上皮向间质转化在消化道肿瘤中的研究进展

 近年研究发现,肿瘤细胞发生上皮向间质转化（EMT）摆脱细胞与细胞间连接而发生转移侵袭,已成为上皮细胞癌转移侵袭以及化疗耐药的一个重要途径。Snail家族成员,尤其是Snail被认为是肿瘤EMT发生的重要调节因子,它可以通过竞争性抑制E 钙黏蛋白基因的表达,引起上皮细胞向间质细胞表型的转变,最终引起EMT。多项研究显示,在消化系统肿瘤中普遍存在EMT现象,并与这些肿瘤的侵袭转移及化疗耐药密切相关。     

Snail、E-cadherin与上皮性肿瘤浸润、转移的关系

肿瘤经常被看作是正常发育过程的破坏形式,一些在胚胎发育期起重要作用的基因常常在癌组织中被发现,提示它们可能参与一些启动肿瘤发生和促进肿瘤转移的关键步骤,包括局限性侵袭,通过体循环播散,甚至转移。抑制E-eadherin转录的一些调控因子被证明是在胚胎发育期启动上皮细胞问充质转化（epithelial-mesenchymal transition,EMT）的重要基因,Snail家族成员作为一类锌指转录因子在此过程中发挥着主要作用。大量研究表明,转录因子Snail通过与E-cadhefin启动子区的E-盒（E-box）结合,下调E-cadhefin的表达进而诱导EMT的发生。EMT与肿瘤细胞的原位侵袭和远处转移有着密切的关系,目前已成为肿瘤研究中的热点。这对于彻底揭示肿瘤发生发展的细胞分子生物学机制,开发肿瘤治疗的新思路、途径具有重要的理论和实际意义。     

转录因子Snail调控上皮-间质转型及对肿瘤转移的逆转作用

背景与目的:研究表明转录因子Snail调控上皮-间质转型(epithelialtomesenchymaltransition,EMT)与肿瘤转移有一定的相关性。本研究通过观察Snail促进EMT以及反义Snail对肿瘤细胞EMT的逆转,明确Snail在肿瘤转移中的作用。方法:分别以SnailcDNA转染MDCK细胞,反义Snail转染MDA-MB231细胞。Westernblot法检测上皮性标记基因上皮钙粘附素(E-cadherin)、β-连环素(β-catenin)、角蛋白18(Cytokeratin18)与间质性标记基因纤粘蛋白(Fibronectin)及转移相关基因基质金属蛋白酶-2(MMP-2)、RhoA蛋白的改变;细胞划痕实验、Boyden小室体外侵袭实验反映细胞转移潜能的变化。结果:转染SnailcDNA的MDCK细胞,上皮标记基因E-cadherin、β-catenin、Cytokeratin18蛋白表达下调,而间质及转移相关基因Fibronectin、MMP-2、RhoA蛋白表达增强(P<0.05);细胞体外运动力与侵袭力增加(P<0.05);反义Snail转染MDA-MB231细胞后,其实验结果与经SnailcDNA处理后的MDCK细胞相反。结论:Snail能促进正常上皮细胞发生EMT,拮抗肿瘤细胞Snail的表达可逆转EMT表型、降低肿瘤转移潜能。     

miRNA通过转录因子及EMT相关调控蛋白在胃癌侵袭转移中的作用机制研究

微小RNA(miRNA)通过调控原癌基因或抑癌基因,参与胃癌细胞的增殖、凋亡、侵袭和转移过程,也可调控上皮-间充质转化(EMT)的生物学过程。EMT是胃癌侵袭和转移的关键步骤,部分转录因子可通过调控细胞因子及相关信号通路参与EMT过程。转录因子和EMT相关作用蛋白的上游靶基因可能作为肿瘤细胞转移的预测性分子标志物。EMT不仅可参与正常胚胎发育过程中器官和组织的生成,还可促进肿瘤细胞的侵袭和转移,而miRNA可通过多个信号通路参与EMT的调控。本文对参与miRNA调控EMT过程的转录因子进行综述,详细介绍miRNA通过转录因子调控胃癌EMT过程的相关调控机制。     

