332

BIRC5

baculoviral IAP repeat containing 5;BIRC5;baculoviral IAP repeat containing 5

apoptosis inhibitor 4|apoptosis inhibitor survivin|baculoviral IAP repeat-containing protein 5|survivin variant 3 alpha

17q25

protein-coding

BACKGROUND: As a known regulator of apoptosis, survivin has positive relationship with lymphatic metastasis in breast cancer. This study aims to detect the difference in expression between survivin and vascular endothelial growth factor-C (VEGF-C) in treated breast cancer cells and tissues, and to analyze the correlation among survivin, VEGF-C and lymphatic metastasis. METHODS: Plasmid with survivin and VEGF-C shRNA and lentivirus with survivin gene were constructed and transfected into breast cancer cell ZR-75-30. Then the expressions of the two genes were examined using western blot analysis and real-time PCR. The change of invasiveness of breast cancer cells was assessed using matrigel invasion assay. Using immunohistochemistry, the expression of survivin and VEGF-C were analyzed in 108 clinical breast cancer cases with breast cancer tissue and lymph node. RESULTS: Survivin regulated the expression of VEGF-C at both protein and mRNA levels in breast cancer cells. Immunohistochemical analysis showed that the level of VEGF-C expression was significantly related with that of survivin in breast cancer tissues (p<0.05). VEGF-C was found to participate in the process of breast cancer cells invasion mediated by survivin. The co-expression of the two and the single expression of any one took significant difference in positive lymph node (p<0.05). CONCLUSIONS: Survivin takes an important part in regulating the expression of VEGF-C. VEGF-C could influence the invasive ability mediated by survivin. The co-expression of survivin and VEGF-C is more statistically significant to assess lymphatic metastasis in breast cancer. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/9193530897100952.

OBJECTIVE: To investigate the expression and the correlation of surviving, bcl-2 and HPV16/18 in cervical carcinoma. METHODS: Hybridization in situ was used to detect the expression of survivin mRNA and HPV16/18 DNA in 74 cases of CIN and 81 cases of cervical carcinoma and 20 cases of normal cervical tissues. And immunohistochemical analysis was used to detect the expression of bcl-2 protein. RESULTS: The positive rates of survivin mRNA, bcl-2 and HPV16/18 in CIN were 44.6%, 39.2% and 41.0% respectively versus 77.8%, 70.4% and 81.2% in cervical carcinoma. The above three indices gradually rose in normal cervical tissue, CIN and cervical carcinoma. The expression of survivin and bcl-2 in CINIII were obviously higher than those in CINI/II. And it was obviously higher in cervical carcinoma with stage IIb-III than those in stage I-IIa. And it was also obviously higher in cervical carcinoma with a poor differentiation than those with a good or medium differentiation. The expression of survivin in cervical carcinoma with lymphatic metastasis was significantly higher than that without lymphatic metastasis. There were no relationship between the expression of survivin or bcl-2 and the pathological type or tumor type of cervical carcinoma. The infection of HPV16/18 also had nothing to do with the clinical stage or pathological type or tumor type of cervical carcinoma. Inverse correlation was both observed in the expression of survivin and bcl-2 with survival rate. Thus a positive correlation between surviving, bcl-2 and HPV 16/18 was observed in cervical carcinoma. CONCLUSION: Survivin, bcl-2 and HPV16/18 participate in the development of cervical carcinoma. It may be a useful guide in early diagnosis of cervical carcinoma, evaluation of surgery and chemotherapy and prediction of outcome.

BACKGROUND: Hepatic metastasis of colorectal carcinomas is the most important factor in prognosis. We examined the level of apoptosis and proliferation, the expression of survivin, bcl-2, p53 and intratumoral microvessel density (IMVD) in paired tissue specimens of primary human colon tumors and hepatic metastases and determined the molecular biological changes of the tumor cells in liver metastasis. MATERIALS AND METHODS: We examined, immunohistochemically, the level of apoptosis and proliferation, the expression of survivin, bcl-2 p53 and intratumoral microvessel density in 37 paired tissue specimens of primary colon tumors and hepatic metastases. RESULTS: The mean apoptotic index (AI) was 0.60+/-0.45 for the primary colon tumors and 1.22+/-0.73 for the hepatic metastases. The mean proliferative index (PI) was 37.4+/-15.8 for the primary colon tumors and 29.4+/-14.1 for the hepatic metastases. Significantly higher AI and lower PI were observed in the hepatic metastases as compared to the primary colon tumor (p<0.0001 and p=0.0049, respectively). The mean-weighted survivin score was 4.32+/-2.78 for primary colon carcinomas, and 1.54+/-1.77 for the hepatic metastases. The mean-weighted bcl-2 score was 2.62+/-2.62 for the primary colon carcinomas and 0.81+/-1.56 for the hepatic metastases. There were significantly decreased scores of immunostaining for both survivin and bcl-2 in the hepatic metastases as compared to the primary carcinomas (p<0.0001 and p<0.0002, respectively). Nuclear accumulation of p53 was demonstrated in 25 cases (67.6%) of the primary carcinomas and 24.cases (64.9%) of the hepatic metastases, without significant differences. The IMVD was 89.9+/-37.5 for primary colon tumors, while it was 55.1+/-32.5 for hepatic metastases. A statistically significant decrease in the IMVD was observed in the hepatic metastases as compared to the primary colon tumors (p<0.0001). CONCLUSION: These data suggest that the tissue kinetics of colorectal carcinoma cells in hepatic metastases are biologically quite different from those of primary tumors, probably because of co-operative effects of both internal (AI, survivin, bcl-2) and external (IMVD) regulation factors.

