Rho蛋白在肿瘤发生发展中的作用

Rho蛋白是参与细胞内信号转导的重要蛋白,Rho家族成员及其各自的已知下游效应分子参与调节细胞的增殖、基因表达,同时是改变细胞骨架组装、调控细胞迁移进而参与肿瘤发生发展的关键因子,具有潜在而罩要的临床应用价值。     

RHGAPs分子与结直肠癌侵袭及转移关系的研究进展

Rho家族参与细胞形态、细胞骨架重组、细胞与基质黏附、细胞周期、细胞凋亡等过程。ARHGAPs作为Rho家族的分子开关，可以极大地提高Rho蛋白内在的RhoGTPase活性，负性调控Rho蛋白，在多种恶性肿瘤的侵袭和转移中发挥重要作用。在结直肠癌组织中，一些ARHGAPs表现出抑制肿瘤侵袭和转移的作用，值得进一步深入研究。     

埃兹蛋白与肿瘤转移相关信号通路的研究进展

埃兹蛋白（Ezrin）不仅参与细胞形态的维持、细胞运动及黏附过程,而且参与肿瘤侵袭和转移的多个环节。Ezrin蛋白在肿瘤转移中参与多个肿瘤相关信号通路如Rho介导的信号转导通路、肝细胞生长因子（HGF）通路、Fas介导的细胞凋亡信号通路、磷脂酰肌醇-3激酶（P13K）-蛋白激酶C（Akt）通路等,并在其中发挥不同的调节作用。     

Rho蛋白在消化系统恶性肿瘤侵袭与转移方面的研究

Rho蛋白是一种小分子G蛋白(small G protein,CTPase),其最重要的功能是调节肌动蛋白细胞骨架,从而参与细胞迁移、调控肿瘤转移,因此,Rho蛋白与消化系统恶性肿瘤侵袭与转移的关系,已成为研究的前沿领域之一.     

Diaphanous相关成蛋白家族的研究

具有两个formin同源结构域(FH1和FH2)的成蛋白(Formins)家族,是维持细胞骨架肌动蛋白的重要调节因子.Diaphanous相关成蛋白家族因具有GTPase结合结构域(GBD)和Diaphanous 自调控结构域(DAD)而被划分为成蛋白家族的一个亚类,该亚家族对细胞黏附、运动、胞质分裂、形态发生、细胞极性的形成、血清反应因子的激活等起重要的调控作用,参与Rho/Rock细胞信号转导通路,并通过调节肌动蛋白细胞骨架重组,促进肿瘤细胞的迁移、侵袭和转移.对Diaphanous相关成蛋白亚家族的深入研究,有助于进一步揭示肿瘤细胞的侵袭和转移机制,并可能为临床提供新的治疗靶点.     

Rho蛋白及其抑制剂

Rho蛋白在调节肿瘤细胞功能方面起着关键作用,包括肿瘤细胞的恶性转化、细胞的移动、细胞周期和细胞凋亡,其中每个环节对肿瘤细胞的发生和进展都极为重要.特异的Rho蛋白抑制剂可以逆转肿瘤细胞的恶性表型,从而达到抗肿瘤治疗的目的.     

癌基因RhoA对乳腺癌细胞血管内皮生长因子表达的调控机制研究

目的探讨乳腺癌细胞MDA-MB-231中癌基因Rho A对VEGF蛋白表达和胞外分泌的影响及可能的分子机制。方法将Rho A过表达质粒pc DNA3.0-V14Rho A、对照质粒pc DNA3.0、Rho A沉默质粒pc DNA3.0-shRho A转染到MDA-MB-231细胞中,通过Western blot和ELISA实验分别检测细胞内外VEGF蛋白的表达,通过Western blot和实时PCR方法分别检测Rho A对p53表达的影响及对VEGF的调控作用。均数比较用t检验;计量资料用x^-±s表示,采用方差分析。结果 MDA-MB-231细胞中上调Rho A表达后,胞内VEGF的蛋白表达水平增加;胞外分泌水平显著增加,与对照组相比差异具有统计学意义（F=4.020,P=0.032）;MDA-MB-231细胞中沉默Rho A表达后,胞内VEGF的蛋白表达水平降低;胞外分泌水平显著降低,与对照组相比差异具有统计学意义（F=5.131,P=0.001）;并且与0 h相比,在MDA-MB-231细胞中上调Rho A可以抑制p53的表达（48 h：F=3.231,P=0.043）,而p53表达的降低可以增加VEGF的表达水平（48 h：F=3.226,P=0.015）,均差异具有统计学意义。结论乳腺癌细胞MDA-MB-231中Rho A表达的变化可以引起胞内外VEGF水平的变化,并且Rho A可能是通过抑制p53的表达从而增加VEGF表达。     

p21激活激酶在肿瘤中的作用及其靶向治疗

p21激活激酶(p21-activated kinases,Paks)是一类丝氨酸/苏氨酸激酶,在进化上高度保守.Paks可被多种上游信号特别是小G蛋白Rho家族的Rac和Cdc42激活,对多种重要的信号通路及细胞功能进行调控.Paks在多种肿瘤中异常表达,参与细胞骨架重构、细胞运动、细胞增殖、分化、凋亡、有丝分裂及血管生成等,在肿瘤的发生、发展中起重要作用.因此,开展Paks靶向治疗的研究,可为肿瘤治疗提供新的思路.     

