Survivin 2B Research Articles

Inhibitors of apoptosis proteins in human cervical cancer

BackgroundIt has been shown that IAPs, in particular XIAP, survivin and c-IAP1, are overexpressed in several malignancies. In the present study we investigate the expression of c-IAP1, c-IAP2, XIAP and survivin and its isoforms in cervical cancer.MethodsWe used semiquantitative RT-PCR assays to analyze 41 cancer and 6 normal tissues. The study included 8 stage I cases; 16 stage II; 17 stageIII; and a control group of 6 samples of normal cervical squamous epithelial tissue.Resultsc-IAP2 and XIAP mRNA levels were similar among the samples, cervical tumors had lower c-IAP1 mRNA levels. Unexpectedly, a clear positive association was found between low levels of XIAP and disease relapse. A log-rank test showed a significant inverse association (p = 0.02) between XIAP expression and tumor aggressiveness, as indicated by disease relapse rates. There were no statistically significant differences in the presence or expression levels of c-IAP1 and c-IAP2 among any of the clinical variables studied. Survivin and its isoforms were undetectable in normal cervical tissues, in contrast with the clear upregulation observed in cancer samples. We found no association between survivin expression and age, clinical stage, histology or menopausal state. Nevertheless, we found that adenocarcinoma tumors expressed higher levels of survivin 2B and DeltaEx3 (p = 0.001 and p = 0.04 respectively, by Kruskal-Wallis). A multivariate Cox's partial likelihood-based analysis showed that only FIGO stage was an independent predictor of outcome.ConclusionThere are no differences in the expression of c-IAP2 and XIAP between normal vs. cancer samples, but XIAP expression correlate in cervical cancer with relapse of this disease in the patients. Otherwise, c-IAP1 was downregulated in the cervical cancer samples. The expression of survivin was upregulated in the patients with cervical cancer. We have found that adenocarcinoma presented higher levels of survivin isoforms 2B and DeltaEx3.

ヒト癌免疫，癌ペプチドワクチン開発と熱ショックタンパク質のかかわり―癌免疫療法の具現化に向けて―

We have studied human tumor antigens applicable for a wide variety of tumors, and determined immunogenic peptide epitopes from these tumor antigen molecules presented particularly by HLA-A24. Our study indicated that peptides (survivin 2B) derived from survivin, an inhibitor of apoptosis proteins (IAP), are immunogenic in more than 50% of cancer patients with a wide variety of tumors. These vaccine candidates are now under clinical trials, and with careful immunological monitoring, we would be able to know finally if these vaccines can work clinically. To establish a potent clinical protocol, the immunological tumor escape mechanism should be more drastically examined in human materials. We have recently succeeded in establishing anti-HLA-A, B, and C alleles-specific monoclonal antibody EMR8-5 which can be used in routine paraffin-embedded sections. Unexpectedly enough, our data indicated that high percentage of human cancers lost HLA-class I molecules in primary cancer tissues. Particularly, more than 80% of breast and prostate cancers lost HLA-class I. Metastatic breast cancers indicated almost complete loss of HLA-class I. I will discuss possibilities for resolution of this old but yet new important problem. Meanwhile, recent evidences have been accumulating for an important role of the heat shock proteins (HSPs) as so called danger signals in initiating innate immunity as well as acquired immunity. The precise immunological basis for this phenomenon remains to be elucidated. T-cell immunity could be achieved after vaccination with tumor cells with MHC mismatching, which could not present antigen to T cells directly. This phenomenon is known as cross priming, and it may be mediated by Hsp-peptide complexes which are released from tumor cells. We show that exogenous Hsp90-peptide complexes can gain access to MHC class I presentation pathway and cause cross priming by bone marrow derived dendritic cells. Interestingly, this presentation is TAP-independent and follows endocytic pathways. We also show Hsp90-peptide complexes as a potential tumor vaccine by using HLA-A24 transgenic mouse model.

In vivo expression patterns of survivin and its splicing variants in chronic liver disease and hepatocellular carcinoma

Our aim was to clarify the significance of expression levels and post-transcriptional splicing patterns of survivin during multistep hepatocarcinogenesis and tumor progression. Using immunohistochemistry, we first elucidated the expression of survivin protein in tissues of hepatocellular carcinoma (HCC) and the adjacent non-cancerous tissues. Furthermore, we investigated survivin gene expression patterns in these tissues. Survivin protein was expressed not only in most HCC tissues but also in some cirrhotic nodules. In non-cancerous regions, the levels of survivin mRNA increased in proportion to their stage of progression. Survivin protein was expressed mainly in periportal areas, where proliferating cells were localized. In HCC, mRNA levels of survivin and survivin Delta Ex3 correlated with high proliferative activity, whereas the levels of surviving 2B did not. These findings of mRNA and protein expressions of survivin in chronically injured avers indicate that it has an important role in hepatocarcinogenesis. A lack of correlation between proliferative activity and survivin 2B mRNA levels in HCC is suggestive of a previous hypothesis that this variant decreases sruvivin function in a dominant negative manner. Thus, our data suggest different functions of these splicing variants and their important roles in tumor progression.

Increased survivin transcript levels: an independent negative predictor of survival in soft tissue sarcoma patients.

Survivin, a recently identified inhibitor of apoptosis protein (IAP), is expressed in diverse embryonic tissues and in various human cancers. We have investigated the quantitative expression of survivin mRNA by a sensitive TaqMan-based RT-PCR assay in tissue samples from 94 patients with soft tissue sarcomas (STS). Survivin transcript levels were measured and normalized to GAPDH transcripts. By using a multivariate Cox regression analysis, we found an inverse correlation between the level of survivin mRNA (ratio >2 zmol survivin/amol GAPDH) and the rate of overall survival (p = 0.009, RR = 2.7). Survivin transcript variants as detected by qualitative RT-PCR analysis were revealed in 36 of 56 STS patients (64%). Only survivin DeltaEx3 and/or full-length survivin variants but not survivin 2B were identified. Our results suggest that a higher level of survivin mRNA is an independent predictor of survival for STS patients.