CIAPIN1基因的生物学功能及其与肿瘤的相关性

CIAPIN1是近年通过克隆表达方法鉴定的新基因,已证实其主要受细胞因子的调控,是Ras信号通路的重要介导者。CIAPIN1基因存在显著的细胞凋亡抑制效应,在肿瘤细胞中高表达,能抑制肿瘤细胞的凋亡和促进其细胞周期进程。进一步的研究还发现,CIAPIN1可促进肿瘤新生血管的形成和肿瘤多药抵抗的产生等。     

凋亡抑制蛋白Survivin 研究进展

存活素(Survivin)是凋亡抑制蛋白家族成员之一,具有抑制细胞凋亡和调节细胞周期的双重功能,主要表达于胚胎和发育的胎儿组织中,高表达于大多数恶性肿瘤组织,而在终末分化成熟的正常成人组织中无表达或低表达.本文就Survivin的结构、作用机制、组织分布及其在肿瘤治疗中的研究进展作一综述.     

新的凋亡抑制因子Livin

Livin是新近发现的一个凋亡抑制因子,属于抑制细胞凋亡蛋白(inhibitor of apoptosis protein,IAP)家族的新成员,主要通过抑制胱天蛋白酶-3／-7／-9(caspase-3／-7／-9)的活性来阻断细胞凋亡过程。Livin特异地表达于胚胎发育组织和大多数实体瘤,正常成人的绝大多数组织中也有表达。Livin抑制细胞凋亡,与肿瘤的发生、发展及预后相关,有望成为肿瘤治疗的新靶点。     

Survivin在口腔颌面部上皮性肿瘤中的研究进展

Survivin是近年发现的结构独特的凋亡抑制蛋白家族成员,具有抑制细胞凋亡、调节细胞有丝分裂的双重功能.Survivin具有肿瘤特异性,在正常成人组织中少见表达却高表达于多种肿瘤组织且与肿瘤细胞的浸润和病人的不良预后密切相关.本文对Surviviu的生物学功能及其与口腔颌面部上皮性肿瘤关系的研究进展进行综述.     

XIAP 基因在肿瘤中的研究进展

XIAP(X链锁凋亡抑制蛋白,X-linked inhibitor-of-apoptosis protain)是凋亡抑制蛋白(IAPs)家族中最有效力的caspase抑制物,具有抑制细胞凋亡,参与肿瘤的发生、发展。本文就XIAP在肿瘤中的作用机制、表达及治疗情况做一综述,有望为肿瘤的诊断及治疗提供一个新方法。     

一种抗凋亡蛋白——存活素的研究

存活素(survivin)是一种新近发现的16．5kD细胞内蛋白,属于抗细胞凋亡蛋白家族。在胚胎和各类肿瘤中均表达,但在除胸腺和睾丸以外的成人组织中未被发现。阐明survivin在细胞凋亡和增生中的分子机制及其作用,在抗癌治疗和抑制对机体有害的细胞凋亡方面具有重要意义。     

XIAP在胰腺癌化疗耐药及治疗中的研究进展

X连锁的凋亡抑制蛋白(X-linked inhibitor of apoptosis protein,XIAP)是凋亡抑制蛋白家族中的一员,具有抗凋亡作用.研究发现XIAP在胰腺癌中呈高表达,并且能诱导胰腺癌细胞及组织对化疗耐药.通过在基因水平及蛋白水平降低XIAP的表达对胰腺癌的治疗具有重要意义.AEG 35156是针对XIAP的反义寡核苷酸分子,能够抑制胰腺癌细胞及组织生长.RNAi能够稳定下调胰腺癌细胞中XIAP水平,从而加强TRAIL诱导的细胞凋亡,并能提高胰腺癌细胞对化疗的敏感性.针对XIAP的小分化合物能够抑制XIAP的功能,释放被XIAP抑制的凋亡起始和效应分子以及XIAP抑制的其他促凋亡蛋白,提高多种肿瘤细胞的凋亡指数及对放化疗的敏感性.XAFl能抑制XIAP的抗凋亡作用.本文就XIAP在胰腺癌化疗耐药及治疗中的研究进展做一综述.     

