Nuclear translocation of survivin in hepatocellular carcinoma: a key to cancer cell growth?

Survivin is a recently described anti-apoptosis protein and regulator of cell division. Its expression and localization in hepatocellular carcinoma (HCC) and in normal liver tissue has not been fully elucidated. We examined the expression of survivin, Fas, proliferating cell nuclear antigen (PCNA), and apoptosis in 47 specimens of hepatocellular carcinoma (HCC) and surrounding nonmalignant hepatic tissues. To further determine the relationship between survivin expression and cell proliferation and apoptosis, we performed double immunostaining for survivin and PCNA TUNEL staining in the same HCC specimens. Positive immunostaining for survivin was present in 35 of 47 (74%) HCCs. Twenty-two of 35 survivin-positive HCCs (63%) showed punctate nuclear staining in HCC cells, and the remaining 13 showed predominant cytoplasmic staining. In contrast, nonmalignant hepatocytes showed only cytoplasmic staining. HCC cells had significantly higher PCNA-labeling and apoptotic indices compared with the case of nonmalignant hepatic tissue (P<0.001). Furthermore, nucleus-positive HCC specimens for survivin showed the highest PCNA labeling index. The nuclear localization of survivin in HCC cells correlated with tumor cell de-differentiation with the exception of the HepG2 cell line. Survivin expression was inversely associated with apoptosis and was strongly associated with Fas expression (P=0.01). All 4 HCC cell lines examined showed survivin expression and punctate nuclear localization. Our results indicate that survivin is localized to the cytoplasm in quiescent nonmalignant liver cells to suppress apoptosis and translocates into the nucleus in HCC cells. In conclusion, translocation of survivin from the cytoplasm to the nucleus may constitute an important regulatory mechanism for cell proliferation and differentiation in HCC.     

Dynamic intracellular survivin in oral squamous cell carcinoma: underlying molecular mechanism and potential as an early prognostic marker

Survivin functions as an apoptosis inhibitor and a regulator of cell division in many tumours. The intracellular localization of survivin in tumours has been suggested as a prognostic marker. However, current reports are inconsistent and the underlying molecular mechanisms are not understood. The present study has examined the localization and prognostic value of nuclear and cytoplasmic survivin in the pre-therapeutic biopsies from 71 oral and oropharyngeal squamous carcinoma (OSCC) patients. Statistical analysis indicated that preferential nuclear versus cytoplasmic survivin correlated with favourable versus unfavourable disease outcome. Uni- and multi-variate analysis showed that in contrast to total survivin expression, the difference between nuclear and cytoplasmic survivin was a strong predictor for relapse-free survival (p=0.0003). As a potential underlying molecular mechanism, it is shown in OSCC cell lines that predominantly cytoplasmic survivin mediates protection against chemo- and radio-therapy-induced apoptosis. Importantly, the cytoplasmic localization of survivin is regulated by its nuclear export signal (NES), and export-deficient nuclear survivin is not cytoprotective. This study suggests that the difference between cytoplasmic and nuclear survivin is an indicator for survivin activity in tumour cells. Thus, this difference may serve as a predictive marker of outcome in OSCC patients undergoing multi-modality therapy. The pharmacogenetic interference with survivin's cytoplasmic localization is also to be pursued as a potential therapeutic strategy.     

Nuclear localization of E-cadherin expression in Merkel cell carcinoma

CONTEXT: Cadherins are cell-cell adhesion proteins that act as tumor suppressor genes and have a critical role in cell sorting and tissue formation during organogenesis. The pattern of cadherin expression constitutes a useful diagnostic and prognostic tool in the evaluation of tumors and for determining the histogenesis of tumor cells. We have previously characterized the cell types of several tumors based on the expression of individual cadherins. OBJECTIVE: To investigate the expression of cadherins in Merkel cell carcinomas. DESIGN: Paraffin immunohistochemical analysis of the 3 best-studied cadherins was performed on 35 cases of Merkel cell carcinoma. RESULTS: E-cadherin was expressed in 34 (97%) of 35 Merkel cell carcinomas examined, N-cadherin was expressed in 22 (63%) of 35 cases, and P-cadherin was expressed in 15 (43%) of 35 cases. This frequency of cadherin expression was similar to a group of small cell and neuroendocrine tumors from other primary sites. Interestingly, the localization of E-cadherin expression was unique in Merkel cell carcinomas compared with other primary neuroendocrine tumors. Merkel cell carcinomas showed marked preference for nuclear versus membrane localization, whereas small cell tumors from other sites showed fewer cases of nuclear E-cadherin expression. The nuclear localization of E-cadherin did not correlate with cadherin-associated protein beta-catenin nuclear expression. CONCLUSIONS: Our findings show that E-cadherin is the most frequently expressed cadherin in Merkel cell carcinoma, followed in frequency by N-cadherin then P-cadherin. The pattern of nuclear E-cadherin expression is more frequent for Merkel cell carcinoma than small cell tumors of other primary sites. These observations suggest that E-cadherin expression and function are altered in Merkel cell carcinoma, and this finding has potential use in the differential diagnosis of these tumors.     