OBJECTIVE: To investigate the effect of short hairpin RNA (shRNA) targeting survivin on adhesion and invasion of human colon carcinoma cell line SW480 in vitro. METHODS: According to the sequence of the coding region of survivin gene, two strings of 19 nucleotides of inverted sequence flanking the loop sequence of two complementary 9-base oligonucleotides were designed and synthesized to prepare the hairpin construct as the DNA templates for the target shRNA. The shRNA templates were cloned into shRNA expression vector pRNAT-U6.1/Neo, and the resulted vector pRNAT-U6.1/Neo-survivin was transfected into SW480 cells using Lipofectamine 2000. Western blotting was performed to evaluate survivin gene silencing induced by shRNA transfection at the protein level, and the biological behaviors of the SW480 cells were investigated by cell-matrix adhesion, invasion and gelatin-zymography assays. RESULTS: Western blotting revealed significantly lowered survivin protein expression in transfected SW480 cells, and survivin gene silencing induced by shRNA significantly suppressed the metastatic potential of SW480 cells in association with suppressed MMPs activity. CONCLUSIONS: Survivin may play an important role in modulating human colorectal carcinoma cell invasion and metastasis, and survivin gene silencing can inhibit human colorectal cancer cell invasion and the production of MMP-2 and MMP-9. Survivin may affect invasion and metastasis of human colorectal carcinoma cells via regulating the production of MMPs.

BACKGROUND & OBJECTIVE: Survivin and Livin, members of the family of inhibitor of apoptosis proteins (IAPs), are specially expressed in embryonic cells and tumor cells, but are seldom expressed in normal adult cells. Some studies showed that they are correlated to poor prognosis of some tumors. This study was to detect the expression of Survivin and Livin in DukesoB colorectal cancer, and analyze the clinical significance. METHODS: The expression of Survivin and Livin in 81 specimens of DukesoB colorectal cancer and 12 specimens of normal colorectal tissues was detected by SP immunohistochemistry. Their correlations to clinical features and survival were analyzed. RESULTS: The positive rates of Survivin and Livin were significantly higher in colorectal cancer than in normal colorectal tissues (58.0% vs. 16.7%, 45.7% vs. 8.3%,P < 0.05). No relationship was found between the expression of Survivin and Livin(P > 0.05). The expression of Survivin and Livin was not correlated to sex, tumor location, primary size, T stage, pathologic category, and degree of differentiation(P> 0.05). The positive rate of Survivin was significantly higher in the patients older than 50 years than in the patients younger than 50 years (70.6% vs. 36.7%, P < 0.05). Both Survivin and Livin were correlated to tumor recurrence and/or metastasis (P = 0.02, P = 0.001), and shorter survival (P = 0.039, P = 0.001). Cox multivariate analysis showed stage T4 and positive Livin expression were independent prognostic factors of DukesoB colorectal cancer (P = 0.002, P = 0.047). CONCLUSIONS: Survivin and Livin are overexpressed in DukesoB colorectal cancer. Livin is closely related to recurrence and/or metastasis and poor prognosis of DukesoB colorectal cancer after curative resection.

BACKGROUND: We previously demonstrated that the detection of circulating cancer cells (CCCs) expressing survivin mRNA could provide valuable information for predicting metastasis and recurrence in breast cancer. The objective of this study was to investigate whether or not the detection of survivin expression in the peripheral blood could also have significant effects on the clinical outcomes of patients with gastric and colorectal cancer. METHODS: Survivin-expressing CCCs in peripheral blood samples obtained from 55 gastric cancer patients, 86 colorectal cancer patients, and 87 healthy volunteers were quantitatively examined by using a RT-PCR ELISA. Its clinical significance was statistically evaluated. RESULTS: The CCCs in the peripheral blood samples were detected in 45.4% and 44.0% of gastric and colorectal cancer patients, respectively. The presence of survivin-expressing CCCs was found to be significantly associated with the degree of tumor penetration, nodal status, and disease stages for both types of cancers. During a follow-up period of 36 months, patients who had a positive detection at the time of the initial assay test had a higher relapse rate than those who had a negative detection. As well, survivin-expressing CCCs were statistically shown to be a significant and independent predictor for cancer recurrence. The detection of survivin-expressing CCCs was also demonstrated to be more accurate in terms of predicting recurrence than traditional detection methods such as plasma carcinoembryonic antigen (CEA) measurements. CONCLUSION: The detection of CCCs expressing survivin mRNA could be used to accurately identify gastric and colorectal cancer patients with high risks of relapse.

PURPOSE: Colorectal cancer is one of the most common cancers worldwide. We tested the hypothesis that differences in the expression of certain molecular markers of colon cancer may account for different clinical outcomes. METHODS: Tissue microarray technology was used to assay the expression of 17 biological markers [beta-catenin, CD44v7, c-myc, cyclin D1, estrogen receptor beta, mitogen-activated protein kinase/extracellular signal-regulated kinase, maspin, matrix metalloproteinase-7 (MMP7), p53, Pin1, peroxisome proliferators-activated receptor-gamma, survivin, T cell transcription factor 4 (TCF4), transforming growth factor beta receptor II (TGFbetaR II), TGFbeta, TROP2, and Wnt] by immunohistochemistry in 620 colon cancer patients. The Cox proportional hazards regression model was applied to analyze the lifetime data, including time to death, time to recurrence, and time to liver metastasis. RESULTS: All the markers were present at significantly higher expression levels in tumor specimens than in normal colonic specimens. Kaplan-Meier analysis showed that high expression of TROP2, MMP7, and survivin were related to decreased survival; TCF4 and TROP2 were related to disease recurrence; and CD44v7, cyclin D1, MMP7, p53, survivin, and TCF4 were related to liver metastasis. However, the results of the multivariate analysis only showed that expression of MMP7, survivin, and TROP2 were significant predictors of lower patient survival, while TROP2 and MMP7 were significantly related to disease recurrence and liver metastasis, respectively. CONCLUSIONS: We conclude that elevated survivin, MMP7, and TROP2 expression levels are related to decreased survival. In addition, elevated MMP7 and TROP2 expression levels are predictors of disease recurrence and liver metastasis, respectively.