肿瘤细胞中存活蛋白与p53的相互作用

存活蛋白(survivin)作为凋亡抑制蛋白(IAP)家族的最小成员,在肿瘤组织中高表达,且具有严格的细胞周期依赖性,而p53作为细胞周期中的负调节因子,参与了细胞周期调控和细胞凋亡等重要的生物学功能。最近研究表明,存活蛋白与p53的相互作用在肿瘤的发生发展中具有重要作用。该文将从细胞周期与细胞凋亡的角度对存活蛋白/p53通路在肿瘤中的研究进展进行阐明。     

miRNA-125家族与肿瘤关系的研究进展

miRNA-125家族是由在进化上高度保守的miRNA-125a-3p、miRNA-125a-5p、miRNA125b-1、miRNA-125b-2组成,其表达紊乱与肿瘤的发生与发展密切相关。miRNA-125家族的下游靶点包括转录因子如STAT3、细胞因子(如IL-6,TGF-β)、相关蛋白(如抑癌蛋白p53、促凋亡蛋白Bak1、RNA结合蛋白Hu R)等。miR-125家族参与调控这些靶点进而影响肿瘤的发生发展。现主要总结了miRNA-125家族及其靶基因在抑制与促进肿瘤发生、发展方面的双重作用,并从增殖、凋亡、侵袭与转移和免疫反应等4个方面详细阐述了其作用机制。     

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.     

Distribution of CIAPIN1 in normal fetal and adult human tissues.

CIAPIN1, a newly identified antiapoptotic molecule that plays an essential role in mouse definitive hematopoiesis, is considered a downstream effector of the receptor tyrosine kinase-Ras signaling pathway. Our previous studies have indicated that CIAPIN1 is involved in the development of multidrug resistance (MDR) in gastric cancer cells. However, the mechanism of CIAPIN1-mediated antiapoptosis and MDR has not been fully elucidated. To reveal the possible physiological role of CIAPIN1, we examined the expression and distribution of CIAPIN1 in fetal and adult human tissues using immunohistochemistry. We found that CIAPIN1 was ubiquitously distributed in fetal and adult tissues, and was localized in both the cytoplasm and the nucleus. The expression patterns of CIAPIN1 were similar in fetal and adult tissues, and was correlated with the previously described expression pattern of p21ras. These observations suggest that CIAPIN1 expression appears to be involved in cell differentiation, and that it might exert universal and possibly important physiological functions under the regulation of Ras in humans.     

CIAPIN1 nuclear accumulation predicts poor clinical outcome in epithelial ovarian cancer

ABSTRACT: BACKGROUND: Epithelial ovarian cancer (EOC) is an aggressive disease with poor prognosis. The expression of cytokine-induced apoptosis inhibitor 1 (CIAPIN1) correlates with the malignant progression of several cancers. However, the relationship between the subcellular localization of CIAPIN1 and clinical characteristics in EOC remains unclear. METHODS: Immunohistochemistry was performed to detect CIAPIN1 expression in 108 EOC tissues. CIAPIN1 expressions in eight fresh EOC tissues were detected by Western blotting. The relationship between CIAPIN1 subcellular expression and patients? clinicopathological features, including prognosis, was evaluated. Immunohistochemistry and immunofluorescence were employed to assess the CIAPIN1 subcellular localization in the EOC cell lines A2780 and HO8910. In addition, all patients were followed up to assess the prognostic value of CIAPIN1 in patients with EOC. RESULTS: CIAPIN1 is highly expressed in EOC, but is present at low levels in paired non-cancerous ovarian epithelial tissues. The results of Western blotting were in accordance with the immunohistochemical results. Poor differentiation of the tumors and EOC cell lines correlated with higher levels of CIAPIN1 nuclear expression. CIAPIN1 nuclear expression significantly correlated with the Federation International of Gynecology and Obstetrics (FIGO) stage and histological differentiation (     

Subcellular localization of CIAPIN1.

