Snf5 tumor suppressor couples chromatin remodeling, checkpoint control, and chromosomal stability

SNF5 is a core subunit of the SWI/SNF chromatin-remodeling complex. Mammalian SNF5 is essential for normal cell viability, and loss or mutation of the human SNF gene is the molecular basis for familial malignant rhabdoid tumorigenesis. Previous studies have suggested that SNF5 suppresses cancer by signaling through the p16Ink4a and retinoblastoma tumor suppressors to negatively regulate cell cycle progression from G0/G1 into S phase. A recent paper in Genes & Development (Vries et al., 2005) reports that human SNF5 also signals via the p16INK4a-Rb-E2F pathway to regulate chromosomal stability, suggesting a new function for this chromatin remodeling protein in tumor suppression.     

Increased tumorigenesis associated with loss of the tumor suppressor gene Cadm1

ABSTRACT: BACKGROUND: CADM1 encodes an immunoglobulin superfamily (IGSF) cell adhesion molecule. Inactivation of CADM1, either by promoter hypermethylation or loss of heterozygosity, has been reported in a wide variety of tumor types, thus it has been postulated as a tumor suppressor gene. FINDINGS: We show for the first time that Cadm1 homozygous null mice die significantly faster than wildtype controls due to an increased tumor incidence (p<0.05) of predominantly lymphomas but also some solid tumors. Furthermore, tumor latency is significantly reduced after irradiation (p<0.003), suggesting there are genes that collaborate with loss of Cadm1 in tumorigenesis. To identify these co-operating genetic events, we performed a Sleeping Beauty transposon-mediated insertional mutagenesis screen in Cadm1 mice, and identified several common insertion sites (CIS) found specifically on a Cadm1-null background (not wildtype background). CONCLUSION: We confirm that Cadm1 is indeed a bona fide tumor suppressor gene and provide new insights into genetic partners that co-operate in Cadm1-mediated tumor suppression.     

Oncogene regulation of tumor suppressor genes in tumorigenesis

We attempted to demonstrate whether there is an epigenetic link between oncogenes and tumor suppression genes in tumorigenesis. We designed a high throughput model to identify a candidate group of tumor suppressor genes potentially regulated by oncogenes. Gene expression profiling of mock-transfected versus v-src-transfected 3Y1 rat fibroblasts identified significant overexpression of DNA methyltransferase 1, the enzyme responsible for aberrant genome methylation, in v-src-transfected fibroblasts. Secondary microarray analyses identified a number of candidate tumor suppressor genes that were down-regulated by v-src but were also re-expressed following treatment with 5-aza-2'-deoxycytidine, a potent demethylating agent. This candidate group included both tumor suppressor genes that are known to be silenced by DNA hypermethylation and those that have not been previously identified with promoter hypermethylation. To further validate our model, we identified tsg, a tumor suppressor gene that was shown to be down-regulated by v-src and found to harbor dense promoter hypermethylation. Our model demonstrates a cooperative relationship between oncogenes and tumor suppressor genes mediated through promoter hypermethylation.     

The TP53 tumor suppressor gene and melanoma tumorigenesis: is there a relationship?

Mutations in the TP53 gene are found in about 11% of melanomas. Although nearly 600 papers have been published with varying degrees of consensus, there does not appear to be any comparable analysis that facilitates more than a glimpse into the role of p53 in melanomagenesis. This article reviews p53 alterations (at the gene and protein levels) in melanocytic skin lesions and discusses the following points: (i) p53 alterations commence as early as at the stage of benign and dysplastic nevi; (ii) these alterations are frequent in melanomas, and gradually increase with their progression; (iii) there is no concordance between the frequent p53 protein expression and the rarity of both TP53 gene mutations in melanomas, and (iv) the entire p53 pathway is a more critical determinant of the fate of the melanocytic skin lesions than the status of the p53 protein or the gene itself.     