The prognosis of metastatic cancer patients is still largely affected by treatment failure, mainly due to drug resistance. The hypothesis that chemotherapy might miss circulating tumour cells (CTCs) and particularly a subpopulation of more aggressive, stem-like CTCs, characterized by multidrug resistance, has been recently raised. We investigated the prognostic value of drug resistance and stemness markers in CTCs from metastatic colorectal cancer patients treated with oxaliplatin (L-OHP) and 5-fluoruracil (5-FU) based regimens. Forty patients with metastatic colorectal cancer were enrolled. CTCs were isolated from peripheral blood and analysed for the expression of aldheyde dehydrogenase 1 (ALDH1), CD44, CD133 (used as markers of stemness), multidrug resistance related protein 5 (MRP5 used as marker of resistance to 5-FU and L-OHP) and survivin (used as a marker of apoptosis resistance). CTCs were found in 27/40 (67%) patients. No correlation was found between the expression of either CD44 and CD133 in CTCs and the outcome of patients, while a statistically significant shorter progression-free survival was found in patients with CTCs positive for the expression of ALDH1, survivin and MRP5. These results support the idea that isolating survivin and MRP5+ CTCs may help in the selection of metastatic colorectal cancer patients resistant to standard 5-FU and L-OHP based chemotherapy, for which alternative regimens may be appropriate.

BACKGROUND: The aim of this study was to investigate the association of survivin expression with metastasis of colorectal cancer (CRC). METHODS: RT-PCR and Western blot assays were performed to detect survivin expression in CRC cells and normal intestinal epithelial cell. The expression of survivin gene was also detected in 15 CRC tissues, surrounding and adjacent colon tissues. Moreover, survivin expression in 48 CRC tissues with or without lymph node metastasis was analyzed. Multivariate analysis for lymph node metastasis was performed using logistic regression model. RNA interference was used to inhibit survivin expression in CRC cells and analyze its effect on invasion and metastasis of CRC cells. RESULTS: The expression levels of survivin mRNA and protein were higher in CRC cells than in normal intestinal epithelial cell line. The average levels of survivin mRNA and protein were higher in CRC tissues than surrounding or adjacent colon tissues (P < 0.05). High survivin expression was an independent factor for predicting lymph node metastasis of CRC (P = 0.043). RNAi-mediated survivin knockdown could significantly inhibit in vitro invasion and in vivo metastasis of CRC cells, which might be inactivation of matrix metalloproteinases. CONCLUSION: Targeting survivin will be a potential strategy to suppress metastasis of CRC.

The mitogen-activated extracellular signal-regulated kinase/extracellular signal-regulated kinase (MEK/ERK) and phosphatidylinositol 3-kinase (PI3K)/AKT pathways are often concurrently activated by separate genetic alterations in colorectal cancer (CRC), which is associated with CRC progression and poor survival. However, how activating both pathways is required for CRC metastatic progression remains unclear. Our recent study showed that both ERK and AKT signaling are required to activate eukaryotic translation initiation factor 4E (eIF4E)-initiated cap-dependent translation via convergent regulation of the translational repressor 4E-binding protein 1 (4E-BP1) for maintaining CRC transformation. Here, we identified that the activation of cap-dependent translation by cooperative ERK and AKT signaling is critical for promotion of CRC motility and metastasis. In CRC cells with coexistent mutational activation of ERK and AKT pathways, inhibition of either MEK or AKT alone showed limited activity in inhibiting cell migration and invasion, but combined inhibition resulted in profound effects. Genetic blockade of the translation initiation complex by eIF4E knockdown or expression of a dominant active 4E-BP1 mutant effectively inhibited migration, invasion and metastasis of CRC cells, whereas overexpression of eIF4E or knockdown of 4E-BP1 had the opposite effect and markedly reduced their dependence on ERK and AKT signaling for cell motility. Mechanistically, we found that these effects were largely dependent on the increase in mammalian target of rapamycin complex 1 (mTORC1)-mediated survivin translation by ERK and AKT signaling. Despite the modest effect of survivin knockdown on tumor growth, reduction of the translationally regulated survivin profoundly inhibited motility and metastasis of CRC. These findings reveal a critical mechanism underlying the translational regulation of CRC metastatic progression, and suggest that targeting cap-dependent translation may provide a promising treatment strategy for advanced CRC.

Cortactin, fascin, and survivin have been documented in several human cancers and play important roles in tumor progression. We collected 57 surgical specimens, including esophageal squamous cell carcinomas (SqCC; 7 well-differentiated, 15 moderately differentiated, and 24 poorly differentiated), 3 dysplasias, and 8 normal esophageal tissues. Tissue microarrays were constructed and the immunostaining scores for cortactin, fascin, and survivin were assessed. In 46 SqCC specimens, we examined the relationship between the expression of three biomarkers and tumor differentiation or clinical parameters. Higher immunostaining scores for cortactin, fascin, and survivin correlated positively with tumor differentiation of esophageal SqCC. Univariate survival analysis showed significantly worse prognosis in patients with high scores of cortactin (>or=290), fascin (>or=245), and survivin (score >or= 175), poor differentiation, T4 stage, positive for lymph node metastasis, and positive for distant metastasis. In multivariate survival analysis, high scores of survivin (>or=175) and poor differentiation were independent risk factors for worse prognosis. Our results demonstrated that higher expression of survivin may be related to tumor progression and it is an independent risk factor for poor survival time of esophageal SqCC. Survivin may be a good biomarker to be applied in clinic to predict the prognosis of esophageal SqCC.

AIM: Survivin, a recently identified member of the inhibitor of apoptosis protein family, is expressed during development and in various human cancers. However, its expression in normal tissues and clinical relevance in cancers are still debated. In the present study, we analyzed the expression of the survivin gene in human primary and metastatic gastric cancer cells as well as in paired epithelial cells from normal gastric mucosa by means of a novel laser capture microdissection (LCM) technique coupled with reverse transcription-polymerase chain reaction (RT-PCR). METHODS: Thirty patients who had undergone gastrectomy with lymph node dissection for gastric cancer without preoperative treatments were included. Neoplastic tissue, metastatic lymph nodes, and apparently uninvolved normal tissue were collected from each patient. LCM-captured "pure" cell groups were respectively subjected to RT-PCR analysis with primers specific for the survivin gene. RESULTS: Of the paired samples from 30 gastric cancer patients studied, 24 (80%) primary gastric cancer cell groups and 7 (23%) adjacent morphologically "normal" gastric epithelial cell groups were shown to have a detectable survivin expression. There was a statistically significant difference in suvivin expression between these two groups (P<0.01). Meanwhile, 95% (19/20) of the metastatic gastric cancer cell groups from lymph nodes had a clear expression of te survivin gene. However, no significant correlation between survivin expression and clinicopathological features of gastric cancer was observed in the present study. CONCLUSION: Survivin expression is present in the majority of gastric cancer cell groups obtained by LCM techniques. The high expression rate in metastatic lesions suggests a possible role of survivin in cancer invasiveness and metastasis. It may contribute to the detection of gastric cancer micrometastasis as a potential molecular marker. In addition, the high expression percentage renders survivin a potential target in the therapy for gastric cancer.