Cytokine-induced apoptosis inhibitor 1 (CIAPIN1) is a newly identified anti-apoptotic molecule. Our previous studies have demonstrated that CIAPIN1 is ubiquitously expressed in normal fetal and adult human tissues and confers multidrug resistance in gastric cancer cells, possibly by upregulating the expression of multidrug resistance gene 1 and multidrug resistance-related protein 1. However, fundamental biological functions of CIAPIN1 have not been elucidated. In this study, we first predicted the subcellular localization of CIAPIN1 with bioinformatic approaches and then characterized the intracellular localization of CIAPIN1 in both human and mouse cells by a combination of techniques including (a)immunohistochemistry and immunofluorescence, (b) His-tagged CIAPIN1 expression, and (c)subcellular fractionation and analysis of CIAPIN1 in the fractions by Western blotting. All methods produced consistent results; CIAPIN1 was localized in both the cytoplasm and the nucleus and was accumulated in the nucleolus. Bioinformatic prediction disclosed a putative nuclear localization signal and a putative nuclear export signal within both human and mouse CIAPIN1. These findings suggest that CIAPIN1 may undergo a cytoplasm-nucleus-nucleolus translocation.     

Successful expression and purification of human CIAPIN1 in baculovirus-insect cell system and application of this system to investigation of its potential methyltransferase activity

CIAPIN1 is a newly identified anti-apoptosis molecule which plays an important role in definitive haematopoiesis in mouse fetal liver and confers multidrug resistance in gastric cancer cells. However, the biophysical function of CIAPIN1 is far from elucidated. Bioinformatics predicts that CIAPIN1 may contain a generic methyltransferase motif and a Zn-ribbon-like motif. Based on these data, we postulated that CIAPIN1 might be a DNA or RNA methyltransferase. To substantiate this proposal, recombinant human CIAPIN1 (rhCIAPIN1) was expressed by a baculovirus-insect cell system and purified by Ni-NTA affinity chromatography. In vitro DNA and RNA methyltransferring tests, DNA demethylation test and S-adenosyl-l-[methyl-3H]methionine (3H-AdoMet) binding test were carried out. Our experiments failed to demonstrate that rhCIAPIN1 had any DNA, RNA methyltransferase activity, DNA demethylase activity, or had the capability of binding AdoMet in vitro. Further studies are needed to definitely clarify whether CIAPIN1 has methyltransferase activity.     

Wogonin enhances antitumor activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo through ROS-mediated downregulation of cFLIPL and IAP proteins

Combination of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) with other agents is a promising strategy to overcome TRAIL resistance in malignant cells. Wogonin, a flavonoid originated from Scutellaria baicalensis Georgi, has been shown to enhance TRAIL-induced apoptosis in malignant cells in in vitro studies. However, whether wogonin enhances TRAIL’s antitumor activity in vivo has never been studied. In this study, the effect of combination of TRAIL and wogonin was tested in a non-small-cell lung cancer xenografted tumor model in nude mice. Consistent with the in vitro study showing that wogonin sensitized A549 cells to TRAIL-induced apoptosis, wogonin greatly enhanced TRAIL-induced suppression of tumor growth, accompanied with increased apoptosis in tumor tissues as determined by TUNEL assay. The expression levels of antiapoptotic proteins including long form of cellular FLICE-like inhibitory protein (cFLIP_L), X-linked inhibitor of apoptosis protein (XIAP), and cellular inhibitor of apoptosis protein 1 and 2 (cIAP-1 and cIAP-2) were markedly reduced in both cultured cells and xenografted tumor tissues after co-treatment with wogonin and TRAIL. The down-regulation of these antiapoptotic proteins was likely mediated by proteasomal degradation that involved intracellular reactive oxygen species (ROS), because wogonin robustly induced ROS accumulation and ROS scavengers butylated hydroxyanisole (BHA) and N-acetyl-l-cysteine (NAC) and the proteasome inhibitor MG132 restored the expression of these antiapoptotic proteins in cells co-treated with wogonin and TRAIL. These results show for the first time that wogonin enhances TRAIL’s antitumor activity in vivo, suggesting this strategy has an application potential for clinical anticancer therapy.