上皮间充质转化与肿瘤干细胞的研究进展

上皮细胞间充质转化(epithelial-mesenchymal transition, EMT) 在胚胎发育和肿瘤发生中具有重要作用, EMT可使上皮性肿瘤细胞获得间充质细胞表型, 在增强肿瘤细胞的侵袭和转移能力的同时, 也使得肿瘤细胞具有自我更新能力等干细胞样特性。多种转录因子、信号转导通路、microRNAs及细胞微环境等因素共同调控此过程。EMT与肿瘤干细胞之间有密不可分的联系, EMT可以促进肿瘤细胞获得干细胞特征, 具有干细胞特征的肿瘤细胞高表达EMT标记分子, microRNA可同时调控EMT和细胞干性。阐明EMT与肿瘤干细胞的相互关系及其调控机制, 有望为肿瘤转移与复发的靶向治疗开辟新思路。      

肿瘤细胞上皮间质转化表观遗传调控机制的研究进展

上皮间质转化(epithelial to mesenchymal transition,EMT)指上皮细胞向间质细胞转变的现象,其在组织损伤修复等生命过程中是必需的.研究发现,EMT在肿瘤细胞侵袭和转移中发挥至关重要的作用,EMT不仅使肿瘤细胞获得迁移、侵袭、转移能力,同时还与肿瘤细胞抑制衰老和凋亡、抵抗放化疗和形成肿瘤干细胞(cancer stem cells,CSCs)密切相关,因此抑制EMT成为抑制肿瘤转移的新策略.肿瘤细胞EMT受到表观遗传的复杂调控,DNA甲基化、组蛋白修饰、非编码RNA在EMT发生中扮演十分重要的角色,因此肿瘤细胞EMT的表观遗传调控已经成为国内外的研究热点.本文就肿瘤细胞EMT表观遗传调控机制的研究进展予以综述.     

STAT3与上皮-间质转化在肿瘤细胞中的作用及其关系

信号转导与转录激活因子(STAT3)可被多种细胞因子激活,参与肿瘤细胞增殖、血管生成、肿瘤侵袭和化疗耐药等过程.上皮-间质转化(EMT)在肿瘤的侵袭转移及化疗耐药等过程中也起重要作用.研究表明,STAT3可通过调控EMT,改变肿瘤的侵袭转移能力,增强肿瘤细胞对化疗药物的耐药性.探讨STAT3与EMT在肿瘤细胞中的作用及其相互关系有助于为分子靶向治疗提供可靠的理论依据.     

Snail和Claudin-3在非小细胞肺癌中的表达及意义

背景与目的 上皮-间质转化( epithelial mesenchymal transition,EMT)是肿瘤浸润和转移的关键步骤,上皮细胞极性丧失是其主要标志,表现为Claudin等上皮标记丢失.锌指转录因子Snail是调控EMT的重要转录因子,近年来对肿瘤侵袭转移机制研究发现Snail能提高多种肿瘤的侵袭能力.本研究旨在利用组织芯片技术探讨转录因子Snail和紧密连接蛋白(Claudin-3)在非小细胞肺癌(non-small cell lung cancer,NSCLC)及其淋巴结转移灶中的表达和意义.方法 分别采用免疫组织化学MaxVision法和EnVision法检测59例癌旁正常肺组织、302例NSCLC原发灶以及57例淋巴结转移灶中Snail和Claudin-3的表达.结果 Snail在癌旁正常肺组织、NSCLC原发灶以及淋巴结转移灶中的表达逐渐增强,差异具有统计学意义(P＜0.05);Claudin-3在癌旁正常肺组织、NSCLC原发灶以及淋巴结转移灶中的表达逐渐减弱,差异具有统计学意义(P＜0.05).在NSCLC原发灶中,Snail和Claudin-3的表达与肿瘤组织学类型有关(P＜0.05).Spearman等级相关分析显示Snail与Claudin-3的表达呈负相关(r=-0.178,P=0.002).Kaplan-Meier生存分析显示肿瘤大小、组织学类型、病理分级、有无癌转移、TNM分期、Snail的表达以及Snail与Claudin-3的差异性表达影响NSCLC患者的术后生存时间(P＜0.05).Cox回归分析提示肿瘤大小、组织学类型、病理分级、有无癌转移和TNM分期是影响NSCLC患者预后的独立危险因素(P＜0.05).结论 Snail和Claudin-3在NSCLC的浸润、转移中具有重要意义,有助于对NSCLC患者预后的评价.     

