FoxO3a转录因子在肿瘤治疗中的作用

FoxO3a是叉头基因（Forkhead）转录因子家族的一个重要成员,在抑制肿瘤发生发展、细胞周期调控、DNA损伤修复、细胞增殖凋亡及应激反应中发挥重要作用,并参与调节干细胞的保持和分化。FoxO3a作为抑癌基因,其激动剂与化疗药物联合应用可提高肿瘤细胞药物敏感性。文章就FoxO3a在肿瘤治疗中的作用作一综述,旨在揭示靶向FoxO3a对于肿瘤治疗的潜在意义。     

TRAIL与泌尿系肿瘤研究进展

肿瘤坏死因子相关凋亡诱导配体（TRAIL）是选择性诱导肿瘤细胞凋亡的重要代表。TRAIL通过与其配体相互作用,并且通过各种信号通路从而诱导肿瘤细胞凋亡。TRAIL具有特异性靶向癌细胞的能力,而对正常细胞没有影响。近年来,越来越多的临床试验证明TRAIL联合各种增敏剂在抗肿瘤方面具有独特的优势。本文就其结构功能、信号通路及诱导泌尿系肿瘤凋亡研究中的最新进展做如下综述。     

紫花牡荆素对SKOV3卵巢癌干细胞样细胞FoxO3a磷酸化的影响

背景与目的：肿瘤干细胞的存在是卵巢癌高复发率和高死亡率的原因。本文研究紫花牡荆素(casticin,CAS)对SKOV3细胞系卵巢癌干细胞样细胞(ovarian cancer stem cell like cells,OCSLCs)自我更新能力的影响及其机制。方法：体外培养SKOV3细胞系细胞,干细胞培养基悬浮培养SKOV3得到和扩增卵巢癌球形成细胞,即OCSLCs。蛋白［质］印迹法(Western blot)分析FoxO3a磷酸化水平。FoxO3a特异性siRNA转染抑制FoxO3a蛋白表达,并测定肿瘤球形成率。结果：与亲本细胞相比,OCSLCs高表达磷酸化FoxO3a蛋白,具有更高的肿瘤球形成率［(3.1±0.3)% vs (34.8±6.8)%,P＜0.05］。CAS显著抑制OCSLCs肿瘤球形成能力,并降低FoxO3a磷酸化水平。FoxO3a特异性siRNA转染抑制FoxO3a蛋白表达,拮抗CAS抑制OCSLCs肿瘤球形成作用。结论：降低FoxO3a磷酸化水平参与CAS抑制SKOV3细胞系OCSLCs肿瘤球形成作用。     

CD146与泌尿系肿瘤关系的研究进展

CD146属于免疫球蛋白超家族（IGSF）成员,CD146的高表达与黑素瘤、前列腺癌等多种肿瘤发生及转移密切相关。然而,令人难以相信的是CD146 在乳腺癌的表达与其他肿瘤的情况有所不同,其在乳腺癌中的表达明显降低,似乎提示CD146 抑制乳腺的发生及进展。本文就CD146基因的结构、特征、功能及其泌尿系肿瘤的关系作一系统综述。     

FoxO3a在三氧化二砷诱导的人乳腺癌MCF-7细胞凋亡中的表达和意义

目的 探讨FoxO3a在三氧化二砷(As2O3)诱导人乳腺癌细胞MCF-7凋亡过程中的表达变化及其可能的机制。方法 将不同浓度的As2O3(2.0、4.0、8.0μmol/L)与MCF-7细胞共同培养24h后,采用流式细胞术检测MCF-7细胞凋亡;采用免疫细胞化学及Western blot技术检测FoxO3a和Caspase 3蛋白的表达,各实验均设相应的阴性对照组。结果 经不同浓度As2O3作用后,MCF-7细胞凋亡率逐渐增加,分别为(6.26±0.94)%、(9.30±1.63)%和(13.02±3.82)%,且呈剂量依赖关系(rs=0.949, P<0.01);免疫细胞化学染色显示FoxO3a蛋白胞核表达增强,且Caspase-3蛋白表达增强（P<0.05);Western blot条带显示FoxO3a蛋白表达水平逐渐升高,且激活型Caspase-3蛋白表达水平逐渐升高（P<0.05)。结论 As2O3可通过增强FoxO3a蛋白的活性,激活Caspase-3蛋白的表达而诱导MCF-7细胞凋亡。     

铁死亡与泌尿系肿瘤的研究进展

摘 要：铁死亡是一种不同于细胞凋亡和坏死的新型死亡类型,主要依赖细胞内铁和脂质氧自由增多、氧化还原稳态失衡而引起的细胞死亡。泌尿系肿瘤发展至中晚期后,大部分患者手术效果不佳,术后通常给予化疗,但有些肿瘤细胞出现对化疗药物的耐受,因此,铁死亡的出现,在泌尿系肿瘤治疗方面增加了新的思路。全文概述铁死亡机制和调节的知识,及其在泌尿系肿瘤细胞生长和增殖中的作用,以期为泌尿系肿瘤的治疗提供新策略。     

凋亡抑制基因Livin与泌尿系肿瘤的研究进展

Livin是凋亡抑制蛋白（ inhibitor of apoptosis proteins,IAPs）家族的最新成员,其在正常成人的大多数终末分化组织中不表达或低表达,而在许多恶性肿瘤组织中明显过表达。Livin及其相关基因的检测,对肿瘤的早期诊断和预后判断具有参考价值;靶向抑制肿瘤细胞中Livin的表达,能为肿瘤的治疗开辟新途径。本文就Livin基因与泌尿系肿瘤的国内外研究进展及其与肿瘤靶向治疗的研究近况予以综述。     