Immunohistochemical localization of survivin in serous tumors of the ovary.

The aim of this study was to determine the immunohistochemical distribution of survivin in benign, borderline, and malignant serous tumors of the ovary. Survivin was localized by an indirect immunoperoxidase method in 42 cases of serous tumors of the ovary (15 cystadenomas, 15 borderline tumors, and 12 cystadenocarcinomas). Nuclear staining and cytoplasmic staining were separately scored. Cytoplasmic staining was detected in 27% of adenomas/borderline tumors and in 58% of carcinomas. Nuclear staining was detected in 87% of adenomas/borderline tumors but in only 42% of carcinomas. Although the differences in the intensity of cytoplasmic staining between adenomas and borderline tumors versus carcinomas were not significant, the differences in the intensity of nuclear staining between low-grade versus malignant tumors were significant. These findings suggest that survivin is widely expressed in benign, borderline, and malignant serous tumors but that nuclear localization of survivin is more common in benign or borderline tumors than in malignant serous tumors of the ovary. The molecular mechanisms that determine the subcellular distribution of this protein may reflect the role of survivin in the regulation of apoptosis during the processes of malignant transformation.     

Analysis of survivin expression in a spectrum of benign to malignant lesions of the breast.

Survivin, a novel inhibitor of apoptosis, is expressed in a variety of human cancers, with reports of prognostic significance in some neoplasms. The authors' aim was to evaluate survivin expression in a spectrum of breast lesions to determine differential expression in malignant versus benign lesions and its potential role as a diagnostic or prognostic marker. The authors found that survivin is expressed in breast tissue in the full spectrum of normal to invasive carcinoma. It is predominantly nuclear with a faint cytoplasmic blush. Survivin expression was independent of patient age and tumor size. Benign breast tissue showed survivin expression in a lower percentage of cells (45%) than malignant lesions. The median values for the percentage of cells that stained for survivin were statistically different among the categories of invasive carcinoma, DCIS, LCIS, and benign breast tissue (P < or = 0.001). The highest percentage of positive-staining cells was seen in high-grade DCIS (95%). The authors found a trend toward a higher percentage of cells staining for survivin in breast carcinoma cases that were ER negative, PR negative, or Her2/neu positive, although this was not statistically significant. Survivin expression was preserved in biopsies from recurrent tumors without loss of nuclear survivin expression. In conclusion, survivin is overexpressed in malignant breast lesions relative to benign lesions or normal breast tissue and in high-grade DCIS relative to nonhigh-grade DCIS. Therefore, survivin may have a role, albeit a limited one, as a prognostic marker in breast lesions.     

Survivin and caspase-3 expression in breast cancer: correlation with prognostic parameters, proliferation, angiogenesis, and outcome.

BACKGROUND: Survivin is an inhibitor of apoptosis protein that is overexpressed in most human cancers, including breast, but is not expressed in normal tissue. Survivin is associated with more aggressive behavior and decreased survival in a variety of tumor types. It regulates the G2/M phase of the cell cycle by associating with mitotic spindle microtubules, and it directly inhibits caspase-3 and caspase-7 activity. We used a breast cancer tissue microarray to assess survivin and caspase-3 expression in breast cancer and to correlate both markers with proliferation (MIB-1), angiogenesis (CD31), and prognosis. DESIGN: A breast cancer tissue microarray with a total of 190 1-mm tissue samples (2 from each specimen) were immunostained for survivin, caspase-3, MIB-1, and CD31. The microarray contains 91 cases of breast carcinoma diagnosed at Emory University Hospital between 1992 and 2000, and 4 normal breast tissue controls. Follow-up information was obtained from hospital records and the Winship Cancer Center database. RESULTS: Eighty-four percent of breast carcinoma showed nuclear survivin expression. Normal breast tissue was immunonegative. Fifty-seven percent and 43% of breast cancer showed reduced and absent caspase-3 expression, respectively. Survivin (nuclear) and caspase (nuclear/cytoplasmic) expression showed significant correlation with histologic grade (P=0.008 and 0.041) and MIB-1 expression (P=0.033 and 0.012). Survivin nuclear expression also correlated significantly with tumor stage (P=0.012) and tended to correlate with estrogen receptor (P=0.050). There was no significant correlation between survivin and caspase expression. Furthermore, there was no correlation of both markers with other clinicopathologic parameters (age, tumor size, histologic type, progesterone receptor, Her-2 neu status, lymph node status), angiogenesis (CD31), or outcome (overall and disease-free survival). CONCLUSIONS: Survivin and caspase-3 expression correlate with poor prognostic parameters (higher histologic grade and high proliferation), but not with outcome, in breast carcinoma patients.     

