remove the hypermethylation of WIF-1 can thus be potentially used to therapeutically treat NPC in patients.

Aberrant activation of Wingless-type (Wnt) signaling pathway plays a critical role in oncogenesis of various human cancers. Wnt inhibitory factor-1 (WIF-1) is a secreted antagonist of Wnt signaling and acts through direct binding to Wnt in the extracellular space. Recently, we reported Wnt signaling in various human malignancies. In addition, we identified in lung cancer that WIF-1 is silenced due to promoter hypermethylation. In this study, we found constitutive activation of Wnt signaling and WIF-1 silencing in nasopharyngeal carcinoma (NPC) cell lines. Furthermore, by utilizing methylation-specific PCR and sequence analysis, we demonstrated that frequent hypermethylation of the WIF-1 promoter correlates with WIF-1 silencing in NPC cell lines. Our results indicate that aberrant Wnt signaling is a common event in NPC carcinogenesis linked with WIF-1 silencing in at least cell lines. Strategies targeting these molecules should be potentially promising in treating NPC.

The phenome represents the observable properties of an organism that have developed under the continued influences of both genome and environmental factors. Phenotypic properties are expressed through the functions of cells, organs and body systems that operate optimally, close to equilibrium. In complex organisms, maintenance of the equilibrium is achieved by the interplay of several regulatory mechanisms. In the elderly, dynamic instability may lead to progressive loss of normal function, failure of adaptation and increased pathology. Extensive research (reported elsewhere in this journal) has demonstrated that genetic manipulations of endocrine signaling in flies, worms and mice increase longevity. Another effective strategy for prolonging the lifespan is caloric restriction: in data presented here, the persistence of estrogen-sensitive cells in the hypothalamus of caloric restricted 22-month-old female mice, may explain the persistence of reproductive function at an age, when reproductive function has long ceased in ad libitum fed controls. Still another strategy utilizes the effects of epidermal growth factor (EGF) to promote in vitro proliferation of neuroglia, astrocytes and oligodendrocytes. Their subsequent de-differentiation generates immature precursor cells potentially capable of differentiating into neuroblasts and neurons. These and other examples suggest that, in terms of functional outcomes, "the genome proposes but the phenome disposes".