D4-鸟苷酸解离抑制因子在肺癌发病机制中的研究进展

D4-鸟苷酸解离抑制因子（GDI）是RhoGDP解离抑制因子家族的主要成员之一,抑制Rho蛋白与GDP解离,参与细胞的收缩、黏附、迁移、增殖、凋亡等多种生物学行为。目前已证实D4-GDI参与了肺癌等多种呼吸系统疾病的病理生理过程,干预D4-GDI的表达能够改善这些疾病的病理改变与预后。     

Rho家族在肿瘤组织的表达及临床意义

Rho即Ras相似物(Ras homologue),在细胞信号传导中具有重要的功能。近年来研究发现Rho家族成员在睾丸精细胞癌、结直肠癌、乳腺癌、胰腺导管腺癌、前列腺癌等癌组织中表达增加,参与多种肿瘤的发生发展过程,提示其可能成为一种新的肿瘤标志物,用于判断良恶性及判断肿瘤转移能力及估计预后,并为控制肿瘤转移提供新的靶点,具有潜在的重要临床价值。     

Rho, Rac, Pak and angiogenesis: old roles and newly identified responsibilities in endothelial cells

Angiogenesis-the develoment of microvasculature-requires, in part, directed endothelial cell motility and responsiveness to external signals. Several of the proteins, which modulate and/or direct endothelial cell motility and morphology in angiogenesis are the Rho GTPases (Rho, Rac, and Cdc42) and Pak (a downstream effector of Rac and Cdc42). Previously, overexpression and activation of Rho GTPases and Pak had been implicated in the development of cancer, through their roles in cancer cell transformation, stimulation of proliferation, inhibition of apoptosis, and migration. Yet regardless of the transformed status of cells within a tumor, without a blood supply most tumors cannot grow larger than 1-2 mm. The blood supply in tumors is provided by capillaries formed of endothelial cells in a process called angiogenesis. Consequently, there is enormous interest in the role of the wild type endothelial cells-and the signaling mechanisms required to support angiogenesis and subsequent growth of metastatic and aggressive cancers. Recent work has begun to uncover the roles of the Rho GTPases and Pak in the regulation of normal endothelial cell function. This review will discuss the current literature regarding the roles of Rho and Rac, and the Rac effector-Pak, in endothelial cells, and we will propose new avenues of research for interaction of the AGC kinase-PKG, with the Rho GTPases and Pak in the cell motility and cell morphology of endothelial cells.     

Ionizing radiation-induced E-selectin gene expression and tumor cell adhesion is inhibited by lovastatin and all-trans retinoic acid

E-selectin mediated tumor cell adhesion plays an important role in metastasis. Here we show that ionizing radiation (IR) induces E-selectin gene and protein expression in human endothelial cells at therapeutically relevant dose level. E-selectin expression is accompanied by an increase in the adhesion of human colon carcinoma cells to primary human umbilical vein endothelial cells (HUVEC). The HMG-CoA reductase inhibitor lovastatin impairs IR-stimulated E-selectin expression as analyzed at the level of the protein, mRNA and promoter. Inactivation of Rho GTPases either by use of Clostridium difficile toxin A or by co-expression of dominant-negative Rho blocked IR-induced E-selectin gene induction, indicating Rho GTPases to be essential. Radiation-induced expression of E-selectin was also blocked by all-trans retinoic acid (at-RA), whereas 9-cis retinoic acid was ineffective. Abrogation of IR-stimulated E-selectin expression by lovastatin and at-RA reduced tumor cell adhesion in a dose-dependent manner. Combined treatment with lovastatin and at-RA exerted additive inhibitory effects on radiation-induced E-selectin expression and tumor cell adhesion. Therefore, application of statins and at-RA might have clinical impact in protecting against E-selectin-promoted metastasis, which might arise as an unwanted side effect from radiation treatment.     

DLC2/StarD13 plays a role of a tumor suppressor in astrocytoma

Astrocytomas are tumors occurring in young adulthood. Astrocytic tumors can be classified into four grades according to histologic features: grades I, II, III and grade IV. Malignant tumors, those of grades III and IV, are characterized by uncontrolled proliferation, which is known to be regulated by the family of Rho GTPases. StarD13, a GAP for Rho GTPases, has been described as a tumor suppressor in hepatocellular carcinoma. In the present study, IHC analysis on grades I-IV brain tissues from patients showed StarD13 to be overexpressed in grades III and IV astrocytoma tumors when compared to grades?I and II. However, when we mined the REMBRANDT data, we found that the mRNA levels of StarD13 are indeed higher in the higher grades but much lower than the normal tissues. Knocking down StarD13 using siRNA led to a decrease in cell death and an increase in cell viability, proving that StarD13 is indeed a tumor suppressor in astrocytomas. This was found to be mainly through cell cycle arrest independently of apoptosis. Finally, we detected an increase in p-ERK in StarD13 knockdown cells, uncovering a potential link between Rho GTPases and ERK activation.     

