局部黏着斑激酶作为肿瘤治疗靶点的研究进展

局部黏着斑激酶（focal adhesion kinase,FAK）是一种非受体型酪氨酸蛋白激酶,是细胞内重要的骨架蛋白与多种信号通路的关键分子。FAK在肿瘤发生、发展、迁移和侵袭的各个阶段都具有重要作用,FAK已经被当作潜在的肿瘤治疗靶点来研究。该综述将对FAK与肿瘤的关系以及FAK作为肿瘤治疗靶点的研究进展进行探讨。     

黏着斑激酶与肿瘤侵袭转移

黏着斑激酶（focal adhesion kinase,FAK）是一种非受体型蛋白酪氨酸激酶,在肿瘤细胞的侵袭和转移中起着重要的作用。FAK是整合素介导的或生长因子受体诱导的调节细胞迁移的信号通路的关键组分。FAK通过与相关分子作用可以调节细胞骨架重构、胞外基质降解、细胞黏附更新以及质膜突出,进而参与肿瘤细胞的运动等多个过程,所以FAK与肿瘤发展的关系已经越来越受到重视。     

黏着斑激酶与肿瘤微环境

黏着斑激酶（focal adhesion kinase, FAK）是一种胞质非受体酪氨酸激酶。FAK和肿瘤密切相关,在多种癌细胞中高表达,促进癌细胞的发生、生长、存活、增殖、粘附、转移和侵袭以及血管生成等过程。肿瘤微环境包括肿瘤细胞、周围血管、免疫细胞、纤维母细胞、内皮细胞、信号分子和细胞外基质,它对癌症的发展和恶化具有重要作用。肿瘤细胞可以通过分泌细胞外信号影响微环境,使其有利于肿瘤生存和发展|肿瘤微环境中的基质细胞能通过产生趋化因子、基质降解酶和生长因子促进肿瘤侵袭和转移。本文综述肿瘤微环境在癌症发生发展过程中的作用及FAK在肿瘤微环境中的调控作用,为肿瘤疾病的治疗提供新思路。     

FAK/mTOR信号通在肿瘤细胞中的调控作用

粘附斑激酶（focal adhesion kinase,FAK）是一种胞质非受体酪氨酸激酶,是整合素信号通路里一个重要的调节因子,在肿瘤细胞中高表达,与细胞迁移、粘附和侵袭有关。mTOR (mammalian target of rapamycin)是非典型性的Ser/Thr激酶,属于PIKK（phosphatidylinositol kinase related kinase）超家族,介导营养信号调控细胞生长、分化及代谢等生理过程。近年的研究发现FAK通过三条途径与mTOR相关联,组成FAK/mTOR信号通路,在肿瘤细胞的增殖、迁移及肿瘤微环境中发挥着重要的调控作用。本文综述了FAK、mTOR和FAK/mTOR信号通路的特点及对肿瘤细胞调控作用的研究概况,为肿瘤治疗提供参考。     

Nature:新药物靶标可打破癌症抵抗治疗的屏障

<正>近日,Barts Cancer Institute科学家发现,靶向血管中的一分子(FAK)可以使癌症治疗显著更有效。研究团队已经发现一种分子粘着斑激酶(FAK)发送信号给肿瘤细胞,从而帮助化疗或放疗(破坏DNA,杀死癌细胞)后的自我修复。当研究人员从黑色素瘤和肺癌模型血管中移除FAK,化疗和放射疗法能更有效地杀死肿瘤。研究人员还研究了淋巴瘤患者的样本,发现那些血管中FAK低水平的患者,有更好的治疗结果。这表明,开发剔除肿瘤血管FAK的药物,可能促进癌症的治疗和预防癌症复发。血管内壁细胞向肿瘤发出化学信号(称为细胞因子)以帮助它抵抗DNA损伤和恢复。研究人员证明,这个过程需要FAK,没有FAK,这些信     

粘附斑激酶(FAK)及其信号通路研究进展

粘附斑激酶(focal adhesion kinase,FAK)是一类胞质非受体蛋白酪氨酸激酶,属于蛋白酪氨酸激酶(protein tyrosine kinase)超家族,因而也称为PTKⅡ.FAK在细胞信号转导中处于十分重要的位置,它是胞内外信号出入的中枢,介导多条信号通路.FAK可以整合来自整合素、生长因子以及机械刺激等的信号,激活胞内PI3K/Akt、Ras/MAPK等信号通路,调节细胞生长.FAK还与胚胎发育、肿瘤发生与迁移有关.     

