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Survivin as a target for Progress in the treatment of colorectal cancer

[Abstract] Survivin is the inhibitor of apoptosis proteins (IAPs) family members can regulate apoptosis and cell division. Survivin in most terminally differentiated normal adult cells, not detected, but in many types of abnormal expression of tumor cells. Recent studies have found a new isomer of Survivin shear, different isomers could cut the incidence of colorectal cancer in the play different roles in the process. Survivin expression in a series of control experiments, and further clarified the process of apoptosis Survivin role, also proved to Survivin as a target for the treatment of colorectal cancer safety, feasibility and effectiveness. [Key words] Survivin; colorectal cancer, apoptosis; treatment of colorectal cancer is a worldwide one of the most common malignant tumor. According to the American Cancer Society estimates that in 2006 only in the U.S. were 106,680 cases and 41,930 cases of new cases of colon and rectal cancer, the incidence of colorectal cancer in China increasing trend was also found. Survivin in tumor tissue and normal tissue expression of the difference between the anti-apoptotic function of colorectal cancer to become the ideal target for targeted therapy. 1 Survivin and shear characteristics of the isomers Survivin in 1997 by Altieri and other effector cell protease receptor using 1 (effector cell protease receptor 1, EPR-1) of the cDNA in the human genome library obtained by hybridization screening of a new separation of inhibitor of apoptosis protein (inhibitor of apoptotic protein, IAP). Survivin gene is located on chromosome 17q25, full 14.7kb, its chain of 426 nucleotides encoding open reading frames, and EPR-1 complementary. Molecular weight of 16.5kD of Survivin protein containing 142 amino acid residues, structure, and with the different IAP family, baculovirus IAP repeat only one (baeuloviral IAP repeat, BIR) domain, C-terminal ring finger was replaced by a long α-helix . Survivin in normal circumstances, only the base of intestinal crypts in the expression of intestinal cell renewal in order to ensure and maintain homeostasis, but in most terminally differentiated normal adult cells do not express. Most tumors have abnormal expression of Survivin, and the incidence of tumor development and prognosis. Survivin gene contains four exons (E1,[link widoczny dla zalogowanych], E2, E3 and E4), 3 introns and exons 3 Hidden (2α, 2b and 3b). Survivin in mRNA precursors through different shear, in addition to Survivin, but also produce Survivin-ΔEx3, Survivin-2B, Survivin-3B [1], Survivin-2α [2] 4 种 shear isomers. Translated protein is thus with different structure and function, Survivin and Survivin-3B has a complete BIR domain, and Survivin-ΔEx3 and Survivin-2α in the BIR domain were truncated, Survivin- 2B of the BIR structure of the exon 2b were hidden peptides encoded into the fracture. Different isoforms seem to have cut a unique subcellular localization and function [3]. One anti-apoptotic function of Survivin-2B significantly decreased in spots distributed in the cytoplasm, Noton et al [4] Construction of expression in the Survivin-2B-GFP cells encountered difficulties, that the expression of Survivin-2B may be cytotoxic. Forced expression of Survivin-2B can induce apoptosis in cancer cells has been reported [5]. Research has also confirmed that Survivin-2B was associated with good prognosis in stage Ⅲ, Ⅳ expression in colorectal cancer than stage Ⅰ, Ⅱ [6]. Such evidence suggests that Survivin-2B in colorectal cancer and a negative regulatory role, and therefore some scholars believe that Survivin-2B is a natural Survivin antagonist, has a protective effect. Survivin-ΔEx3 retained anti-apoptotic properties, primarily in the nucleus, only a small portion located in the mitochondria, there was no expression in the cytoplasm [7]. Taubert and other constructed multivariable Cox proportional hazards regression model showed that, Survivin-ΔEx3 overexpression of cancer patients will increase 7.3 times the risk of death [8]. Cut the two isomers of the newly discovered remains to be further study, but were closely related with apoptosis. Different shear isomer effects of differences in colorectal cancer needs further study. Is worth noting that, in patients with colorectal cancer in stage Ⅱ,[link widoczny dla zalogowanych], the patients did not express Survivin 5 year survival rate was 94%, there is no difference in patients with stage Ⅰ, and the good response to adjuvant therapy; expression of Survivin in 5-year survival rate of patients with only 52%, close to the stage Ⅲ patients to adjuvant therapy is not sensitive to [9]. This helps to distinguish between the clinical stage Ⅱ patients with colorectal cancer to determine whether to use adjuvant therapy to improve survival of patients. 