C-kit is a trans-membrane receptor tyrosine kinase (RTK) encoded by the proto-oncogene KIT located at 4q11-12. Gain-of-function mutations arising to c-kit activation independent of its ligand were observed in various tumors related to germ cells, mast cells, and interstitial cells of Cajal. C-kit also participates in melanocyte development; hence, its involvement in oral mucosal melanoma (OMM) tumorigenesis was investigated. Immunohistochemistry and mutation analysis were performed using 18 cases of human primary OMM. Results revealed 16 cases positive to c-kit protein. Atypical melanocytes expressed c-kit. All in situ components expressed c-kit, but only four cases exhibited intense expression in the invasive component. Missense mutations were observed in four cases, and two of those correlated with increased protein expression. C-kit expression in atypical melanocytes suggests the role of c-kit in the early stage of OMM tumorigenesis. C-kit protein expression correlated with activating mutations indicating the pertinent role of the proto-oncogene KIT in the tumorigenesis of OMM.

The discovery of ING1 gene paved the way to the identification of other ING members (ING2-5) and their isoforms associated with cell cycle, apoptosis and senescence. The ING family has been an emerging putative tumor suppressor gene (TSG) in which the major mechanism is through interaction with the determinants of chromatin function and gene-specific transcription factors. The regulatory mechanism highly involves the conserved plant homeodomain (PHD), which binds to histones in a methylation-sensitive manner, suggesting that ING proteins may contribute to the maintenance of the epigenetic code. Furthermore, ING family members contain nuclear localization signals and N-terminal sequences important in the interaction with histone acetyltransferase (HAT) and histone deacetyltransferase (HDAC) that regulate gene promoter activity within chromatin. Although ING proteins have the same PHD motif, the variation in the N-terminal dictates the differences in tumor the suppressive ability of ING in various tumors. Inactivation of the normal function is achieved through allelic loss of genomic regions containing the ING gene, alteration in the ING promoter region, variation of mRNA splicing efficacy or reduced mRNA stability. It is most probably the apparent combination of these aberrant mechanisms that resulted in reduced availability of functional ING protein. In cancer cells, ING transcript levels are often suppressed but the genes are rarely mutated. The mechanism of suppression of ING expression may have to do with the abnormally high methylation levels of the ING gene promoter, which have been correlated with low transcript levels. Emerging evidence on the function of ING and related regulatory mechanisms strongly points to ING as a candidate TSG and therefore a potential target in the molecular therapy of some types of tumor.

No abstract

The use of recombinant human bone morphogenetic protein-2 (rhBMP-2) to induce ectopic bone formation requires a carrier. Type I atelocollagen, a biomaterial with a porous structure, excellent operational features, and biocompatibility, is an effective carrier for rhBMP-2. However, the conventionally used lyophilized rhBMP-2/collagen mixture does not necessarily give adequate bone-induction effect. In the present study, we examined the effect of immobilizing rhBMP-2 to type I atelocollagen on the cellular activity of ST2 cells. The following results were obtained: (1) rhBMP-2 was effectively immobilized to succinylated type I atelocollagen, indicating the usefulness of succinylated type I atelocollagen in immobilization; (2) studies of alkaline phosphatase activity confirmed the effectiveness of rhBMP-2 immobilized on succinylated atelocollagen in augmenting cellular activity.

Oral mucosal melanoma is an aggressive neoplasm with poor prognosis. Heparanase is an endo-ß-dglucuronidase, which cleaves heparan sulphate chains. The vascular endothelial growth factor (VEGF) is the most potent angiogenic mitogen and interaction with its receptor (VEGFR) has been associated with angiogenesis. We investigated the expression of these molecules in the progression of oral mucosal melanoma. Immunohistochemistry was carried out in 15 oral melanotic macules and 19 oral melanomas using heparanase, VEGF, VEGFR-2, CD34 and Ki-67. Microvessel density was determined and subjected to statistical analysis. Heparanase and VEGFR-2 were not expressed in the oral melanotic macule. Atypical melanocytes and melanoma cells expressed heparanase, VEGF and VEGFR-2. An intense expression was noted in the early invasive phase, which marks the crucial transition from in situ to the invasive phase. In the invasive component, heparanase was intense but selective in the invasive fronts and at the periphery of nests unlike the extensive expression of VEGF and VEGFR-2. However, hot spots were only observed at the periphery of the nests. In conclusion, melanoma cells expressed heparanase, VEGF and VEGFR-2. The coexpression of these molecules in atypical melanocytes and melanoma cells suggests their function in cell migration and invasion. Moreover, the intense expression in the crucial transition from in situ to the invasive phase suggests their role in the progression of the tumor. The role of VEGF and VEGFR-2 in angiogenesis was evident only at the periphery of the nests in the invasive components.

The results suggest that the distal part of chromosome 14 may host a TSG that may lead to the development and/or progression of HNSCCs. Several genes such as CHES1, BMP4, SAV, and PNN have arisen as candidate tumor suppressors in the region.

The results implied that heparanase expression may be correlated with the neoplastic properties of KCOT, particularly in NBCCS-associated cases.

Present findings suggest that Notch signaling molecules may play differing roles in the acquisition of different ameloblastoma phenotypes.