Prognostic significance of anti-apoptosis proteins survivin and bcl-2 in non-small cell lung carcinomas: a clinicopathologic study of 102 cases.

Inhibitors of apoptosis, including bcl-2 and survivin (a novel gene encoding a unique apoptosis inhibitor), regulate cell proliferation by promoting cell survival. Although survivin has been detected in several human cancers, its prognostic significance and relationship to bcl-2 are not well characterized in lung cancer. Tissue sections from 102 non-small cell lung carcinomas (NSCLC) were immunostained using antibodies against survivin and bcl-2. Staining results were correlated with prognostic variables. Immunoreactivity for survivin and bcl-2 was observed in 53% and 21% of NSCLCs, respectively. Fifty-two percent of the 50 squamous cell carcinomas and 54% of the 52 adenocarcinomas expressed survivin. Survivin positivity correlated with tumor stage in squamous cell carcinoma. On univariate analysis, survivin expression correlated with decreased patient survival in NSCLC and in the subset of squamous cell carcinomas, but not in adenocarcinomas. On multivariate analysis, survivin was an independent predictor, along with distant metastasis and large tumor size. Eighteen percent of squamous cell carcinomas and 24% of adenocarcinomas expressed bcl-2. On univariate analysis, bcl-2 expression correlated with increased patient survival in NSCLC and in the subset of squamous cell carcinomas. An inverse correlation between the expression of survivin and bcl-2 was noted. Survivin immunoreactivity is an independent predictor of shortened survival in NSCLC, while bcl-2 protein expression correlated with prolonged patient survival. These findings indicate an inverse relationship between survivin and bcl-2 expression and suggest that these two inhibitors of apoptosis function through different pathways in the regulation of tumorigenesis in NSCLC.     

Immunohistochemical expression of nuclear and cytoplasmic survivin in gastrointestinal carcinoma

Survivin is a protein that is highly expressed in many embryonic tissues, as well as most human tumors. Prior studies have reported both positive and negative correlations between survivin expression and cancer prognosis, but these associations remain controversial. In the present study, we assessed the expression of nuclear and cytoplasmic survivin in gastrointestinal carcinomas. Using these data, we determined the correlation between nuclear and cytoplasmic survivin and, further, investigated correlations between survivin expression and clinicopathological parameters. Seventy-two advanced gastric adenocarcinomas and 78 colorectal adenocarcinomas were analyzed for survivin expression by immunohistochemistry. Expression of both nuclear and cytoplasmic survivin was significantly higher in colorectal carcinomas than in gastric carcinomas (P < 0.01). There was a positive correlation between nuclear and cytoplasmic expression of survivin (r = 0.42, P < 0.001). In gastric carcinomas, the level of survivin protein expression was associated with tumor differentiation, patient age, and lymphatic invasion (P < 0.05, 0.01, and 0.01, respectively). In colorectal carcinomas, the level of nuclear survivin expression was significantly higher in females than in males (P < 0.05). There were no significant associations between survivin expression and most of the clinicopathological parameters. Nevertheless, there was a trend towards an inverse correlation between nuclear survivin expression and tumor aggressiveness in gastric carcinoma; there was a similar trend for cytoplasmic survivin expression. In summary, our results suggest that levels of nuclear and cytoplasmic survivin expression differ between gastric carcinoma and colorectal carcinoma.     

Expression of the apoptosis inhibitor, survivin, in nonmelanoma skin cancer and gene targeting in a keratinocyte cell line.