与肿瘤转移相关的上皮间质转化信号通路研究进展

恶性肿瘤细胞的侵袭和转移是患者死亡的主要原因,而上皮间质转化（epithelial　mesenchymal　transition,EMT）是肿瘤细胞侵袭和迁移的关键步骤。肿瘤细胞发生上皮间质转化可通过多种信号通路介导产生,深入了解与EMT相关的信号通路,可在信号通路中设立靶点,中止EMT的发生,进而阻止肿瘤侵袭、转移。本文就与肿瘤转移相关的EMT信号通路研究进展作一综述。     

核转录因子-κB与肿瘤上皮间质转化

 核转录因子-κB（NF-κB）是肿瘤上皮间充质转化（EMT）的重要调节因子。肿瘤发生EMT能够增强肿瘤浸润及远处转移能力,是肿瘤耐药的原因之一。目前研究发现,信号转导因子Snail、Slug、Twist、Zeb等在NF-κB调控肿瘤EMT中起重要作用。药物及靶向干扰NF-κB可以逆转肿瘤EMT。NF-κB有望成为将来肿瘤治疗的有效靶点之一。     

Constitutively active MEK1 is sufficient to induce epithelial‐to‐mesenchymal transition in intestinal epithelial cells and to promote tumor invasion and metastasis

Constitutive activation of the MAP kinase kinase MEK1 induces oncogenic transformation in intestinal epithelial cells. Loss of cell–cell adhesion followed by the dissociation of epithelial structures is a prerequisite for increased cell motility and tumor invasion. This phenotypic switch is designated epithelial‐to‐mesenchymal transition (EMT). EMT also plays an important role in determining the dissemination of tumors. However, the role of MEK1 in intestinal EMT, tumor invasion and metastasis has not been elucidated. To determine the functions of activated MEK1 in intestinal tumorigenesis, we established intestinal epithelial cell lines that overexpress wild‐type MEK1 (wtMEK) or activated MEK1 (caMEK). Our results indicate that expression of caMEK is sufficient to induce EMT as confirmed with the induction of N‐cadherin, vimentin, Snail1 and Snail2, whereas a reduction in E‐cadherin, occludin, ZO‐1 and cortical F‐actin was noted. The Snail1 and Snail2 promoter analyses revealed that Egr‐1 and Fra‐1, an AP‐1 protein, are responsible for MEK1‐induced Snail1 and Snail2 expression, respectively. Cells expressing activated MEK1 clearly acquired an invasive capacity when compared to wtMEK‐expressing cells. Zymography studies confirmed elevated levels of MMP2 and MMP9 activities in media of caMEK‐expressing cells. Importantly, cells expressing activated MEK1 induced tumors with short latency in correlation with their ability to induce experimental metastasis in vivo and to express factors known to promote colorectal cancer cell metastasis. In conclusion, our results demonstrate, for the first time, that constitutive activation of MEK1 in intestinal epithelial cells is sufficient to induce an EMT associated with tumor invasion and metastasis. © 2009 UICC     

PRMT9 promotes hepatocellular carcinoma invasion and metastasis via activating PI3K/Akt/GSK‐3β/Snail signaling

