Regulation of survivin by PI3K/Akt/p70S6K1 pathway

PI3K activation is commonly observed in many human cancer cells. Survivin expression is elevated in cancer cells, and induced by some growth factors through PI3K activation. However, it is not clear whether PI3K activation is sufficient to induce survivin expression. To investigate the role of PI3K pathway in the regulation of survivin, we expressed an active form of PI3K, v-P3k in chicken embryonic fibroblast cells (CEF), and found that overexpression of PI3K-induced survivin mRNA expression. Forced expression of wild-type but not mutant tumor suppressor PTEN in CEF decreased survivin mRNA levels. PI3K regulates survivin expression through Akt activation. To further investigate downstream target of PI3K and Akt in regulating the expression of survivin mRNA, we found that PI3K and Akt-induced p70S6K1 activation and that overexpression of p70S6K1 alone was sufficient to induce survivin expression. The treatment of CEF cells by rapamycin decreased the survivin mRNA expression. This result demonstrated that p70S6K1 is an important target downstream of PI3K and Akt in regulating suvivin mRNA expression. The knockdown of survivin mRNA expression by its specific siRNA induced apoptosis of cancer cells when the cells were treated with LY294002 or taxol. Taken together, these results demonstrated that PI3K/Akt/p70S6K1 pathway is essential for regulating survivin mRNA expression.     

抗凋亡因子Survivin研究进展

Survivin是在肿瘤组织及胚胎中发现的一类细胞因子,它是IAPs(inhibitorsofapoptosisprotein)家族的成员之一,具有其独特的分子结构和组织表达特异性,在细胞中参与细胞周期的调控,主要在细胞周期的G2/M期通过抑制caspase-3及caspase-7的活性发挥作用.Survivin在细胞中的活性可能受p53的调节.Survivin也是胚胎发育早期过程中调节细胞分裂分化的一类重要的因子.对Survivin的研究对于肿瘤治疗的研究及揭示胚胎早期的发育机制有重要的意义.     

Prognostic significance of survivin expression in renal cell cancer and its correlation with radioresistance

Survivin, an important inhibitor of apoptosis, has been found to play an important role in the initiation, progression, and chemoradioresistance of human malignancies. Previously, we have reported that upregulation of survivin in oral squamous cell carcinoma correlates with poor prognosis and chemoresistance. The aim of this study was to assess prognostic significance of survivin protein expression in RCC and analyze its correlation with radiosensitivity of RCC cells. RT-PCR and Western blot assays were performed to detect survivin mRNA and protein expression in normal human kidney epithelial cell line (HKEC) or RCC cell lines. The expression of survivin mRNA in RCC and corresponding nontumor kidney tissues was also detected by RT-PCR. Immunohistochemistry was performed to determine survivin protein expression in 75 cases of RCC tissue samples. Moreover, the association of survivin protein expression with clinicopathogical factors and prognosis of RCC patients was statistically analyzed. Small interfering RNA was used to knockdown the endogenous survivin expression in RCC cell line (ACHN) and evaluate the effects of survivin knockdown on proliferation, apoptosis, and radiosensitivity of RCC cell line. RCC cells showed sufficient expression of survivin mRNA and protein, but the expression of survivin gene was not detected in normal HKEC. Moreover, the expression level of survivin mRNA in RCC tissues was significantly higher than that in corresponding nontumor kidney tissues. The immunostaining of survivin protein was mainly located in cytoplasm of RCC tumor cells. Tumor pathological stage (P = 0.028), grade (P = 0.004), and lymph node metastasis (P = 0.017) of RCC patients were significantly correlated with survivin protein expression. In addition, patients with high survivin levels had a significantly shorter overall survival than those with low levels (P < 0.001), and the expression of survivin protein was an independent prognostic factor for RCC patients (P = 0.008). The expression of survivin gene could be reduced in RCC cell line and survivin knockdown could inhibit growth and enhance in vivo radiosensitivity of RCC cell line by inducing apoptosis enhancement. Taken together, the status of survivin protein expression may be an independent factor for predicting the prognosis of RCC patients and tumor-specific survivin knockdown combined with radiotherapy will be a potential strategy for RCC therapy.     