The recently described apoptosis inhibitor survivin is expressed in many human cancers, thus potentially contributing to disease progression and resistance to therapy. Its potential role in nonmelanoma skin cancer is unknown. By immunohistochemistry, survivin was expressed in 81% (17 of 21) of basal cell carcinomas (BCC) of both nodular and morpheaform subtypes, and in 92% (24 of 26) of cutaneous squamous cell carcinomas (SCC). Survivin was also expressed in 19 premalignant lesions of Bowen's disease (SCC in situ) and hypertrophic actinic keratosis (HAK), suggesting that its appearance occurs early during keratinocyte transformation. Survivin expression was detected by Western blotting in a model keratinocyte cell line, HaCat. Transfection of HaCat cells with green fluorescent protein (GFP)-conjugated survivin antisense or GFP-conjugated survivin dominant negative mutant (Cys84Ala) resulted in spontaneous apoptosis in the absence of other genotoxic stimuli. In GFP-conjugated survivin antisense transfectants, a decreased level of endogenous survivin was confirmed by flow cytometry. This was associated with a five-fold increase in the sub-G0/G1 fraction corresponding to apoptotic cells and a decrease in proliferating cells with 4N DNA content. These data demonstrate that apoptosis inhibition by survivin may participate in the onset and progression of both BCC and SCC, and suggest that therapeutic targeting of survivin may be beneficial in patients with recurrent or advanced disease.     

Nuclear, but not cytoplasmic, localization of survivin as a negative prognostic factor for survival in upper urinary tract urothelial carcinoma

Survivin, a member of the inhibitor of apoptosis protein gene family, inhibits apoptosis and promotes mitosis. We determined whether nuclear or cytoplasmic localization of survivin could predict survival of patients with upper urinary tract urothelial carcinoma (UUTUC). Immunohistochemical staining for survivin was carried out on archival specimens from 125 consecutive patients with UUTUC who underwent radical nephroureterectomy. Nuclear and cytoplasmic staining of survivin was scored and compared with clinicopathologic features and cancer-specific survival (CSS). Nuclear expression of survivin was significantly correlated with tumor grade (p?<?0.001), lymphovascular invasion (p?=?0.022) and poor survival with an estimated 5-year CSS probability of 54 % for tumors with nuclear expression of survivin vs. 73 % for those without nuclear expression of survivin (hazard ratio?=?2.19; 95 % confidence interval?=?1.02–4.70; p?=?0.043). The 5-year cancer-specific survival rates of patients with cytoplasmic survivin-negative and -positive tumors were 66 and 67 %, respectively. There was no difference in survival between patients with cytoplasmic survivin-negative tumors and those with cytoplasmic survivin-positive tumors. Using univariate analysis, nuclear survivin expression, tumor grade, pathological T stage, pathological N stage, and lymphovascular invasion were the predictive variables for CSS. In contrast, cytoplasmic survivin expression had no prognostic relevance. These data suggest that nuclear accumulation of survivin represents biologic aggressiveness and that nuclear survivin is a negative prognostic marker in patients with resected UUTUC.     

Nuclear E-cadherin immunoexpression: from biology to potential applications in diagnostic pathology

E-cadherin is a well-recognized molecule that is important in cell adhesion. Its abrogation has been linked to increased invasiveness in several malignancies. The normal immunohistochemical localization of E-cadherin is the cell membrane, however, both cytoplasmic and nuclear immunostaining has been reported. Loss of membrane staining and/or nuclear staining for E-cadherin is seen in 100% of cases of solid pseudopapillary tumors (SPTs) of the pancreas. In the context of SPT, E-cadherin staining is of diagnostic use. Nuclear staining has been seen in cases of pancreatic neuroendocrine tumors, Merkel cell carcinomas, clear cell renal cell carcinoma, esophageal squamous carcinoma, colorectal and gastric cancer, and synovial sarcoma. The difference in the staining patterns seen (complete loss vs. nuclear staining) is due to the type of E-cadherin antibody used. Antibodies recognizing the extracellular domain show loss of E-cadherin staining in SPT, whereas the antibody to the cytoplasmic domain results in nuclear staining in all cases of SPT. Therefore, E-cadherin staining is of diagnostic use in the immunohistochemical work-up of SPT. Nuclear E-cadherin staining of pancreatic neuroendocrine tumors identified a subset of cases with more aggressive potential, whereas nuclear staining of clear cell renal cancers identified a subset of tumors with a better prognosis. The exact mechanism by which E-cadherin enters the nucleus is not known but it is likely that it is closely related to several partner molecules such as beta-catenin, p120, and presenilin-1.     