黏着斑激酶的结构与功能

黏着斑激酶(focal adhesion kinase,FAK)是细胞内一种重要的信号转导分子,参与多条重要信号通路和多种细胞生物学行为的调控。该文结合当前的研究进展,总结了FAK通过其复杂的信号转导通路在细胞迁徙、增殖、抗凋亡方面的功能,并简要归纳了FAK与肿瘤之间的密切联系。     

不同亚细胞定位的黏着斑激酶对肿瘤的调控机制

黏着斑激酶(focal adhesion kinase, FAK)是一种非受体蛋白酪氨酸激酶。在细胞质黏着斑中,FAK通过调控细胞黏着斑的解聚与组装及多个蛋白质的磷酸化从而调节细胞的增殖和迁移。FAK也定位于细胞核和内体中。在细胞核中,FAK可导致p53的多聚泛素化及降解,从而影响正常细胞的存活和肿瘤细胞的生长。此外,核FAK还能够通过调节细胞因子和趋化因子的表达促进肿瘤免疫逃逸的发生。在内体中,FAK通过FERM结构域定位到内体并被激活。内体中整合素的信号转导时间比质膜上持续的时间更长,并且能够阻止肿瘤细胞发生失巢凋亡,因此,内体FAK可通过抵抗失巢凋亡促进肿瘤细胞的转移。现就不同亚细胞定位的FAK对肿瘤发生和发展的调控作用及机制进行讨论。     

FAK在胃癌组织中的表达及与Hp-L型感染的关系

目的探讨局部黏着斑激酶(focal adhesion kinase,FAK)在胃癌组织中的表达意义及与幽门螺杆菌L型(Helicobacter pylori-L,Hp-L)感染的关系。方法 (1)应用免疫组织化学Elivision法检测120例胃癌组织及40例切缘正常胃粘膜组织(对照组)中FAK蛋白的表达情况,采用免疫组织化学和革兰染色法检测Hp-L型的感染情况;(2)采用逆转录多聚酶链反应(RT-PCR)技术检测40例新鲜胃癌组织及对应切缘正常胃黏膜组织(对照组)中FAK的mRNA表达。结果胃癌组FAK蛋白的表达阳性率高于对照组(P0.05),且FAK的高表达与分化程度、浸润深度、淋巴结转移和TNM分期有关(P0.05),与年龄、性别、肿瘤大小无关(P0.05);RT-PCR显示,肿瘤组织、远端正常对照组织的FAK表达量差异明显(P0.01)。胃癌组Hp-L型检出率72.5%(87/120)与对照组37.5%(15/40)有显著性差异(P0.05),与免疫组化Hp-L型抗原表达率65.0%(78/120)无显著性差异(P0.05),Hp-L检出阳性率为69.2%(83/120);胃癌组中Hp-L型感染阳性组的FAK表达阳性率高于Hp-L型阴性组(P0.05),且Hp-L型阳性率和FAK蛋白的表达呈正相关(r=0.291,P0.05)。结论FAK蛋白和mRNA在胃癌中的表达增加,且与胃癌的浸润、转移相关,其机制可能与幽门螺杆菌L型(Hp-L型)感染有关。     

黏着斑激酶及其小分子抑制剂作为抗肿瘤药物的研究进展

抗黏着斑激酶是一种非受体型酪氨酸蛋白激酶,在许多肿瘤的发生和发展过程中均有过表达。研究表明,作为细胞内重要的骨架蛋白和调节多种细胞信号通路的关键分子,黏着斑激酶在肿瘤发生、发展、迁移和侵袭的各个阶段都起着重要作用。因此,以黏着斑激酶作为抗肿瘤靶点开发其抑制剂的研究受到广泛关注。综述黏着斑激酶的结构与功能、它与肿瘤的关联及其小分子抑制剂的研究与开发。     

Heat shock protein 90β stabilizes focal adhesion kinase and enhances cell migration and invasion in breast cancer cells

Focal adhesion kinase (FAK) acts as a regulator of cellular signaling and may promote cell spreading, motility, invasion and survival in malignancy. Elevated expression and activity of FAK frequently correlate with tumor cell metastasis and poor prognosis in breast cancer. However, the mechanisms by which the turnover of FAK is regulated remain elusive. Here we report that heat shock protein 90β (HSP90β) interacts with FAK and the middle domain (amino acids 233–620) of HSP90β is mainly responsible for this interaction. Furthermore, we found that HSP90β regulates FAK stability since HSP90β inhibitor 17-AAG triggers FAK ubiquitylation and subsequent proteasome-dependent degradation. Moreover, disrupted FAK-HSP90β interaction induced by 17-AAG contributes to attenuation of tumor cell growth, migration, and invasion. Together, our results reveal how HSP90β regulates FAK stability and identifies a potential therapeutic strategy to breast cancer.     