AIM: To study the relationship between Survivin and PTEN expression and lymph node metastasis, depth of invasion and prognosis of gastric cancer patients in China. METHODS: Specimens of gastric cancer tissue were collected from the Affiliated Hospital of Jianghan University. All the 140 patients had complete examination data. All lymph nodes were found by the fat-clearing method. The interrupted serial 4-micron sections, routine hematoxylin and eosin staining and immunohistochemical methods were used to detect the lymph node metastases. Gastric cancer tissue microarray was performed to test the expression of Survivin and PTEN (17A) in gastric cancer by immunohistochemical method. All data were processed using chi2 test, Fishers exact test, Kaplan-Meyer Log-rank method and Cox multivariate analysis (SPSS 12.0 software). RESULTS: One hundred and eighteen specimens were used in our tissue microarray (utilization rate was 82.4%). A total of 7580 lymph nodes were found. Metastases were found in 90 specimens and 1618 lymph nodes were detected. The positive rate of Survivin and PTEN expression was 52.5% (62/118) and 76.2% (90/118), respectively. A highly positive correlation was found between Survivin and PTEN expression (chi2 = 4.17, P = 0.04). Survivin expression was positively correlated with UICC N stage (chi 2 = 8.69, P = 0.03) and histological classification (chi2 = 4.41, P = 0.04) by chi2 tests. PTEN expression was positively correlated with depth of invasion (P = 0.02) and histological classification (chi2 = 5.47, P = 0.02). But Survivin and PTEN expressions were not related with prognosis of gastric cancer patients. A significant correlation between lymph node metastasis and prognosis was demonstrated by Cox multivariate analysis (chi2 = 4.85, P = 0.028). CONCLUSION: Survivin is positively correlated with PTEN expression in gastric cancer and is a molecular marker of lymph node metastasis while PTEN expression is a molecular marker of advanced gastric cancer. UICC N stage is the most important prognostic factor of gastric cancer in China.

BACKGROUND: We previously demonstrated that the detection of circulating cancer cells (CCCs) expressing survivin mRNA could provide valuable information for predicting metastasis and recurrence in breast cancer. The objective of this study was to investigate whether or not the detection of survivin expression in the peripheral blood could also have significant effects on the clinical outcomes of patients with gastric and colorectal cancer. METHODS: Survivin-expressing CCCs in peripheral blood samples obtained from 55 gastric cancer patients, 86 colorectal cancer patients, and 87 healthy volunteers were quantitatively examined by using a RT-PCR ELISA. Its clinical significance was statistically evaluated. RESULTS: The CCCs in the peripheral blood samples were detected in 45.4% and 44.0% of gastric and colorectal cancer patients, respectively. The presence of survivin-expressing CCCs was found to be significantly associated with the degree of tumor penetration, nodal status, and disease stages for both types of cancers. During a follow-up period of 36 months, patients who had a positive detection at the time of the initial assay test had a higher relapse rate than those who had a negative detection. As well, survivin-expressing CCCs were statistically shown to be a significant and independent predictor for cancer recurrence. The detection of survivin-expressing CCCs was also demonstrated to be more accurate in terms of predicting recurrence than traditional detection methods such as plasma carcinoembryonic antigen (CEA) measurements. CONCLUSION: The detection of CCCs expressing survivin mRNA could be used to accurately identify gastric and colorectal cancer patients with high risks of relapse.

The aim of this study was to investigate the correlation between the expression of survivin and vascular endothelial growth factorC (VEGFC) in gastric cancer and the pathway by which survivin may affect gastric cancer lymphatic metastasis. The study may provide novel targets for treating gastric cancer lymphatic metastasis and distal dissemination. Survivin and VEGFC expression in gastric carcinoma and pericarcinoma (2 cm away from the carcinoma) tissues, obtained from 195 patients who underwent curative gastrectomy surgery (130 cases presented with lymph node metastasis and 65 cases presented without metastasis), was examined immunohistochemically using a tissue microarray. Plasmids containing survivin and VEGFC shRNA were constructed and transfected into SGC7901 gastric cancer cells. The expression levels of the two genes were examined using western blot analysis and qPCR, and the results were statistically analyzed. The expression levels of survivin and VEGFC were 51.3 and 55.4%, respectively, in gastric carcinoma. Survivin and VEGFC were located mainly in the cytoplasm of the tumor cells. The expression levels of survivin and VEGFC were significantly higher in patients with lymph node metastasis than in those without metastasis (P=0.008 and 0.001, respectively). Patients with high expression levels of survivin and VEGFC showed significantly less favorable survival rates compared with patients with low expression levels of those two genes (P=0.003 and 0.039, respectively). Moreover, patients with coexpression of the two genes usually had a poorer prognosis (P=0.003). However, multivariate analysis demonstrated that neither of the two genes were an independent prognostic determinant. The levels of VEGFC expression may be regulated by survivin expression. Conversely, inhibiting VEGFC gene expression by shRNA did not reduce survivin expression at the mRNA or protein levels. Survivin and VEGFC were expressed in gastric cancer cells and were significantly associated with lymphatic metastasis. Survivin may be a regulator of VEGFC expression in gastric cancer cells, and is essential in invasion and lymphatic metastasis. Moreover, survivin may be able to serve as a chemotherapy target for gastric cancer.