Nuclear localization of Merkel cell polyomavirus large T antigen in Merkel cell carcinoma

To clarify whether mutations in the large T gene encoded by Merkel cell polyomavirus affect the expression and function of large T antigen in Merkel cell carcinoma cases, we investigated the expression of large T antigen in vitro and in vivo. Immunohistochemistry using a rabbit polyclonal antibody revealed that large T antigen was expressed in the nuclei of Merkel cell carcinoma cells with Merkel cell polyomavirus infection. Deletion mutant analyses identified an Arg-Lys-Arg-Lys sequence (amino acids 277-280) as a nuclear localization signal in large T antigen. Sequence analyses revealed that there were no mutations in the nuclear localization signal in any of the eleven Merkel cell polyomavirus strains examined. Furthermore, stop codons were not observed in the upstream of the nuclear localization signal in any of the Merkel cell carcinoma cases examined. These data suggest that the nuclear localization signal is highly conserved and functional in Merkel cell carcinoma cases.     

Survivin, a member of the inhibitors of apoptosis family, is down-regulated in breast carcinoma effusions

We analyzed the expression and prognostic role of inhibitors of apoptosis in breast carcinoma effusions. We used immunoblotting to analyze 22 effusions for XIAP, survivin, and livin expression. Based on immunoblotting results, 49 effusions and 46 corresponding solid tumors were immunostained for XIAP and survivin. Results were analyzed for association with anatomic site, clinicopathologic parameters, and survival. Immunoblotting showed frequent expression of XIAP and survivin and no expression of livin. Carcinoma cells in effusions showed lower survivin immunostaining compared with lymph node metastases (P = .008) and primary carcinomas (P = .041). Higher cytoplasmic survivin expression correlated with poor disease-free survival for patients with postchemotherapy effusions (P = .035). XIAP and survivin, but not livin, are frequently expressed in advanced breast carcinoma. Survivin is down-regulated in effusions compared with solid tumors, possibly in relation to the different cellular economy at this anatomic site. Survivin expression may predict disease-free survival for patients with postchemotherapy effusions.     

Immunohistochemical analysis of survivin expression in thyroid follicular adenoma and carcinoma.

Survivin is one of the 8 members of human inhibitor of apoptosis , which is differentially expressed in cancerous/transformed cells versus normal differentiated tissues. This retrospective study of thyroid histologic samples aimed to assess the clinical usefulness of survivin immunostaining for discrimination between follicular adenoma and carcinoma of thyroid. Immunohistochemical staining for survivin was performed on 41 lesions from patients who had undergone surgery for either follicular adenoma or carcinoma of thyroid. Survivin expression was significantly (P < 0.005) higher in the cases that received a diagnosis of carcinoma in comparison with follicular adenomas cases. Odds ratio of follicular carcinoma for survivin expression was 21.375 (95% CI: 3.283 to 139.177). Our results showed potential value of survivin in discrimination between follicular thyroid adenoma and follicular thyroid carcinoma. We conclude that survivin is a potential candidate for further investigation in the proper histologic diagnosis of thyroid cancers.     

Immunohistochemical localization of survivin in benign cervical mucosa,cervical dysplasia,and invasive squamous cell carcinoma

Survivin is an inhibitor of apoptosis protein (IAP) that is expressed in fetal development and in cancer Survivin expression in premalignant lesions remains undefined. We obtained 73 samples of cervical squamous tissue, including 31 normal, 17 low- and 15 high-grade squamous intraepithelial lesions (LSILs, HSILs), and 10 squamous cell carcinomas (SCCs)from cone biopsy and hysterectomy specimens, and stained for survivin using an immunoperoxidase method. Nuclear staining was detected in normal mucosa, LSILs, and HSILs; staining intensity was greatest in cases with morphologic evidence of human papillomavirus (HPV) infection. In situ hybridization of serial sections demonstrated colocalization of HPV DNA and survivin. Cytoplasmic staining was observed in immature squamous metaplasia and in SCCs. Survivin expression in immature metaplastic squamous mucosa may reflect a rolefor survivin in normal squamous differentiation. However, the histologic correlation between nuclear staining and HPV infection suggests involvement of survivin in HPV-mediated disruption of normal cellular maturation.     

Expression of the apoptosis inhibitor survivin in aggressive squamous cell carcinoma.