蛋白质组学研究进展及在泌尿系肿瘤研究中的应用

  蛋白质组学是一门以蛋白质组为研究对象、以全面的蛋白质性质研究为基础，在蛋白质水平对疾病机制进行探索的科学。蛋白质芯片SELDI- TOF-MS技术是蛋白质组学研究的全新技术平台，具有广阔的应用前景。作者就蛋白质组学相关技术原理、研究进展及在泌尿系肿瘤研究中的应用作了阐述。     

FoxO3a and nilotinib-induced erythroid differentiation of CML-BC cells

We explored the potential involvement of FoxO3a activation in erythroid and granulocytic differentiation for Ph⁺ cells of chronic myeloid leukemia blast crisis (CML BC). We demonstrate that FoxO3a activation in CML blast crisis (BC) cells by overexpressing FoxO3a leads to the maturation of CML BC cells. Hemoglobin production significantly increased upon FoxO3a activation in CML BC cells. FoxO3a activation upregulated erythroid surface protein (glycophorin A, GPA), but did not significantly modulate granulocytic markers (CD11b). Additionally, FoxO3a activation reduced the mRNA and protein expression of Tal1. Similar results were observed in cells that were given nilotinib. Our results indicate that FoxO3a activation may promote erythroid differentiation of BC cells via down-regulating Tal1 expression.     

Inhibition of AKT/FoxO3a signaling induced PUMA expression in response to p53-independent cytotoxic effects of H1: A derivative of tetrandrine

PUMA (p53 unregulated modulator of apoptosis), a BH3-only Bcl-2 family member, can be induced by p53-dependent and p53-independent manners. It plays an important role as regulator of cellular apoptosis. Herein, we evaluate the effects of H1 (a derivative of tetrandrine) on induction of PUMA and underlie its potential mechanism in p53-independent cytotoxic response. Anti-proliferative activity and evidently cytotoxic activity of H1 were observed in wild-type and p53 null cells. Further studies demonstrated that H1 resulted in an increase of cleaved PARP, decease of survivin and elevation of p-H2AX. What is more, H1 significantly induced PUMA expression in a concentration- and time-dependent manner and caused an increase of Bax/Bcl-2 ratio in p53 null cells. Of note, knockdown of PUMA attenuated cytotoxic activity of H1. Further studies demonstrated that inhibition of AKT/FoxO3a signaling contributed to H1-mediated PUMA induction. Targeted suppression of AKT/FoxO3a signaling by siRNA could overcome H1-mediated PUMA induction. In addition, H1 significantly suppressed NF-κB activity and caused an increase of early apoptotic and late apoptotic cells, and elevated caspase-3 activity. Taken together, we found that inhibition of AKT/FoxO3a signaling may contribute to H1-mediated PUMA induction, suggesting that inhibition of AKT/FoxO3a signaling result in PUMA expression in response to p53-independent cytotoxic effects of H1.     

Wnt5a Signaling--A New and Attractive Target for Specific Anticancer Therapy

Wnt signaling has been shown to engage a multifunctional pathway that is involved in the regulation of a wide variety of normal and pathologic processes, including embryogenesis, differentiation and tumorigenesis. Recent studies have demonstrated that Wnt5a expression is frequently seen in various human cancers. In contrast to the transforming members of the Wnt family, shown to be upregulated in many cancers, the role of Wnt5a is still controversial in its expression in different tumors. There is increasing evidence that Wnt5a has tumor suppressor function in some malignancies, and in addition, it elicits promigratory and proinvasive effects via the planar cell polarity pathway, which suggests that Wnt5a might be an effective marker for the progression and prognosis of tumors. Obviously,the outcome of Wnt5a signaling is dependent on a multitude of variables, ranging from receptors, downstream effectors and inhibitors, to external influences coming from the tumor microenvironment. This review will focus on the role of Wnt5a signaling and, as a consequence, provide an outline describing the expression and functions of Wnt5a in cancer progression.     

双硫仑的抗肿瘤作用及在泌尿系肿瘤中的研究进展

双硫仑（disulfiram,DSF）为一种安全有效的戒酒药物。大量临床前研究表明,DSF具有明显的抗肿瘤作用,其抗肿瘤的分子机制包括乙醛脱氢酶（ALDH）抑制作用、抑制丝氨酸生物合成、诱导凋亡、抑制泛素-蛋白酶体蛋白核蛋白定位蛋白4(NPL4)和提高化疗药物的敏感性等。本文详细论述了双硫仑抗肿瘤活性成分、分子机理以及在泌尿系肿瘤中的研究进展及其应用前景。     

PI3K-Akt信号通路与肿瘤相关性的研究进展

PI3K-Akt信号通路作为细胞内重要信号转导通路之一,通过影响下游多种效应分子的活化状态,在体内发挥着促进细胞增殖和抑制凋亡的关键作用,它与人类多种肿瘤的发生和发展密切相关。本文就PI3K—Akt信号通路的功能、调节与肿瘤的相关性及其在肿瘤治疗中的应用等方面进行文献综述,以期能为以PI3K-Akt信号通路中某些关键分子为靶点的肿瘤治疗及靶向药物研究提供参考。