BACKGROUND: Gastric cancer is the second leading cause of cancer-related deaths worldwide, and is characterized by invasion and metastasis. Increasing attention is being focused on discovering molecular markers for diagnosis and prognosis. Our objective was to evaluate PI3K, Akt and survivin protein expression in gastric cancer, and their correlations with clinicohistological features and prognosis in patients with gastric cancer. METHODS: Tissue samples were obtained from 70 patients with gastric cancer patients and 20 patients with normal gastric mucosa. The protein levels of PI3K, Akt and survivin were evaluated by immunohistochemistry. Statistical analyses were performed to establish the correlations between their expressions and patients' clinicopathologic characteristics. RESULTS: The positive expression rates of PI3K, Akt and survivin were significantly higher in the gastric cancer tissues compared to normal gastric mucosa (P<0.05). expression levels of PI3K, Akt and survivin proteins were significantly correlated with TNM stage, differentiation grade, lymph node metastasis and metastases to other organs (P<0.05). Cooperative relationships were identified between PI3K and Akt, and PI3K and survivin (P<0.01), suggesting the involvement of the PI3K/Akt/survivin signaling pathway in the tumorigenesis of gastric cancer. CONCLUSIONS: Protein expression of PI3K, Akt and survivin were significantly associated with the development, progression and metastasis of gastric cancer and may have value as diagnostic and prognostic markers in gastric cancer.

OBJECTIVE: To investigate the expression of Survivin and p63 and their biological significance in laryngeal squamous cell carcinomas (LSCC). METHOD: The expression of Survivin and p63 in 47 cases of tumor tissues, adjacent and normal tissues were detected using in situ hybridization. RESULT: Percentage of Survivin expression was 59.6% (28/47), 25.5% (12/47) in tumor tissues and adjacent tissues respectively. In contrast, normal laryngeal tissues did not express Survivin. Over expression of Survivin was strongly associated with tumor grade, TNM stage and cervical nodal metastasis. Percentage of p63 expression was 91.5% (43/47), 93.6% (44/47), 57.1% (8/14) in tumor tissues, adjacent and normal tissues respectively. The expression of p63 was not related to any clinicopathological features. CONCLUSION: Survivin may play an important role in the pathway of carcinogenesis and progression of LSCC and it may be identified as a new therapeutic target. The up-regulation of the expression of Survivin predicts more invasion and poor prognosis. p63 has less effect on biological behaviors of LSCC.

OBJECTIVE: To study the expressions and biological behavior of Survivin and VEGF in squamous cell carcinoma of larynx (LSCC) and the correlation between Survivin and VEGF. METHOD: The expressions of Survivin and VEGF in LSCC tissues of 40 cases and normal mucosa of larynx tissues of 5 cases were studied by immunohistochemical staining. RESULT: The expressions of Survivin and VEGF in LSCC tissues were higher than those in normal mucosa of laryngeal cavity (P <0.01). The expressions of the two marks in LSCC with the metastasis of lymph nodes were higher than those without metastasis (Survivin: P <0.05, VEGF: P <0.01). Age and sex did not change the expressions obviously (P > 0.05). There was a negative correlation between T-stage and Survivin expressions (P < 0.05). There was also a negative correlation between T-stage and VEGF expressions (P < 0.05). But, there was a positive correlation in staining intensity between Survivin and VEGF (r = 0.676, P < 0.01). CONCLUSION: Significant correlation between Survivin/VEGF expression and T-stage (P <0.05), lymph node metastasis (P <0.05) and prognosis (P <0.01) was revealed in squamous cell carcinoma of larynx. The high expression of it suggests bad prognosis. The up-regulate of the two genes suggest that they play important roles in the formation and metastasis of LSCC.

AIM: To investigate expression and significance of inhibitor of apoptosis protein survivin in hepatocellular carcinoma (HCC). METHODS: The expression of survivin and vascular endothelial growth factor (VEGF) was investigated in 38 cases of HCC tissues and 38 liver cirrhosis tissues by immunohistochemistry and Western blot. The relationship between the expression of survivin and clinicopathological factors of HCC was analyzed. RESULTS: Survivin protein was detected in 23 (60.5%) of 38 HCCs and 3 (7.9%) of 38 liver cirrhosis tissues. In 23 cases of HCC which expressed survivin, the expression of VEGF was positive in 18 cases and slight positive or negative in 5 cases. While in 15 cases of HCC which did not express survivin, 12 cases did not express or slightly expressed, and 3 cases expressed VEGF. In liver cirrhosis tissues, the expression of VEGF was as follows: 24 cases were negative, 10 cases were weak positive and 4 cases were strong positive. The expression of survivin was coincident with the expression of VEGF in HCC (P<0.01). The expression of survivin in HCC had no relationship with the patients' age, gender, tumor size and differentiation level of HCC, while it was related to the metastasis of HCC. The protein quantitative analysis by Western blot also showed that overexpression of survivin in HCC was closely correlated to the expression of VEGF (P<0.01). Furthermore, stronger expression of survivin and VEGF was also found in patients with metastasis rather than in those with no metastasis (P<0.01). CONCLUSION: Survivin plays a pivotal role in the metastasis of HCC, and it has some correlation with tumorigenesis. The expression of survivin in the primary lesion is very useful as an indicator for metastasis and prognosis of HCC. It could become a new target of gene therapy of HCC.

BACKGROUND: Survivin has multiple functions during the progression of cancer. However, the role of survivin in the progression and metastasis of hepatocellular carcinoma (HCC) remains unknown. MATERIALS AND METHODS: Survivin expression in HCC cells (Mahlavu and Hep3B) was assessed using reverse transcription real-time PCR and Western blot analyses. In addition, survivin expression in HCC cells was manipulated using small interfering RNA (siRNA) or overexpression and proliferation and transwell migration assays were performed to monitor the effect of manipulated survivin expression on the growth rate and migratory ability of the transfected cells. RESULTS: Among the HCC cell lines tested, we found high endogenous expression of survivin mRNA and protein in Mahlavu cells. After silencing survivin expression in Mahlavu cells, there was a dramatic decrease in the cell growth rate and an increase in the metastatic potential of the cells. Overexpression of survivin in Hep3B cells suppressed the ability of the cell to migrate. The mechanism of enhanced cell migration caused by decreased survivin expression is mediated through the downregulation of glucose-regulated protein 78 (GRP78) and the upregulation of the epithelial-mesenchymal transition (EMT) marker, vimentin. CONCLUSIONS: Survivin may mediate metastasis in HCC. The knockdown of survivin expression may enhance cancer metastasis through the downregulation of GRP78 and upregulation of vimentin expression.

