The statuses of some molecules are useful to predict DFS in patients with SDC. Ki-67 overexpression suggests that cytotoxic agents are effective for SDC. Since the majority of SDCs express AR, HER2, and/or EGFR, assessing and targeting these molecules are promising strategies to improve the prognosis of unresectable, metastatic or recurrent SDC, and a classification system according to the molecular expression status may be useful to select appropriate therapy.

Purpose: Promoter hypermethylation is one of the major mechanisms in the transcriptional inactivation of certain carcinoma-associated genes. Concurrent methylation analysis of multiple, functionally distinct genes may provide important information on their differential alterations and potential association in head and neck squamous carcinogenesis.Experimental Design: Methylation-specific PCR analysis of the CpG islands of 8 cancer-related genes was performed on 19 cell lines and 32 primary head and neck squamous cell carcinoma (HNSC) specimens with matched histologically normal mucosa and 6 dysplastic lesions. The methylation status and histological features of the specimens were investigated.Results: In histologically normal squamous mucosa, no to low-level methylation (0 -22%) was noted in some specimens at all genes except RAR␤2 (50%). Considerable variation in the incidence of methylation of these genes within and between cell lines and tumor specimens was noted. The highest incidences of methylation in the cell lines and primary tumors were noted in RAR␤2 (53%), MGMT (37%), p16 (33%), and DAP-K (25%); low incidence of methylations were noted in E-cadherin (2%), p73 (2%) RASSF1A (10%), and p14 (20%) genes. The incidences of methylation of each gene were almost similar between the HNSC cell lines and primary cancer specimens, although methylation of RASSF1A was observed in cell line (26%), but not in dysplasia and primary tumor. RAR␤, p16, and MGMT genes showed the highest incidences of methylation in premalignant and invasive carcinomas.Conclusions: Methylation of p16, RAR␤, and MGMT may constitute early events in HNSC tumorigenesis. The infrequent methylation at certain genes suggests a minimal role for this feature in their functional assessment in HNSC. The variability within and between cell lines and tumor specimens supports a heterogeneous and dynamic state of methylation in genes associated with HNSC tumorigenesis.

The 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors, also called statins, are commonly used as lipid-lowering drugs that inhibit cholesterol biosynthesis. An anticancer effect, as a pleiotropic function of certain statins, has been hypothesized. In the present study, we investigated the effect of simvastatin, one of the natural statins, on cell proliferation, cell cycle, invasive activity, and molecular expressions associated with cell-extracellular matrix adhesion, signal transduction, and DNA synthesis in Tu167 and JMAR cells from head and neck squamous cell carcinoma. The addition of simvastatin resulted in a dose-dependent inhibition of cell growth and migration into the extracellular matrix. Considerable morphological changes occurred after treatment with simvastatin, demonstrating loss of cell adhesion and disruption of actin filaments in cytoplasm. The inhibitory effect of simvastatin on cell proliferation seemed to be associated with cell cycle arrest and increased expression of p21, p27, and activated caspase-3. The expression of β β β β1-integrin, a counter adhesion for the extracellular matrix, phosphorylated FAK, and phosphorylated ERK was decreased by treatment with simvastatin. The proapoptotic effect of simvastatin was inhibited by treatment with mevalonate. cDNA microarray assay demonstrated that molecular changes resulting from treatment with simvastatin included the up-regulation of cell cycle regulators and apoptosisinducing factors and the down-regulation of integrin-associated molecules and cell proliferation markers. Of down-regulated genes induced by simvastatin treatment, a significant depletion of thymidylate synthase was confirmed using western blot analysis. These results imply that simvastatin has the potential to be effective for the prevention of the growth and metastasis of cancer cells. S imvastatin, one of the 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors, derived from fungal fermentation, is currently used widely as a safe and effective therapeutic agent in the treatment of hypercholesterolemia, contributing to the reduction in morbidity and mortality of atherosclerosis and coronary artery disease.(1) HMG-CoA reductase inhibitors are also commonly referred to as the statins. In addition to their original role in lowering serum cholesterol levels, statins exert antiproliferative and proapoptotic effects in cancer cells by causing cell cycle arrest at the G1-S phase.(2) An anticancer effect with in vitro simvastatin treatment has been reported in several human malignancies, including multiple myeloma, malignant lymphoma, small cell lung carcinoma, and nasopharyngeal undifferentiated carcinoma.(3-6) However, the efficacy and the molecular mechanism of simvastatin on tumor progression has yet to be clarified.Statins target mevalonate, one of the cholesterol precursors, which is catalyzed by HMG-CoA reductase. Overexpression of mevalonate has been reported to be associated with cell survival and proliferation of cancer cells.(7) Another mechanism that plays a ro...

Purpose: We investigated the methylation status and protein expression of four tumor suppressor genes to determine their role in salivary gland tumorigenesis. Experimental Design: We performed methylation-specific PCR and protein analyses of 29 normal salivary glands, 23 benign, and 79 malignant salivary gland neoplasms to determine the pattern and potential diagnostic and/or biological role of the RASSF1, RARb2, DAPK, and MGMT tumor suppressor gene methylation in these tumors. Results: No methylation was detected in the normal tissues. Methylation occurred in 9 of 23 (39.1%) benign tumors; 3 (25.0%) pleomorphic adenomas and 6 (66.7%) Warthin's tumors at the MGMT, DAPK , or RASSF1 genes. Methylation occurred in 33 of 79 (41.8%) malignant tumors; 8 (30.8 %) adenoid cystic carcinomas, 6 (33.3 %) mucoepidermoid carcinomas, 6 (42.9%) acinic cell carcinomas, and 13 (62.0 %) salivary duct carcinomas. RASSF1 and RARb2 represented 75.8% of methylation events occurring most frequently in salivary duct and acinic cell carcinomas. Overall, we found no significant correlation between protein expression and methylation status of individual genes, but observed low or absent protein expression in several methylated tumors. Significant correlations were found between methylation and aggressive malignant phenotypes (P = 0.0004) and age (P = 0.05). Conclusions: (a) Benign and malignant salivary tumors differed in the frequency and pattern of gene methylation; (b) high-grade carcinomas were significantly methylated compared with low-grade phenotypes; (c) RASSF1 and RARb2 were highly methylated in malignant tumors and can be targeted for therapy; and (d) methylation pattern may serve as a diagnostic and biological marker in assessing these tumors.Salivary gland neoplasms are composed of histopathologically and clinically diverse entities of disputed histogenesis and unpredictable behavior (1 -3). Efforts to identify biomarkers that assist in diagnosing these tumors and in explaining their evolution and progression have been unrewarding (4 -6). The underlying reasons for such slow progress in understanding these tumors include rarity, failure to grow cell lines, clinical and methodologic interstudy differences, and the lack of a phenotypic progression model of their evolution. However, recent molecular genetic studies have provided important information on common chromosomal loci and genes alterations in a spectrum of the tumors (7 -15). These data are critical in advancing our understanding of their biology and identifying new targets of potential therapeutic applications.Epigenetic alterations may also play a role in the development of these tumors. A particular advantage of these alterations is that, unlike genetic alterations, they are reversible and can be restored in vitro and in vivo by using demethylating agents in cell lines and tumors (16 -19). Methylation is one of the epigenetic modifications that play an important role in the transcriptional inactivation of tumor suppressor genes in human cancer (20). Several m...

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