靶向Survivin基因与肿瘤

Survivin基因不仅表达于绝大多数的肿瘤细胞中,也存在于人体正常的细胞中,它具有抑制凋亡和调节有丝分裂的双重作用．临床研究表明：下调Survivin基因的表达或者抑制Survivin蛋白的功能,可以降低肿瘤细胞的生长潜力、增加凋亡的比例,而且可以增强肿瘤细胞对抗肿瘤药物和放射线的敏感性．许多抗肿瘤药物通过诱导细胞凋亡而发挥功能．但某些肿瘤表现出对它们的耐药性。导致肿瘤耐药性的一个最重要的因素就是Survivin的表达．有关细胞凋亡途径和Survivin基因表达等方面的研究可为发现和发展新型抗肿瘤药物提供新的途径．     

Survivin regulates the expression of VEGF-C in lymphatic metastasis of breast cancer

ABSTRACT: 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.     

胰腺癌反义寡核苷酸技术治疗的新靶点-survivin

survivin对维持肿瘤细胞恶性增殖具有重要功能,是目前发现IAP家族中唯一与细胞凋亡和周期调控都相关的成员,其机理是与caspase-3、caspase-7结合而阻止细胞凋亡的发生。反义寡核苷酸具有高特异性、靶向性、无毒性等特点。以互补的形式与DNA或RNA的特异靶序列结合,抑制其转录和翻译上特定基因的表达,干扰致病蛋白质的产生,从而使肿瘤基因无法表达。存活素在胰腺癌中的表达具有一定的肿瘤特异性,可能是胰腺癌治疗的一个理想靶目标。下面就着重以survivin作为治疗靶点在肿瘤发生中的作用机制、表达和Survivin ASODN在临床应用中的应用前景作一简要综述。     

Role of survivin in mitosis

Human survivin is a member of the IAP (Inhibitor of Apoptosis) family. It was reported that survivin expression is associated with drug resistance, cancer progression and low patient survival rate in many cancers. Survivin is implicated in both: inhibition of apoptosis and regulation of cell division. As a member of Chromosomal Passenger Complex (CPC) it is involved in sister chromatids segregation during mitosis. On the other hand, survivin plays an important role in the surveillance mechanism called mitotic spindle assembly checkpoint (MSAC) which regulates metaphase to anaphase transition during mitosis. Additionally, survivin is necessary for cytokinesis progression. The present review is a summary of survivin's functions, focused on its role in cell division in normal and cancer cells, as well as introduction to discussion about anticancer therapies based on survivin depletion.     

Rapamycin decreases survivin expression to induce NSCLC cell apoptosis under hypoxia through inhibiting HIF-1α induction

Survivin is a member of the inhibitor of apoptosis protein family that is overexpressed in various tumors and is important in restricting apoptosis. Understanding the molecular events of apoptosis may provide information for developing novel therapeutic agents targeting non-small cell lung cancer (NSCLCs). This study used three human NSCLC cell lines, NCI-H1299, SK-MES-1, and NCI-H460. Changes in apoptosis, the mRNA and protein expression of survivin under normoxia and hypoxia, with or without rapamycin treatment were analyzed. In addition, siRNA and ChIP assay were further applied to demonstrate the role of hypoxia-inducible factor 1 (HIF-1)α in regulating survivin expression regulation under hypoxia during rapamycin induced NSCLC cell apoptosis. Treatment with rapamycin resulted in significantly increased NSCLC cells apoptosis under hypoxia. We demonstrated for the first time that rapamycin inhibited hypoxia-induced survivin expression in NSCLC cell lines. We further demonstrated that HIF-1α participated in hypoxia-induced survivin expression, and that rapamycin inhibited hypoxia-induced HIF-1α expression by enhancing its degradation. The results above collectively showed that rapamycin inhibits HIF-1α-induced survivin expression under hypoxia to induce NSCLC apoptosis.     