Protein arginine methyltransferases (PRMT) catalyze protein arginine methylation and play an important role in many biological processes. Aberrant PRMT expression in tumor cells has been documented in several common cancer types; however, its precise contribution to hepatocellular carcinoma (HCC) cell invasion and metastasis is not fully understood. In this study, we identified a new oncogene, PRMT9, whose overexpression strongly promotes HCC invasion and metastasis. PRMT9 expression was detected more frequently in HCC tissues than in adjacent noncancerous tissues. PRMT9 overexpression was significantly correlated with hepatitis B virus antigen (HBsAg) status, vascular invasion, poor tumor differentiation and advanced TNM stage. Patients with higher PRMT9 expression had a shorter survival time and higher recurrence rate. PRMT9 expression was an independent and significant risk factor for survival after curative resection. Functional studies demonstrated that PRMT9 increased HCC cell invasion and lung metastasis. Knocking down PRMT9 with short hairpin RNA (shRNA) inhibited HCC cell invasion. Further investigations found that PRMT9 increased cell migration and invasion through epithelial‐mesenchymal transition (EMT) by regulating Snail expression via activation of the PI3K/Akt/GSK‐3β/Snail signaling pathway. In clinical HCC samples, PRMT9 expression was positively associated with Snail expression and was negatively associated with E‐cadherin expression. In conclusion, our study demonstrated that PRMT9 is an oncogene that plays an important role in HCC invasion and metastasis through EMT by regulating Snail expression via activation of the PI3K/Akt/GSK‐3β/Snail signaling pathway. Thus, PRMT9 may serve as a candidate prognostic biomarker and a potential therapeutic target.     

Snail is critical for tumor growth and metastasis of ovarian carcinoma

Snail, a key inducer of epithelial‐mesenchymal transition (EMT), plays an important role in cancer metastasis. To better understand the role of Snail in the metastasis of ovarian carcinoma, expression of Snail was knocked down by antisense‐Snail in the highly metastatic ovarian cancer cell line HO8910PM. Gene array analysis revealed that blocking Snail expression suppressed the activity of matrix metalloproteinases (MMPs) and upregulated TIMP3, an MMP inhibitor. These findings suggest that Snail interacts with MMP during tumor invasion and metastasis. In addition, we examined the role of Snail in an ovarian cancer orthotopic model by using the antisense‐Snail HO8910PM cell line. We found that the size of primary ovarian cancer tumor and the number of metastatic lesions were significantly reduced when Snail was knocked down. Confirming our initial findings, the activity of MMP2 was greatly inhibited in tumors from antisense‐Snail cells. Furthermore, immunohistochemical analysis on ovarian cancer progression tissue array demonstrated that the expression of Snail was significantly higher in metastatic lesions, and Snail expression correlated with the stage of ovarian cancer. Interestingly, in early‐stage tumors, Snail was localized in both the cytoplasm and nucleus. In late stage and metastatic lesions, the level of Snail was elevated, and Snail was localized to the nucleus. The expression level and nuclear localization of Snail were also inversely correlated with E‐cadherin expression. Overall, our study indicates that Snail plays a critical role in tumor growth and metastasis of ovarian carcinoma through regulation of MMP activity.     

RhoGDI2 promotes epithelial-mesenchymal transition via induction of Snail in gastric cancer cells

Rho GDP dissociation inhibitor 2 (RhoGDI2) expression correlates with tumor growth, metastasis, and chemoresistance in gastric cancer. Here, we show that RhoGDI2 functions in the epithelial-mesenchymal transition (EMT), which is responsible for invasiveness during tumor progression. This tumorigenic activity is associated with repression of E-cadherin by RhoGDI2 via upregulation of Snail. Overexpression of RhoGDI2 induced phenotypic changes consistent with EMT in gastric cancer cells, including abnormal epithelial cell morphology, fibroblast-like properties, and reduced intercellular adhesion. RhoGDI2 overexpression also resulted in decreased expression of the epithelial markers E-cadherin and β-catenin and increased expression of the mesenchymal markers vimentin and fibronectin. Importantly, RhoGDI2 overexpression also stimulated the expression of Snail, a repressor of E-cadherin and inducer of EMT, but not other family members such as Slug or Twist. RNA interference-mediated knockdown of Snail expression suppressed RhoGDI2-induced EMT and invasion, confirming that the effect was Snail-specific. These results indicate that RhoGDI2 plays a critical role in tumor progression in gastric cancer through induction of EMT. Targeting RhoGDI2 may thus be a useful strategy to inhibit gastric cancer cell invasion and metastasis.