2 Survivin and apoptosis Survivin is a regulation of both apoptosis and cell proliferation of dual function regulator [10]. This article focuses on inhibition of apoptosis in Survivin function and the relationship between colorectal cancer targeted therapy. Survivin is the strongest ever found the inhibitor of apoptosis, apoptosis inhibition is much greater than the bcl-2 family members. There is growing evidence that, Survivin regulates both caspase dependent and non-caspase dependent apoptosis pathway. Survivin-positive mitochondria in normal adult tissue does not contain Survivin, but many types of cancer cells present in a mitochondrial pool of Survivin in the stimulation of apoptotic signal, mitochondria rapidly released into the cytoplasm of Survivin to two homologous dimer form and caspase-3 or caspase-7 to form a stable combination, to prevent caspase activation, cutting effect of the failure of both proteins, thereby inhibiting caspase-9-mediated apoptosis [11]. The use of pan-caspase inhibitor only partially reduced the anti-apoptotic ability of Survivin, Survivin confirmed in non-caspase dependent apoptosis pathway play a regulatory role [12]. Survivin still exist within the pool of cytoplasmic and nuclear pools, immunohistochemistry was observed during the study of certain antibodies can identify one of the two,[link widoczny dla zalogowanych], and some antibodies recognize both simultaneously, both Survivin pool their role and regulatory mechanisms should be further studied. It is reported that if patients with colorectal cancer the expression of Survivin in the cytoplasm, it has a protective effect, relative risk 0.35 [13]. If the subcellular distribution of Survivin outcome scale used, support clinicians to classify patients with colorectal cancer, it will help to achieve individualized treatment. 3 Survivin targeted therapy for colorectal cancer current cancer treatment targets Survivin 4 categories [3]: (1) inhibits Survivin expression, including the use of antisense oligonucleotide acid, antisense expression vector, RNAi, ribozyme, anti-cancer drugs, etc.; (2) inhibits the function of Survivin, including the application of dominant inactive mutant, drug inhibitors, peptide mimics, etc.; (3) Application of cDNA Survivin ,[link widoczny dla zalogowanych], RNA, protein or peptide immunotherapy; (4) application of Survivin promoter of tumor-specific cytotoxic genes. 3.1 inhibited the expression of Survivin antisense expression vector, including reverse and synthetic antisense oligonucleotides (antisense oligonucleotides, ASON), which is more suitable for clinical application. Penuelas et al [14] using 21-mer ASON role in colorectal cancer cells to chemotherapeutic agents can be enhanced (MTX) sensitivity. siRNA has a stronger relative to the effectiveness of ASON and anti-degradation ability, has become the mainstream in recent years means the target gene silencing. The use of siRNA reduced the expression of Survivin, cancer cells can promote DNA double-strand of the fault, eventually showed increased sensitivity to radiotherapy patients, indicating that Survivin may serve as prognostic factors used to determine the degree of patient response to radiotherapy [15]. Based on the new Survivin in tumor vascular endothelial cells also showed overexpression of the fact that, Coma et al [16] while the use of ASON and siRNA in endothelial cells and found that Survivin mRNA and protein in the lower, not only apoptotic cells increased 4 times endothelial cell growth was strongly inhibited, and endothelial cell migration was inhibited in a dose dependent and endothelial cell tube formation of papillary cavity capacity declined. The experiment also confirmed that, siRNA levels in the 30 ~ 100nM ASON can achieve the level of the 800 ~ 1000nM inhibitory effect can be achieved, the effect of siRNA is not difficult to draw stronger conclusions. Find the best target segment is the key to the success of these two methods, the methodology is still under discussion. EPR-1 is a natural antisense Survivin, inducing its expression in human colon cancer cell lines can be reduced Survivin, led to decreased cell proliferation, apoptosis increased,[link widoczny dla zalogowanych], and can increase sensitivity to anticancer drugs [17] This method can overcome the gene therapy, antisense oligonucleotides specific differences exist, the shortcomings of gene transfer is not complete, has a good prospect. Ribozyme is a specific nucleic acid degradation ability of RNA molecules, some of the hammerhead enzyme can be specifically Survivin degradation of mRNA, but this method is mainly used in laboratories, there is a great distance away from the clinical application . Non-steroidal anti-inflammatory drug Sulindac can be sustained suppression of Survivin mRNA and protein levels of expression could inhibit the ability of colorectal cancer and the preventive effect [18], the specific mechanism of Wnt pathway may be increased APC protein and degradation of β  catenin, the former can directly inhibit the expression of Survivin, which will reduce the downward T cell factor (T cell factor, Tcf) activation, transcriptional activator β  catenin / Tcf target gene Survivin complex also will be down. Small-molecule compounds, looking for material with good treatment effect, is a effective way can not be ignored. ICG-001 in vivo and in vitro can be specifically reduced β  catenin / Tcf target genes, strongly inhibit
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