COX inhibitors modulate bFGF-induced cell survival in MCF-7 breast cancer cells

Basic fibroblast growth factor (bFGF) serves as a modulator of survival in breast cancer cells. The mechanisms by which bFGF transduces the anti-apoptotic signal and interacts with COX inhibitors were investigated. bFGF reduced apoptosis in MCF-7 breast cancer cells and up-regulated the expression of mitocondrial Bcl-2, whereas COX inhibitors meloxicam (selective COX-2) and aspirin (non-selective), induced apoptosis. bFGF up-regulated survivin protein expression and induced cdc-2 phosphorylation moderately at early (2-6 h), and substantially at late (24 h), time-points. Survivin mRNA expression was up-regulated only at the later time-point. COX inhibitors prevented up-regulation of survivin protein expression at both 2 and 24 h and prevented early modest increases in cdc-2 phosphorylation. Up-regulation of survivin mRNA was not found to be modulated by the COX-2 inhibitor meloxicam. bFGF regulation of survivin expression was found to be ERK1/2 kinase dependent and bFGF-induced phosphorylation of c-raf was prevented by the COX-2 inhibitor. bFGF was, however, unable to induce COX-2 protein expression or modulate COX-2 activity in MCF-7 cells as evidenced by unaltered PGE(2) production. These results indicate that bFGF regulates survivin expression in MCF-7 breast cancer cells by signaling through an ERK1/2 dependent pathway. COX-2 inhibitors can modulate bFGF-induced survivin expression in a COX-2 independent manner.     

OCT4 Positively Regulates Survivin Expression to Promote Cancer Cell Proliferation and Leads to Poor Prognosis in Esophageal Squamous Cell Carcinoma

Background

OCT4 and Survivin are important factors for cancer cell proliferation, renewal and dedifferentiation, and correlate with resistance to radiotherapy and chemotherapy in most human cancers, but their regulatory mechanisms are not well known.

Methodology/Principal Findings

In this study, 50 patients with esophageal squamous cell carcinoma (ESCC) were retrospectively analyzed. OCT4 was expressed in 13 cases (26%), and survivin was positively expressed in 31 cases (62%), examined by immunochemistry. OCT4 was found to be an independent predictive factor for median survival time, and the patients from the subgroup with both high expression of OCT4 and Survivin had the worst prognosis investigated by log-rank test. To further explore the molecular regulatory mechanism between OCT4 and Survivin, we constructed the specific small hairpin RNA (shRNA)-expressing vectors targeting OCT4 or/and Survivin and manipulated the expression of OCT4 and Survivin. By Western blotting and RT-PCR, we found that OCT4 could up-regulate Survivin expression in the esophageal cancer cell lines Eca109 and TE1. Simultaneously knockdown of OCT4 and Survivin expression induced cell apoptosis and G2-phase decrease of cell cycle by flow cytometry, and finally exerted an enhanced anti-proliferation potency in Eca109 and TE1 cell lines by MTT assay.

Conclusions

This study shows that OCT4 and Survivin expression were correlated with poor survival in patients with ESCC. OCT4 and Survivin may be regarded as targets in ESCC biotherapy.     

Expression of survivin mRNA and protein in gastric cancer cell line (MKN-45) during cisplatin treatment

Survivin is a member of the inhibitor of apoptosis protein (IAP) family. Survivin has been reported to be expressed in many cancers, but not in differentiated normal tissue. Recent studies revealed that survivin correlated with the chemo-resitance of cancer cells. In the present study, the changes in expression levels of survivin messenger RNA (mRNA) and survivin protein in a gastric cancer cell line (MKN-45) during cisplatin (CDDP) treatment were analyzed and compared with the occurrence of apoptotic cell death. Cell growth was inhibited even with a low dose CDDP (0.1 or 1 g/ml) 1 hr treatment. However, the percentage of apoptotic cells did not change after 48 hr incubation with low dose CDDP. Only with high dose CDDP (10 g/ml), did the percentage of apoptotic cells explosively increase between 12 and 24 hr treatment. Relative expression levels of survivin mRNA and survivin protein increased after CDDP treatment. The cell expression rates of survivin mRNA after 48 hr treatment with 0.1 and 1 g/ml of CDDP were 2 to 6 fold higher than that of the survivin mRNA of untreated cells. Also, the relative cell expression level of survivin protein after 24 hr treatment with 0.1 or 1 g/ml of CDDP was 3 to 6.5 fold higher than that of the survivin protein of untreated cells. These results indicate that survivin expression may correlate with the chemo-resistance of malignant cells.     