髓源性抑制细胞在肿瘤发生发展中的作用

髓源性抑制细胞(myeloid-derived suppressor cells,MDSCs)是一组异质细胞,在肿瘤相关免疫抑制中起关键作用.MDSCs通过免疫抑制作用,使肿瘤逃避免疫监控.肿瘤组织中MDSCs的浸润与患者预后不良及治疗的抵抗密切相关.MDSCs在转移中发挥重要作用,但MDSCs在远处器官建立转移前微环...     

Inactivation of p53 tumor suppressor gene acts synergistically with c-neu oncogene in salivary gland tumorigenesis

Transgenic mice expressing specific oncogenes usually develop tumors in a stochastic fashion suggesting that tumor progression is a multi-step process. To gain further understanding of the interactions between oncogenes and tumor suppressor genes during tumorigenesis, we have crossed a transgenic strain (TG.NK) carrying an activated c-neu oncogene driven by the MMTV enhancer/promoter with p53-deficient mice. c-neu transgenic mice have stochastic breast tumor formation and normal appearing salivary glands. However, c-neu mice heterozygous for a p53 deletion develop parotid gland tumors and loose their wild type p53 allele. c-neu mice with a homozygous p53 deletion have increased rates of parotid tumor onset suggesting that inactivation of p53 is required and sufficient for parotid gland transformation in the presence of activated c-neu. In contrast to the dramatic effect of p53 in parotid gland transformation, p53 loss has little effect on the rate or stochastic appearance of mammary tumors. In addition, p53 loss was accompanied by the down regulation of p21 in parotid gland tumors but not breast tumors. The parotid gland tumors were aneuploid and demonstrated increased levels of Cyclin D1 expression. These observations suggest that in c-neu transgenic mice, p53 alterations have differential tissue effects and may be influenced by the tissue specific expression of genes influencing p53 activity.     

WWOX 抑癌基因研究进展

WWOX 基因定位于染色体16q23.3-24.1,在卵巢癌、乳腺癌、肝细胞癌、前列腺癌及其他肿瘤中检测到其杂合性缺失及染色体重排.该基因位于染色体普通脆性位点16D, 包含9个外显子,编码414个氨基酸相对分子量为46 000大小的蛋白.原发肿瘤组织及细胞系的研究证明该基因为肿瘤抑制基因,其失活可能导致肿瘤的发生,基因敲除实验证实了上述假设.WWOX可能和c-Jun, TNF, p53, p73, AP-2γ,及E2F-1等相互作用而发挥凋亡作用.目前对于该基因是否为肿瘤抑制基因仍存在不同观点,随着研究结果的积累,WWOX基因的功能会日渐明了,并对肿瘤的诊断、治疗和预防产生积极的影响.     

抑癌基因的失活机制

肿瘤的发生发展与抑癌基因的失活和原癌基因的激活密切相关.对抑癌基因失活机制的深入研究,不但可揭示肿瘤发生发展的机制,同时也有助于肿瘤的诊断及基因治疗.     

Epigenetic inactivation of paired box gene 5, a novel tumor suppressor gene, through direct upregulation of p53 is associated with prognosis in gastric cancer patients

Using genome-wide methylation screening, we identified that paired box gene 5 (PAX5) is involved in human cancer development. However, the function of PAX5 in gastric cancer (GC) development is largely unclear. We analyzed its epigenetic inactivation, biological functions and clinical application in GC. PAX5 was silenced in seven out of eight GC cell lines. A significant downregulation was also detected in paired gastric tumors compared with adjacent non-cancerous tissues. The downregulation of PAX5 was closely linked to the promoter hypermethylation status and could be restored with demethylation treatment. Ectopic expression of PAX5 in silenced GC cell lines (AGS and BGC823) inhibited colony formation and cell viability, arrested cell cycle, induced apoptosis, suppressed cell migration and invasion and repressed tumorigenicity in nude mice. Consistent with the induction of apoptosis by PAX5 in vitro, terminal deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick end labeling (TUNEL) staining showed significantly enhanced apoptotic cells in PAX5-expressed tumors compared with the vector control tumors. On the other hand, knockdown of PAX5 by PAX5-short hairpin RNA increased the cell viability and proliferation. The anti-tumorigenic function of PAX5 was revealed to be mediated by upregulating downstream targets of tumor protein 53 (p53), p21, BCL2-associated X protein, metastasis suppressor 1 and tissue inhibitors of metalloproteinase 1, and downregulating BCL2, cyclin D1, mesenchymal-epithelial transition factor (MET) and matrix metalloproteinase 1. Immunoprecipitation assay demonstrated that PAX5 directly bound to the promoters of p53 and MET. Moreover, PAX5 hypermethylation was detected in 77% (144 of 187) of primary GCs compared with 10.5% (2/19) of normal gastric tissues (P<0.0001). GC patients with PAX5 methylation had a significant poor survival compared with the unmethylated cases as demonstrated by Cox regression model and log-rank test. In conclusion, PAX5 is a novel functional tumor suppressor in gastric carcinogenesis. Detection of methylated PAX5 can be utilized as an independent prognostic factor in GC.     