OBJECTIVE: To study the expression of EGFR, survivn and hnRNPA2/B1 proteins in ThinPrep bronchial brushing cytology specimens and their significance in diagnosis of lung cancer. METHODS: The protein expression of EGFR, survivn and hnRNPA2/B1 was detected by immunocytochemistry (ICC) in the specimens from 110 cases of non-small cell lung cancer (NSCLC), 32 cases of small cell lung cancer (SCLC) and 37 cases of non-neoplastic lung lesions. The relationship between EGFR, survivn and hnRNPA2/B1 protein expression and clinical characteristics of the patients was analyzed using SPSS 16.0 software. RESULTS: (1) Positive expression was observed in 81.1% of NSCLC for EGFR, 66.2% for survivn, 90.9% for hnRNPA2/B1, significantly higher in NSCLC than in the control specimens (P = 0.000, P = 0.000, P = 0.010). The positive expression rate of hnRNPA2/B1 in SCLC was 92.3%, significantly higher than that in the control specimens (P = 0.021). (2) The expression of EGFR was associated with differentiation (P = 0.003), clinical stage (P = 0.023) and lymph node metastasis (P = 0.038), but was not associated with gender, age and histological types. The survivn expression was not related with the above mentioned clinicopathological features (P>0.05). expression of hnRNPA2/B1 was associated with clinical stage (P = 0.017), but not associated with gender, age, histological type, differentiation and lymph node metastasis. (3) There was a significant difference between the co-expression of EGFR and survivn in NSCLC (98.0%) and benign conditions (2.0%, P = 0.000), also a significant difference between the negative expression of both EGFR and survivn in NSCLC (38.2%) and nonneoplastic lesions (61.8%, P = 0.000). CONCLUSIONS: Analysis of EGFR, survivn and hnRNPA2/B1 expression may be an useful adjunct method to stratify controversial cases. The positive expression of EGFR might be associated with invasion, progression and poor prognosis of NSCLC.

A model system of cultivated melanoma cells and melanomas from patients were used in this study to clarify whether survivin protein was involved in UVB induced cell damage and in melanoma progression. The melanoma cells in culture were exposed to different doses of UVB and post-cultivated for various periods of time. Cell viability, apoptotic index and expression of survivin proteins were estimated. expression of the survivin in normal tissue, nevi, primary and metastatic melanomas from the patients were also examined by immunohistochemistry. Results showed that UVB induced cell damage and apoptosis in melanoma cells. Primary and wt p53 cells were more sensitive than metastatic and mutant p53 melanoma cells. expression of survivin protein was markedly decreased in the primary melanoma cells after exposure to UVB compared to the metastasis. The expression was markedly decreased in wt p53 melanoma cells, but not in the mutant p53 melanoma cells. Survivin protein was expressed in nevi, primary and metastatic melanomas. However, the normal tissues were not expressed in the survivin protein. Survivin plays an important role in UVB-induced apoptosis. Overexpression of survivin might be a biomarker for early diagnosis for melanoma.

Survivin and livin are members of the inhibitor of apoptosis protein (IAP) family. We hypothesized that elevated expression levels of these 2 IAP genes in resected advanced-stage metastatic melanoma lesions would be associated with poor disease outcome in patients receiving a polyvalent therapeutic cancer vaccine (Canvaxintrade mark). A quantitative real-time RT-PCR (qRT) assay for survivin and livin genes was used to assess mRNA expression in 63 metastatic melanomas obtained during cytoreductive surgery of American Joint Committee on cancer (AJCC) stage IV melanoma. Nineteen of 63 metastatic melanoma patients received Canvaxin pre- and postoperatively, and 37 patients received only postoperative Canvaxin. expression of survivin and livin protein was assessed by immunohistochemistry (IHC) and then correlated with mRNA. Survivin mRNA was detected in 62 of 63 (98%) melanoma specimens ranging from 0-5.96 x 10(4) mRNA copies of total RNA. Lower mRNA copy levels of survivin significantly correlated with improved overall survival among the 37 patients who received Canvaxin postoperatively but not preoperatively (log-rank test, p = 0.023). Among patients with low survivin mRNA copies, those who received postoperative Canvaxin did significantly better than patients who received pre- and postoperative Canvaxin (p = 0.003). Livin mRNA was detectable in 60 of 63 (95%) metastatic melanoma specimens but had no significant prognostic utility. These studies demonstrate that lower levels of survivin in recurrent metastatic melanomas are associated with significantly improved survival in patients receiving postoperative adjuvant immunotherapy. Overall, the study indicates survivin expression in metastatic melanomas can significantly influence disease outcome and patient responses to immunotherapy.

Survivin is an apoptotic and mitotic regulator that is overexpressed in melanoma and a poor prognostic marker in patients with metastatic disease. We recently showed that Survivin enhances melanoma cell motility through Akt-dependent upregulation of alpha5 integrin. However, the functional role of Survivin in melanoma metastasis is not clearly understood. We found that overexpression of Survivin in LOX and YUSAC2 human melanoma cells increased colony formation in soft agar, and this effect was abrogated by knockdown of alpha5 integrin by RNA interference. We employed melanoma cell xenografts to determine the in vivo effect of Survivin overexpression on melanoma metastasis. Although Survivin overexpression did not affect primary tumor growth of YUSAC2 or LOX subcutaneous tumors, or indices of proliferation or apoptosis, it significantly increased expression of alpha5 integrin in the primary tumors and formation of metastatic colonies in the lungs. Additionally, Survivin overexpression resulted in enhanced lung colony formation following intravenous (i.v.) injection of tumor cells in vivo and increased adherence to fibronectin-coated plastic in vitro. Importantly, in vivo inhibition of alpha5 integrin via intraperitoneal injection of an alpha5beta1 integrin-blocking antibody significantly slowed tumor growth and reduced Survivin-enhanced pulmonary metastasis. Knockdown of alpha5 integrin in cells prior to i.v. injection also blocked Survivin-enhanced lung colony formation. These findings support a direct role for Survivin in melanoma metastasis, which requires alpha5 integrin and suggest that inhibitors of alpha5 integrin may be useful in combating this process.