MicroRNA-7 Inhibits Epithelial-to-Mesenchymal Transition and Metastasis of Breast Cancer Cells via Targeting FAK Expression

Focal adhesion kinase (FAK) is an important mediator of extracellular matrix integrin signaling, cell motility, cell proliferation and cell survival. Increased FAK expression is observed in a variety of solid human tumors and increased FAK expression and activity frequently correlate with metastatic disease and poor prognosis. Herein we identify miR-7 as a direct regulator of FAK expression. miR-7 expression is decreased in malignant versus normal breast tissue and its expression correlates inversely with metastasis in human breast cancer patients. Forced expression of miR-7 produced increased E-CADHERIN and decreased FIBRONECTIN and VIMENTIN expression in breast cancer cells. The levels of miR-7 expression was positively correlated with E-CADHERIN mRNA and negatively correlated with VIMENTIN mRNA levels in breast cancer samples. Forced expression of miR-7 in aggressive breast cancer cell lines suppressed tumor cell monolayer proliferation, anchorage independent growth, three-dimensional growth in Matrigel, migration and invasion. Conversely, inhibition of miR-7 in the HBL-100 mammary epithelial cell line promoted cell proliferation and anchorage independent growth. Rescue of FAK expression reversed miR-7 suppression of migration and invasion. miR-7 also inhibited primary breast tumor development, local invasion and metastatic colonization of breast cancer xenografts. Thus, miR-7 expression is decreased in metastatic breast cancer, correlates with the level of epithelial differentiation of the tumor and inhibits metastatic progression.     

黏附分子CD24在肿瘤转移中作用

CD24属糖基磷脂酰肌醇锚蛋白。作为P-选择素配体的黏附分子,其可调节B细胞发育和神经发生。研究显示,CD24高表达在多种肿瘤细胞表面,参与肿瘤的发生发展。已通过体外试验和动物模型证实CD24对多种肿瘤生长和转移相关的肿瘤细胞特性具有调节作用;结合人肿瘤组织研究显示,CD24和乳腺癌、前列腺癌、胰腺癌及肝内胆管癌等肿瘤患者的生存率及预后密切相关。因此,以CD24为靶向的肿瘤诊断和治疗有着诱人的临床应用前景。     

Paradoxical roles of FAK in tumor cell migration and metastasis

Focal adhesion kinase (FAK), as a key mediator of signaling induced by integrins, plays an instrumental role in many cellular functions, including cell survival and proliferation. Many studies have reported that FAK is a positive regulator of normal cell migration and cancer cell metastasis. However, emerging evidence shows that FAK—under certain oncogenic signaling, such as that initiated by activated Ras and some growth factor receptor kinases—negatively regulates cancer cell migration. Activated Ras may promote tumor cell migration by dephosphorylation of FAK at Y397 and facilitation of focal adhesion turnover at the leading edge of cells.     

MYC-mediated upregulation of PNO1 promotes glioma tumorigenesis by activating THBS1/FAK/Akt signaling

PNO1 has been reported to be involved in tumorigenesis, however, its role in glioma remains unexplored. In the present study, PNO1 expression in glioma from on-line databases, cDNA, and tissue microarrays was upregulated and associated with poor prognosis. PNO1 knockdown inhibits tumor cell growth and invasion both in vitro and in vivo; whereas PNO1 overexpression promoted cell proliferation and invasion in vitro. Notably, PNO1 interacted with THBS1 and the promotion of glioma by PNO1 overexpression could be attenuated or even reversed by simultaneously silencing THBS1. Functionally, PNO1 was involved in activation of FAK/Akt pathway. Moreover, overexpressing MYC increased PNO1 promoter activity. MYC knockdown decreased PNO1 and THBS1 expression, while inhibited cell proliferation and invasion. In conclusion, MYC-mediated upregulation of PNO1 contributes to glioma progression by activating THBS1/FAK/Akt signaling. PNO1 was reported to be a tumor promotor in the development and progression of glioma and may act as a candidate of therapeutic target in glioma treatment.Subject terms: Oncogenes, CNS cancer     

Focal adhesion kinase regulation by oxidative stress in different cell types

Focal adhesion kinase (FAK) is a tyrosine kinase ubiquitously expressed in cells. It was initially shown to be the initiator of focal adhesion formation in adherent cells, after its binding to integrins which induce its autophosphorylation. However, it can be also activated by a great variety of other stimuli able to act on different intracellular signaling. Reactive oxygen species (ROS), which have been shown to act as external or internal cell stimuli, induce tyrosine phosphorylation of FAK. Its autophosphorylation is followed by a submembranous localization which is crucial for many of the biological roles of FAK, including cell spreading, cell migration, cell proliferation, and prevention of apoptosis. It plays an important role in development of tumor cells, its regulation could be thus a way of impairing cell proliferation in cancer. We describe in this review the structure, activity, and functions of FAK in different cells and how ROS are able, like other stimuli, to induce its phosphorylation and modification of cell morphology and structure. The link between ROS and FAK activation could explain the role of ROS in mediating cell proliferation, cell migration, or apoptosis.