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The Expression of Deleted in Liver Cancer-1 (DLC-1) in Bladder Cancer and Its Molecular Mechanism

Author: GuoZuo
Tutor: PanBaiShen
School: Fudan University
Course: Clinical Laboratory Science
Keywords: Bladder cancer Methylation DLC-1 Inactivation of gene expression Methylation specific PCR
CLC: R737.14
Type: Master's thesis
Year: 2009
Downloads: 48
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Abstract

Bladder cancer is the most common malignancy of the urinary system. According to the American Cancer Society statistics 2006 bladder cancer in men following prostate, lung and colorectal cancer after ranking fourth malignant ranked ninth in the female. In China, bladder cancer is ranked in the top ten malignant one, and more often in the elderly over the age of 50, and a corresponding increase in the incidence increases with age, and mortality in urban than rural areas, higher in men than women. The annual number of newly diagnosed cases of bladder cancer in the world there are about 275,000, the number of deaths of approximately 108,000. The majority of bladder cancer, transitional cell carcinoma, infiltration growth, the recurrence rate was 50% to 70%, attributed the cause of death of most cancer patients progressive growth of metastases. Bladder cancer treated with surgical resection, radiation therapy and systemic chemotherapy. Surgery, radiotherapy and chemotherapy have some effect, but the prognosis is usually poor, vulnerable to relapse and the emergence of bone metastases, lung metastases, multiple metastases. Most of bladder cancer has been found for the middle and late. Advanced existing local or distant metastases in patients with bladder cancer, clinical lack of effective treatment, surgery is difficult, even if we manage surgical resection often have poor prognosis. In short, the diagnosis and treatment of bladder cancer is a difficult subject. Therefore, the mechanisms of the molecular biology of bladder cancer, and more understanding of the molecular events of bladder cancer, in order to ascertain the incidence of bladder cancer, the development is particularly important. People in the past generally considered abnormal inactivation of the tumor suppressor gene or oncogene activation is due to the structure of DNA mutations. Mutations result in certain genes for additional functionality or lost somehow already present in the normal function, causing tumorigenesis. Recent years, with the depth of cancer research, it was discovered that DNA sequences outside the epigenetic regulation mechanism more common abnormalities in tumor occurrence and development process, but also play an important role. The epigenetic (epigenetic) DNA sequence does not change gene expression genetic change. Mechanism induced by the genetic information outside the cell genetic material and passing to stabilize the process of cell growth and proliferation. Many types of epigenetic phenomena, but the DNA methylation and histone modifications and other epigenetic phenomenon with malignant development are closely related, in particular, CpG island methylation-induced transcription of the tumor suppressor gene inactivation epigenetics become and epigenomics important topic in the field of cancer research. For example, the gene promoter region CpG island methylation patterns, found that many tumors are abnormal DNA methylation phenomenon exists. The tumor suppressor gene is often an excess of methylation and transcriptional expression is suppressed, the structure of the gene itself has not changed. Demethylating drug 5 - azacytidine (5-Aza-2'-deoxycytidine) acting on the gene promoter hypermethylation of tumor cells, and found that the recovery of the corresponding mRNA and protein expression, and the expression levels vary The cell type and drug dose change, which confirmed that the methylation of the promoter of gene expression off related reasons. Combine the function of tumor-related genes and methylation gene inactivation mechanism, large amounts of data that CpG island hypermethylation status plays an important role in tumor development, but also the silence gene expression related tumorigenesis mechanisms, in particular, may affect tumor suppressor genes and mismatch repair gene transcriptional expression of tumor occurrence and development of great significance. To assess the risk of cancer in the early diagnosis of tumor, tumor chemotherapy, abnormal DNA methylation sites has become a molecular marker has broad application prospects. In recent years, the study found, including DAPK, PTEN, BLU, RASSFlA a variety of tumor suppressor genes in bladder cancer have shown varying degrees of CpG island hypermethylation. Liver cancer gene to -1 (frequently deleted in liver cancer, DLC-1) is a tumor suppressor gene found in recent years. DLC-1 is located on human chromosome 8p21.3-p22 region, its length cDNA 3800 bp, and consists of 14 exons, encoding a protein product containing 1091 amino acid residues, a molecular weight of 122kDa, and rat p122 RhoGAP Gene 86% homology, were expressed in most human tissues. DLC-1 in breast cancer, liver cancer, colon cancer, lung cancer, stomach cancer and brain tumors found that methylation of its promoter. DLC-1 methylation status in bladder cancer research has not been reported. In this study, by detecting the methylation status and transcription level of DLC-1 gene in bladder cancer and to add a new member for the methylation profile of bladder cancer, and to explore the role of the gene in bladder cancer development. DLC-1 gene promoter methylation status of 52 bladder cancer tissues detected by MSP, methylation of which 15 were positive, the normal control group found no methylation-positive cases, the case group and normal group difference statistics significance (P <0.001), the presence of abnormal methylation of DLC-1 gene promoter in bladder cancer. Promoter methylation is one of the main mechanisms of gene silencing, we also detected mRNA and protein expression levels in bladder cancer using quantitative PCR and immunohistochemical techniques also were 40.6% and DLC-1 mRNA and protein expression of 31.1% of the tumor tissue is missing. Lack of methylation expression and mRNA expression correlation (P <0.01), the DLC-1 methylation and its gene expression down significant display may be associated with the occurrence of bladder cancer developments. Clinical studies have shown that DLC-1 gene is a good epigenetic markers. DLC-1 gene and its downstream signaling molecules may become effective biomarkers for early diagnosis of malignant tumors and treatment assessment. Gene deletion or DNA methylation DLC-1 downregulation, this phenomenon may be prompted to tumor aggressiveness progress. It is worth noting that DNA methylation changes can occur in the early stages of cancer formation, detection of bladder cancer-specific DNA methylation gene profiling possible early diagnosis of malignant cells. Single methylation markers lack of specificity in the diagnosis of tumors, tumor-specific methylation profile (DNA methylation profile) early diagnosis of the tumor are increasingly caught our attention. As a spectrum of methylation, DLC-1 gene methylation is undoubtedly the early diagnosis of bladder cancer, Prognosis are useful signs.

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