The Polymorphisms And Mutation In Caspase 3 And Fas Gene On Healthy People And B-NHL Patients Of Han Nationality In China, And Discuss Their Relationships With The Pathogenesis Of B-NHL

It has been well acknowledged that imbalance between cell proliferation and cell apoptosis contribute to the genesis of various tumours. When apoptosis is inhibited or invalid, on one hand, it allowing the escape of injured and unrepaired cell from immune surveillance, and on the other hand, it may leading to longer survival of affected tumour cells, provide opportunity for the genetic changes in unstable genes, and may contribute to cell transformation and tumourigenesis. In recent years, studies of occurrence and regulation mechanism of apoptosis show that the two major apoptotic pathways are the mitochondrial and death receptor pathways. These two pathways are all dependent on the action of a family of cystein proteases call caspase.Caspase family is highly similar to the protein CED of Caenorhabditis elegans on gene sequence and protein structure. All the family members are play important roles in apoptosis initiation, singaling transduction and apoptosis execution.Caspase 3 was famous known as a main apoptotic effector in succession, it' s central role in apoptosis was sustained by large numbers of experiment. Some cases even suggest that caspase 3 couldn' t be substituted by others in apoptotic process. In vitro, the lack of caspase 3 activity was found to be the result of a fortuitous mutation in which Trp206 was replaced by Arg (W206R). The replacement of Trp at 206 by Arg makes caspase 3 unactivated. Previously, our and other groups have found that the abnormal expression of caspase 3 protein correlates with several tumours, such as lymphoma, gastric cancer and non-small cell lung cancer, et al. But we still have little known about whether this abnormality correlates with gene polymorphisms and mutation or not. The Fas/FasL system has been recognized as a major pathway for the induction of apoptosis in cells and tissues. Fas, also known as CD95 or APO-1, is a key molecule for death signaling. Recent study indicated that resistance to Fas-mediated apoptosis is a widespread phenomenon in B cell non-Hodgkin' s lymphoma (B-NHL). Most B-NHL was found resistant to Fas-mediated apoptosis pathway, and associated with cancer development and prognosis. But the study on the mechanism of apoptosis resistance is still in the elementary step. Our and other groups have found that even in sorts of Fas-resistant B-NHL cell lines, the patterns of expression and function of Fas and subsequent apoptotic proteins are usually well-balanced. And further studies indicate that the resistance of Fas-mediated apoptosis was connected with the unconventionally expression of some apoptotic modulating proteins, like, cellular caspase-8/FLICE-inhibitory protein ( c-FLIP ) ,inhibitor of apoptosis proteins ( lAPs ) , Myc and soluble Fas protein, et al. At the same time, the nexus between the impaction of Fas gene mutation on protein expression and the B-NHL tumourigenesis was reported accumulatively. Loss of Fas regulatory function is thought as an important step in early MALT-type lymphoma development. Also, Fas gene mutation was found in diffuse large B cell lymphoma (DLBL), follicular lymphoma (FL) and anaplasic large cell lymphoma (ALCL), et al. But the relationship between gene mutation and each B-NHL subtype is far from clarity. Discuss the effect of Fas gene variation on cell apoptosis may shed light on the resistant mechanism.Single nucleotide polymorphisms (SNPs) is the most abundant polymorphism marker in human genome, about 90% of the DNA polymorphisms is SNPs. The Human Genome Project (HGP) has ascertained that the variety and frequency of SNPs are differentiable in diverse nationalities. SNPs which in the regulatory region or coding region would change the mRNA transcription or the expression and function of protein respectively. This variation is also the substantial base of individual difference in common disease manifestation and therapeutic response. The polymorphism sites and their haplotypes in the promoter region of Fas gene have been reported to have relations with cervical carcinoma, ALPS and AML...