Renal cyst development in mice with conditional inactivation of the von Hippel-Lindau tumor suppressor

Inactivation of the von Hippel-Lindau tumor suppressor, pVHL, is associated with both hereditary and sporadic renal cysts and renal cell carcinoma, which are commonly thought to arise from the renal proximal tubule. pVHL regulates the protein stability of hypoxia-inducible factor (HIF)-alpha subunits and loss of pVHL function leads to HIF stabilization. The role of HIF in the development of VHL-associated renal lesions remains to be determined. To investigate the functional consequences of pVHL inactivation and the role of HIF signaling in renal epithelial cells, we used the phosphoenolpyruvate carboxykinase (PEPCK) promoter to generate transgenic mice in which Cre-recombinase is expressed in the renal proximal tubule and in hepatocytes. We found that conditional inactivation of VHL in PEPCK-Cre mutants resulted in renal cyst development that was associated with increased erythropoietin levels and polycythemia. Increased expression of the HIF target gene erythropoietin was limited to the liver, whereas expression of carbonic anhydrase 9 and multidrug resistance gene 1 was up-regulated in the renal cortex of mutant mice. Inactivation of the HIF-alpha binding partner, arylhydrocarbon receptor nuclear translocator (Arnt), but not Hif-1alpha, suppressed the development of renal cysts. Here, we present the first mouse model of VHL-associated renal disease that will provide a basis for further genetic studies to define the molecular events that are required for the progression of VHL-associated renal cysts to clear cell renal cell carcinoma.     

肿瘤抑制基因PTEN研究新进展

PTEN是具有磷酸酶活性的抑癌基因,其低表达或缺失与肿瘤的进展及不良预后密切相关,其抑制肿瘤作用机制系通过抑制P13K／AKT信号通路,FAK／P130C和MAPK信号通路,FRAP／mTOR信号通路及影响核转录因子-kB／IB信号通路;另外,NEDIM-1通过泛素化蛋白体降解途径调节PTEN,BMP通过RAS／ERK信号通路抑制PTEN表达,IGF-1通过IGF-1／P13K／Akt信号通路调节PTEN。     

肿瘤抑制基因maspin的研究进展

maspin基因是一种肿瘤抑制基因,其产物是丝氨酸蛋白酶抑制剂,在细胞的迁徙、运动和增殖中起重要作用,并能抑制肿瘤的发生和发展.近年来的研究特别是对maspin基因在肿瘤转移中作用的研究为阐明肿瘤转移机制和抗转移治疗提供了途径.现阐述maspin的结构、功能及其临床应用的研究进展.     

肿瘤抑制基因PTEN研究新进展

PTEN是具有磷酸酶活性的抑癌基因,其低表达或缺失与肿瘤的进展及不良预后密切相关,其抑制肿瘤作用机制系通过抑制PI3K/AKT信号通路,FAK/PI30C和MAPK信号通路,FRAP/Mtor信号通路及影响核转录因子-Kb/IB信号通路;另外,NEDD4-1通过泛素化蛋白体降解途径调节PTEN,BMP通过RAS/ERK信号通路抑制PTEN表达,IGF-1通过IGF-1/PI3K/Akt信号通路调节PTEN.