Regulatory role of microRNAs in cancer through Hippo signaling pathway

Cancer is the major cause of death worldwide in countries of all income levels. The Hippo signaling pathway is a Drosophila kinase gene that was identified to regulate organ size, cell regeneration, and contribute to tumorigenesis. A huge variety of extrinsic and intrinsic signals regulate the Hippo signaling pathway. The Hippo signaling pathway consists of a wide array of components that merge numerous signals such as mechanical signals to address apoptosis resistance, cell proliferation, cellular outputs of growth, cell death and survival at cellular and tissue level. Recent studies have shed new light on the regulatory role of microRNAs in Hippo signaling and how they contribute to cancer progression. MicroRNAs influence various cancer-related processes such as, apoptosis, proliferation, migration, cell cycle and metabolism. Inhibition and overexpression of miRNAs via miRNA mimics and miRNA inhibitors, respectively, can uncover a hopeful and reliable insight for treatment and early diagnosis of cancer patients. In this review we will discuss our current understanding of regulatory role of miRNAs in Hippo signaling pathway.     

Regulation of organ size: Insights from the Drosophila Hippo signaling pathway

Organ size control is a fundamental and core process of development of all multicellular organisms. One important facet of organ size control is the regulation of cell proliferation and cell death. Here we address the question, What are the developmental mechanisms that control intrinsic organ size? In several multicellular animals including humans and flies, organs develop according to an instructive model where proliferation is regulated by extracellular signals. However, the signals that regulate proliferation (and organ size) remain poorly understood. Recent data from flies have shed some light on the molecular mechanisms that regulate growth and size of organs. In this review, we will briefly discuss classic studies that revealed the mysteries of growth regulation. We will then focus on the recent findings from the Drosophila Hippo signaling pathway and its role in the regulation of organ size. Finally, we will discuss the mammalian Hippo pathway, and its implications in regulation of growth/proliferation during development and disease. Developmental Dynamics 238:1627–1637, 2009. © 2009 Wiley‐Liss, Inc.     

The Hippo signaling pathway restricts the oncogenic potential of an intestinal regeneration program

Although a developmental role for Hippo signaling in organ size control is well appreciated, how this pathway functions in tissue regeneration is largely unknown. Here we address this issue using a dextran sodium sulfate (DSS)-induced colonic regeneration model. We find that regenerating crypts express elevated Yes-associated protein (YAP) levels. Inactivation of YAP causes no obvious intestinal defects under normal homeostasis, but severely impairs DSS-induced intestinal regeneration. Conversely, hyperactivation of YAP results in widespread early-onset polyp formation following DSS treatment. Thus, the YAP oncoprotein must be exquisitely controlled in tissue regeneration to allow compensatory proliferation and prevent the intrinsic oncogenic potential of a tissue regeneration program.     

Inhibition of visfatin alleviates sepsis-induced intestinal damage by inhibiting Hippo signaling pathway

Background

The aim of this study is to investigate role of Visfatin, one of the pro-inflammatory adipokines, in sepsis-induced intestinal injury and to clarify the potential mechanism.

Methods

C57BL/6 mice underwent cecal ligation and puncture (CLP) surgery to establish sepsis model in vivo. Intestinal epithelial cells were stimulated with LPS to mimic sepsis-induced intestinal injury in vitro. FK866 (the inhibitor of Visfatin) with or without XMU-MP-1 (the inhibitor of Hippo signaling) was applied for treatment. The expression levels of Visfatin, NF-κB and Hippo signaling pathways-related proteins were detected by western blot or immunohistochemistry. The intestinal cell apoptosis and intestinal injury were investigated by TUNEL staining and H&E staining, respectively. ELISA was used to determine the production of inflammatory cytokines.