Cell proliferation and cell death pathways meet at a pivotal crossroad, crucial to maintain normal homeostasis and to eliminate dangerous cells before they start dividing. Survivin (SVV) is an intriguing and fascinating protein at this crossroad that interfaces life and death, through its dual role in facilitating cell division and encountering apoptosis. SVV's prominent expression in essentially all human malignancies, and low or no expression in most normal tissues, suggests that it would be an ideal target for cancer-directed therapy. However, SVV has been recently described as a target for fine tuning by alternative splicing mechanism generating five defined splice variants and a number of other uncharacterized/bizarre isoforms. This diversity indicates that SVV, in addition to its known functions in tumorgenesis, angiogenesis and cardiovascular diseases, might be associated with other unknown functions. Intriguingly, new accumulating evidence from our own work and others, suggest a novel role for SVV in the mechanisms of tumor invasion and metastasis. The SVV pathway has now provided tangible opportunities for targeted, rational cancer therapy. It is therefore an attractive and promising therapeutic target not only for cancer but also for other diseases. Although a number of studies utilizing SVV as an anti-cancer strategy are well underway, further investigation into the exact molecular interactions underpinning its functions is critical for the success of such trials. Impeding development of safe and effective SVV antagonists for clinical use is due to a lack of understanding the molecular mechanisms by which SVV differentially affects apoptosis and cell division in both normal and malignant cells. In this report, in addition to reviewing the SVV known functions, we discuss the newly proposed mechanisms by which SVV might serve as a survival tool for invading tumor cells.

BACKGROUND: Survivin has multiple functions during the progression of cancer. However, the role of survivin in the progression and metastasis of hepatocellular carcinoma (HCC) remains unknown. MATERIALS AND METHODS: Survivin expression in HCC cells (Mahlavu and Hep3B) was assessed using reverse transcription real-time PCR and Western blot analyses. In addition, survivin expression in HCC cells was manipulated using small interfering RNA (siRNA) or overexpression and proliferation and transwell migration assays were performed to monitor the effect of manipulated survivin expression on the growth rate and migratory ability of the transfected cells. RESULTS: Among the HCC cell lines tested, we found high endogenous expression of survivin mRNA and protein in Mahlavu cells. After silencing survivin expression in Mahlavu cells, there was a dramatic decrease in the cell growth rate and an increase in the metastatic potential of the cells. Overexpression of survivin in Hep3B cells suppressed the ability of the cell to migrate. The mechanism of enhanced cell migration caused by decreased survivin expression is mediated through the downregulation of glucose-regulated protein 78 (GRP78) and the upregulation of the epithelial-mesenchymal transition (EMT) marker, vimentin. CONCLUSIONS: Survivin may mediate metastasis in HCC. The knockdown of survivin expression may enhance cancer metastasis through the downregulation of GRP78 and upregulation of vimentin expression.

OBJECTIVE: To evaluate the expression and prognostic significance of survivin, CD117, and C-erbB-2 in neuroendocrine carcinoma of the uterine cervix. MATERIALS AND METHODS: Immunohistochemical stains of survivin, CD117, and C-erbB-2 were evaluated in 100 cases of cervical neuroendocrine carcinoma. The findings were correlated with clinicopathologic variables and disease-free survival. RESULTS: expressions of survivin, CD117, and C-erbB-2 were detected in 27.0%, 12.0%, and 2.0% of the cases, respectively. Survivin-positive patients had a significantly younger mean age than the survivin-negative group (P=0.033). In early-stage cases, tumor recurrence was significantly associated with lymph node metastasis (P=0.005), depth of invasion (P=0.028), and the presence of lymphovascular space invasion (P=0.031) but not with the expression of survivin or CD117. Subgroup analysis in early-stage cases without lymph node metastasis (n=32) showed that only survivin expression had a significant association with decreased disease-free survival (P=0.041). CONCLUSIONS: Survivin expression may be a prognostic indicator for survival in early-stage neuroendocrine carcinoma of the uterine cervix without lymph node metastasis. Adjuvant survivin-targeted therapy may have potential benefit in patients with this tumor.

BACKGROUND AND OBJECTIVE: The expression of transcription factor Elf-1 and inhibitor of apoptosis survivin in non-small cell lung cancer (NSCLC) is correlated with the angiogenic factor vascular endothelial growth factor (VEGF), and are both factors affecting the cell cycle. This study investigated the expression of Elf-1, survivin, and intratumoral microvessel density (iMVD) assessed by monoclonal antibody CD105 in NSCLC, and explored their correlations with clinicopathologic features and angiogenesis of NSCLC. METHODS: PowerVision(TM)-9000 immunohistochemistry was used to evaluate the expression of Elf-1, survivin, and CD105 in tissue microarrays containing 60 specimens of NSCLC and 9 specimens of normal tissue. Western blot analysis was used to evaluate the protein levels of Elf-1 and survivin in 17 specimens of NSCLC and 5 specimens of normal tissue. RESULTS: Elf-1 and survivin were detected in 1 of the 9 normal tissues. The positive rates of Elf-1 and survivin in NSCLC were 70.0% and 65.0%, respectively. The expression levels of both Elf-1 and survivin were significantly related to tumor differentiation, lymphatic metastasis, clinical stage, and postoperative survival time (P < 0.05). Overexpression of both were related to poor prognosis: the survival rates were significantly lower in patients with positive expression than in those with negative expression (P < 0.01). Elf-1 expression was positively correlated with survivin expression (r = 0.769, P < 0.01). Elf-1 and survivin expressions were positively correlated with iMVD (r = 0.446, P < 0.01; r = 0.435, P < 0.01). CONCLUSIONS: The expression of Elf-1 and survivin in NSCLC is related to differentiation, lymphatic metastasis, clinical stage, and prognosis, and both are positively correlated with iMVD. Detection their combined expression can help to predict the malignant behavior of NSCLC. Blocking the activity of Elf-1 and survivin may be a new way to inhibit angiogenesis in NSCLC.