RhoGDI deficiency induces constitutive activation of Rho GTPases and COX-2 pathways in association with breast cancer progression

Rho GDP Dissociation Inhibitor (RhoGDI) is a key regulator of Rho GTPases. Here we report that loss of RhoGDI significantly accelerated xenograft tumor growth of MDA-MB-231 cells in animal models. At the molecular level, RhoGDI depletion resulted in constitutive activation of Rho GTPases, including RhoA, Cdc42, and Rac1. This was accompanied by Rho GTPase translocation from the cytosol to membrane compartments. Notably, COX-2 protein levels, mRNA expression, and biological activity were markedly increased in RhoGDI-deficient cells. The upregulated expression of COX-2 was directly associated with increased Rho GTPase activity. Further, we assessed the expression level of RhoGDI protein in breast tumor specimens (n = 165) by immunohistochemistry. We found that RhoGDI expression is higher in the early stages of breast cancer followed by a significant decrease in malignant tumors and metastatic lesions (p 0.01). These data suggest that downregulation of RhoGDI could be a critical mechanism of breast tumor development, which may involve the hyperactivation of Rho GTPases and upregulation of COX-2 activity. Additional studies are warranted to evaluate the therapeutic potential of inhibiting Rho GTPases and COX-2 for treating breast cancers.     

Inflammatory breast cancer: Relationship between growth factor signaling and motility in aggressive cancers

A variety of phenotypic characteristics are required for a cancer cell to successfully complete the metastatic cascade. Acquisition of a motile and invasive phenotype is one requirement for a cell to become metastatically competent. The Rho (Ras homology) GTPases are a subfamily of small GTP-binding proteins, which are related to the Ras oncogene. All aspects of cellular motility and invasion are controlled by the Rho GTPases and are closely linked to signals from the extracellular environment, particularly in response to growth factors. Dysregulation of Rho activation through aberrant growth-factor signaling, loss of function of key Rho-regulatory proteins or overexpression of Rho mRNA could result in increased Rho activity and cellular motility. Therefore, the importance of the Rho GTPases in the progression of aggressive cancers, is becoming more appreciated.     

Role of DLC-1, a tumor suppressor protein with RhoGAP activity, in regulation of the cytoskeleton and cell motility

DLC-1 was originally identified as a potential tumor suppressor. One of the key biochemical functions of DLC-1 is to serve as a GTPase activating protein (GAP) for members of the Rho family of GTPases, particularly Rho A-C and Cdc 42. Since these GTPases are critically involved in regulation of the cytoskeleton and cell migration, it seems clear that DLC-1 will also influence these processes. In this review we examine basic aspects of the actin cyoskeleton and how it relates to cell motility. We then delineate the characteristics of DLC-1 and other members of its family, and describe how they may have multiple effects on the regulation of cell polarity, actin organization, and cell migration.     

Rho GTPases as Key Transducers of Proliferative Signals in G1 Cell Cycle Regulation

Mitogenic growth factor- and integrin-dependent signaling pathways cooperate to control the proliferation of nontransformed cells. As integral mediators of these networks, the Rho family of GTPases play a pivotal role in G1 cell cycle progression, primarily through regulation of cyclin D1 expression, as well as the levels of the cyclin-dependent kinase inhibitors p21cip1 and p27kip1. Such dual control of both the critical positive and negative regulators of G1 progression make the Rho GTPases prime candidates to target the autonomous proliferation which typifies cancer cells. Cyclin D1 has been identified as an important oncogene and the cdk inhibitors as tumor suppressors in human breast carcinogenesis. Evidence pointing to the potential role of Rho-dependent pathways and their interaction with oncogenic Ras in contributing to such cell cycle abnormalities that characterize human breast cancer is also presented.     

Regulation of cancer cell motility through actin reorganization

Cell migration is a critical step in tumor invasion and metastasis, and regulation of this process will lead to appropriate therapies for treating cancer. Cancer cells migrate in various ways, according to cell type and degree of differentiation. The different types of cell migration are regulated by different mechanisms. Reorganization of the actin cytoskeleton is the primary mechanism of cell motility and is essential for most types of cell migration. Actin reorganization is regulated by Rho family small GTPases such as Rho, Rac, and Cdc42. These small GTPases transmit extracellular chemotactic signals to downstream effectors. Of these downstream effectors, Wiskott-Aldrich syndrome protein (WASP) family proteins are key regulators of cell migration. Activated WASP family proteins induce the formation of protrusive membrane structures involved in cell migration and degradation of the extracellular matrix. Inhibition of Rho family small GTPase signaling suppresses the migration and invasion of cancer cells. Thus, control of cell migration via the actin cytoskeleton provides the possibility of regulating cancer cell invasion and metastasis.