Deregulated expression of inhibitors of apoptosis (programmed cell death) may contribute to cancer by aberrantly extending cell viability and facilitating the insurgence of resistance to therapy. In this study, we investigated the potential expression and prognostic significance of the apoptosis inhibitor survivin in squamous cell carcinoma (SCC). A series of 135 cases of SCC including 46 oral SCC and 89 cutaneous SCC was analyzed for survivin expression by immunohistochemistry and Western blotting. Survivin was found in 57 cases (64%) of skin SCC and 26 cases (56%) of oral SCC, with weighted survivin scores ranging from 1 to 12. In contrast, normal oral epithelium, normal skin epithelium, and skin annexa did not express survivin. Survivin expression significantly (P < 0.05) segregated with high-grade and undifferentiated tumors with size >1.5 cm and invariably associated with lymph node metastasis. These data suggest that survivin expression may predictively identify cases of SCC with more aggressive and invasive clinical phenotype, potentially warranting closer follow-up protocols.     

Expression of survivin does not predict survival in patients with transitional cell carcinoma of the upper urinary tract

The members of the IAP (inhibitors of apoptosis) family, which includes survivin, have recently emerged as modulators of an evolutionarily conserved step in apoptosis. Survivin is present during embryonic and fetal development, but it is downregulated in normal adult tissues. However, it becomes re-expressed in a variety of cancers. We investigated the prognostic importance of the expression of survivin in transitional cell carcinoma of the upper urinary tract (TCC-UUT). In 126 cases of TCC-UUT, we examined its expression (using immunohistochemistry), and also its relationship with the expressions of bcl-2 oncoprotein, p53 oncoprotein, and proliferating cell nuclear antigen (PCNA) immunoreactivity, clinicopathologic parameters, and clinical outcome. A positive expression of survivin was recognized in 12.7% of samples, a granular pattern being apparent within the cytoplasm of tumor cells. Survivin expression did not correlate with clinicopathologic findings, bcl-2 oncoprotein expression, p53 oncoprotein expression, PCNA index, or prognosis. In the normal urothelium, its expression was not detected. In conclusion, the expression of survivin does not predict prognosis in TCC-UUT.     

Expression of IAP family proteins in esophageal cancer

Members of the inhibitor of apoptosis protein (IAP) family, including survivin, have been reported to be expressed in many tumors. However, their expression in esophageal cancer has not been clarified completely. We investigated the expression of mRNA for IAP family proteins in samples from esophageal cancers and their adjacent normal mucosa tissues by real-time quantitative RT-PCR. The survivin expression in esophageal cancer was significantly higher than that in normal mucosa (P < 0.05). Other IAP family proteins including cIAP1, cIAP2, NAIP and XIAP tended to show stronger expression in cancer tissue than normal mucosa, although the differences were not significant. As to the histological type of tumor, poorly differentiated squamous cell carcinomas exhibited significantly higher level of expression than well-differentiated carcinomas (P < 0.05). The proportion of apoptotic cells of cancer tissue inversely correlated with the intensity of survivin expression (P < 0.05). Immunohistochemical staining demonstrated cytoplasmic as well as nuclear expression of survivin in esophageal cancer, and further, in situ hybridization analysis demonstrated cytoplasmic expression of mRNA for survivin. The results suggest that the expression of IAP family proteins, especially survivin, may be associated with the biological character of esophageal cancer, such as apoptosis.     

Expression of survivin in fetal and adult normal tissues of rat

Survivin is an inhibitor of apoptosis protein and regulates the cell cycle in the G2/M phase. Survivin is expressed during embryonic and fetal development, selectively over-expressed in common human cancers and completely down-regulated in normal adult tissue. This work was aimed at studying the expression of the survivin homologues and their subcellular distribution in fetal and normal adult tissues of rat. Survivin expression was evaluated by immunohistochemistry in formalin-fixed, paraffin-embedded tissue sections of fetal and normal adult tissues of rat using the polyclonal serum SUR12A-CFI. This serum demonstrated intense positive survivin staining in adult kidney, ovary and oviduct, and a variable expression in different fetal organs, with particularly intense expression detected in the adrenal gland, liver, stomach, small intestine, colon, kidney and skin. In both fetal and adult tissues, the expression was predominantly cytoplasmic. It was concluded that survivin was abundantly and prominently expressed during fetal development in rat and that the polyclonal anti-human survivin antibody SUR12A-CFI is reactive with rat survivin.