cancerous inhibitor of protein phosphatase 2A (CIP2A) and survivin are aberrantly expressed in a wide range of human cancers, including lung tumors. In order to assess the expressions of these two proteins in Chinese non-small-cell lung cancer (NSCLC) patients and determine their correlation with prognosis, NSCLC tissues and adjacent non-cancerous normal lung tissues were collected from 97 patients undergoing surgical treatment and evaluated by immunohistochemistry staining. CIP2A or survivin immunoreactivity was detected in significantly more NSCLC tissues than in adjacent non-cancerous lung tissues (P < 0.05). Moreover, CIP2A expression in NSCLC correlated with TNM stage, while survivin expression correlated with TNM stage and lymph node metastasis. Kaplan-Meier survival analysis showed that the overall survival times in patients expressing either CIP2A or survivin protein in NSCLC were shorter. COX regression analysis indicated that expression of CIP2A protein was an independent prognostic factor for NSCLC patients (HR = 3.631, P = 0.015). Therefore, CIP2A expression in Chinese NSCLC patients may be a useful biomarker of biological malignancy.

Survivin and Bcl-2 are generally considered to be inhibitors of apoptosis and are frequently overexpressed in several types of human cancers. However, their role in regulating the biological behavior of non-small cell lung carcinoma (NSCLC) remains controversial. We aimed to determine the expression of survivin and Bcl-2 and explore their correlation with clinicopathological features and prognosis. The expression of survivin and Bcl-2 proteins in 62 specimens of NSCLC tissues and 30 specimens of tumor adjacent tissues was detected using immunohistochemistry. The correlation between protein expression and clinicopathological features and prognosis was analyzed. The percentage of survivin-positive samples obtained from NSCLC tissues was 58.06% (36/62), which was significantly higher compared to that in normal lung tissues (10%, 3/30; P<0.05). Similarly, the percentage of Bcl-2-positive samples obtained from NSCLC tissues was statistically higher compared to that from normal lung tissues (51.61%, 32/62 vs. 6.67%, 2/30; P<0.05). Survivin expression was closely correlated with tumor differentiation, lymph node metastasis and TNM stage (P<0.05), while Bcl-2 expression was only associated with TNM stage (P<0.05). The expression of survivin was positively correlated with that of Bcl-2 (P<0.05). A five-year follow-up study revealed that the expression of survivin and Bcl-2 was negatively correlated with post-operative survival duration. Our findings suggest that survivin and Bcl-2 may act synergistically in the occurrence, development, invasion and metastasis of NSCLC, both of which are up-regulated in NSCLC tissues. The co-expression of survivin and Bcl-2, which is closely related to malignancy, may serve as a biomarker for predicting prognosis.

OBJECTIVE: To determine the role of oestrogen receptor alpha (ERalpha) in the regulation of survivin expression by 17beta-estradiol (E(2)) in ovarian cancer cells and to evaluate the mechanism of E(2) action on ovarian cancer cell migration. METHODS: We performed RT-PCR and Western blot analysis to assess the expression of ERalpha in the ovarian cancer cell lines NIH:OVCAR-3 and SKOV-3. Full-length ERalpha cDNA was reintroduced into SKOV-3 cells through stable transfection. After treatment with E(2), with or without pre-incubation of anti-oestrogen compound ICI 182780, RT-PCR and Western blot analysis were performed to detect survivin expression at the mRNA and protein levels. RNA interference (RNAi) was used to inhibit the expression of survivin in SKOV-3 cells. Wound healing-induced migration and Matrigel invasion experiments were performed to determine the motility of ovarian cancer cells. RT-PCR and gelatin zymography were used to detect the expression and activity of MMP-9 in SKOV-3 cells. RESULTS: A stably transfected clone with over-expression of ERalpha, SKOV-alpha, was isolated. Exogenous or endogenous expression of ERalpha in SKOV-3 or NIH:OVCAR-3 cells resulted in a significant up-regulation of survivin in the presence of E(2). Pre-treatment with ICI 182780 attenuated the up-regulation of survivin by E(2). Previous data from our laboratory showed that E(2) enhanced the motility of ovarian cancer cells. RNAi strongly inhibited survivin expression in SKOV-3 cells. Knock-down of survivin expression reduced the migration and invasion of SKOV-3 cells, which correlated with down-regulation of MMP9 mRNA expression and activity. CONCLUSIONS: ERalpha may be responsible for the up-regulation of survivin after E(2) treatment in ovarian cancer cells. The mechanism of oestrogen-promoted ovarian cancer metastasis may due to the up-regulation of survivin conducted through the ERalpha signalling pathway.

OBJECTIVE: To study the expressions and biological behavior of Survivin and VEGF in squamous cell carcinoma of larynx (LSCC) and the correlation between Survivin and VEGF. METHOD: The expressions of Survivin and VEGF in LSCC tissues of 40 cases and normal mucosa of larynx tissues of 5 cases were studied by immunohistochemical staining. RESULT: The expressions of Survivin and VEGF in LSCC tissues were higher than those in normal mucosa of laryngeal cavity (P <0.01). The expressions of the two marks in LSCC with the metastasis of lymph nodes were higher than those without metastasis (Survivin: P <0.05, VEGF: P <0.01). Age and sex did not change the expressions obviously (P > 0.05). There was a negative correlation between T-stage and Survivin expressions (P < 0.05). There was also a negative correlation between T-stage and VEGF expressions (P < 0.05). But, there was a positive correlation in staining intensity between Survivin and VEGF (r = 0.676, P < 0.01). CONCLUSION: Significant correlation between Survivin/VEGF expression and T-stage (P <0.05), lymph node metastasis (P <0.05) and prognosis (P <0.01) was revealed in squamous cell carcinoma of larynx. The high expression of it suggests bad prognosis. The up-regulate of the two genes suggest that they play important roles in the formation and metastasis of LSCC.