抗凋亡蛋白survivin研究与癌治疗新策略的进展

survivin是凋亡抑制蛋白家族中的一个新成员,在近乎所有的人类肿瘤中都显示高表达,而在终末分化的正常组织中未能检测出表达。survivin表达的另一个独特性质是,其表达受细胞周期调控,在G2／M期有异常高的特异性表达。survivin的功能意义在于参与细胞凋亡调控和细胞分裂调控。引人兴趣的是,新近癌生物学基础与应用研究则更关注它是一个枢纽癌基因。本文将重点讨论与survivin在细胞死亡和细胞分裂功能相联系的、当前一些新的癌治疗策略的进展。     

Oxaliplatin down-regulates survivin by p38 MAP kinase and proteasome in human colon cancer cells

Oxaliplatin, a platinum derivative cancer drug, has been used for treating human colorectal cancers. Survivin has been proposed as a cancer target, which highly expressed in most cancer cells but not normal adult cells. In this study, we investigated the regulation of survivin expression by exposure to oxaliplatin in human colon cancer cells. Oxaliplatin (3–9 μM for 24 h) markedly induced cytotoxicity, proliferation inhibition and apoptosis in the human RKO colon cancer cells. The survivin protein expression of RKO cells is dramatically reduced by oxaliplatin; however, the survivin gene expression is slightly altered. The survivin blockage of oxaliplatin elevated caspase-3 activation and apoptosis in RKO cells. Over-expression of survivin proteins by transfection with a survivin-expressed vector resisted the oxaliplatin-induced cancer cell death. Meantime, oxaliplatin elicited the phosphorylation of p38 mitogen-activated protein (MAP) kinase. SB202190, a specific p38 MAP kinase inhibitor, restored the survivin protein level and attenuated oxaliplatin-induced cancer cell death. In addition, oxaliplatin increased the levels of phospho-p53 (Ser-15) and total p53 proteins. Inhibition of p53 expression by a specific p53 inhibitor pifithrin-α reduced the phosphorylated p38 MAP kinase and active caspase-3 proteins in the oxaliplatin-exposed RKO cells. In contrast, SB202190 did not alter the oxaliplatin-induced p53 protein level. Furthermore, treatment with a specific proteasome inhibitor MG132 restored survivin protein level in the oxaliplatin-treated colon cancer cells. Taken together, our results demonstrate for the first time that survivin is down-regulated by p38 MAP kinase and proteasome degradation pathway after treatment with oxaliplatin in the human colon cancer cells.     

The survivin molecule as a double-edged sword in cellular physiologic and pathologic conditions and its role as a potential biomarker and therapeutic target in cancer

Survivin is a member of the family of apoptosis inhibitory proteins with increased expression level in most cancerous tissues. Evidence shows that survivin plays regulatory roles in proliferation or survival of normal adult cells, principally vascular endothelial cells, T lymphocytes, primitive hematopoietic cells, and polymorphonuclear neutrophils. Survivin antiapoptotic role is, directly and indirectly, related to caspase proteins and shows its role in cell division through the chromosomal passenger complex. Survivin contains many genetic polymorphisms that the role of some variations has been proven in several cancers. The −31G/C polymorphism is one of the most important survivin mutations which is located in the promoter region on a CDE/CHR motif. This polymorphism can upregulate the survivin messenger RNA. In addition, its allele C can increase the risk of cancers in 1.27-fold than allele G. Considering the fundamental role of survivin in different cancers, this protein could be considered as a new therapeutic target in cancer treatment. For this purpose, various strategies have been designed including the prevention of survivin expression through inhibition of mRNA translation using antagonistic molecules, inhibition of survivin gene function through small inhibitory molecules, gene therapy, and immunotherapy. In this study, we describe the structure, played roles in physiological and pathological states and genetic polymorphisms of survivin. Finally, the role of survivin as a potential target in cancer therapy given challenges ahead has been discussed.     

新的凋亡抑制因子Survivin的研究进展

Survivin是近年来发现的一种凋亡抑制因子,属于凋亡抑制蛋白（inhibitor of apoptosis proteins,IAP）家族的新成员;主要通过抑制caspase-3和caspase-7的活性而阻断细胞凋亡过程. Survivin选择性地表达于胚胎发育组织和大多数肿瘤组织,而正常成人终末分化组织中不表达. Survivin参与了细胞周期调控,与肿瘤的发生、发展和预后密切相关,可作为肿瘤治疗的新靶点.