Results

The expression of Visfatin increased in CLP mice. FK866 reduced intestinal pathological injury, inflammatory cytokines production, and intestinal cell apoptosis in sepsis mice. Meanwhile, FK866 affected NF-κB and Hippo signaling pathways. Additionally, the effects of FK866 on inflammatory response, apoptosis, Hippo signaling and NF-κB signaling were partly abolished by XMU-MP-1, the inhibitor of Hippo signaling. In vitro experiments also revealed that FK866 exhibited a protective role against LPS-induced inflammatory response and apoptosis in intestinal cells, as well as regulating NF-κB and Hippo signaling, whereas addition of XMU-MP-1 weakened the protective effects of FK866.

Conclusion

In short, this study demonstrated that inhibition of Visfatin might alleviate sepsis-induced intestinal injury through Hippo signaling pathway, supporting a further research on Visfatin as a therapeutic target.

     

Hippo信号通路与肾病

Hippo信号通路是近年来备受关注的一条调节器官生长和组织大小的重要信号通路,其已被证实在肿瘤的发生、发展中发挥重要作用.目前Hippo信号通路与肾病的相关性研究仍处于起步阶段.在急性肾损伤(acute renal injury,AKI)方面,Hippo信号通路可能参与小管上皮细胞的凋亡、上皮-间质转化(epithelial-mesenchymal transition,EMT)以及AKI进展至慢性肾脏病(chronic kidney disease,CKD)等多个环节.此外,Hippo信号通路还参与多种慢性肾脏病,包括局灶节段性肾小球硬化症、糖尿病肾病、多囊肾等的发生和疾病进展.     

Notch信号通路及其在肺癌发生中的作用

Notch信号通路存在于多种动物体内,是许多细胞信号转导通路的交汇点,不仅对正常组织、细胞的分化、发育起重要作用,而且和一些肿瘤的发生、发展相关。Notch信号在肺癌中的作用多样，在不同类型肺癌中呈现出不同的促癌或抑癌功能。了解Notch和肺癌的关系有利于进一步阐明肺癌发生机制,提出预防和治疗肺癌的新途径，为肿瘤基因治疗提供一个新的有希望的靶点。     

不同信号通路基因在心脏和先天性心脏病发生和发展中的作用

先天性心脏病是一种常见的新生儿出生缺陷疾病,我国每年有12万～20万先心病患儿出生,其中多数为复杂型先天性心脏病,严重危害新生儿的健康,给社会和患者家庭带来沉重的负担。先天性心脏病的发病机制非常复杂,多数是由于环境因素和遗传因素共同作用的结果,其中许多患者是由于多种基因和信号通路共同作用的结果,例如, TGF-β、Nodal、MAPK、Wnt、Notch 等信号通路以及同型半胱氨酸甲硫氨酸循环途径与心脏发育密切相关,其中任何一个基因或信号通路异常都有可能导致先天性心脏病。该文以各种信号通路为主线,总结各信号通路及相关基因在心脏发育中的作用,以及这些信号通路和基因改变或异常表达引发先天性心脏病的致病机制。     

焦亡在心脏疾病中的研究进展

焦亡是一种新发现并证实与炎症相关的细胞死亡方式,其特征为依赖于半胱天冬氨酸蛋白酶-1(cysteinyl aspartate specific proteinase-1,Caspase-1)的细胞程序性死亡,并伴有促炎症因子的释放,主要为白介素-1β(interleukin-1β,IL-1β)和白介素-18(interleukin-18,IL-18).越来越多的研究发现,焦亡相关信号通路在心脏疾病中起重要作用,包括心肌梗死、缺血再灌注损伤、心肌肥厚、心肌纤维化和心力衰竭等.本文就焦亡相关信号通路与心脏疾病关系研究进展作一综述.     

A temporal requirement for Hippo signaling in mammary gland differentiation,growth, and tumorigenesis

Despite recent progress, the physiological role of Hippo signaling in mammary gland development and tumorigenesis remains poorly understood. Here we show that the Hippo pathway is functionally dispensable in virgin mammary glands but specifically required during pregnancy. In contrast to many other tissues, hyperactivation of YAP in mammary epithelia does not induce hyperplasia but leads to defects in terminal differentiation. Interestingly, loss of YAP causes no obvious defects in virgin mammary glands but potently suppresses oncogene-induced mammary tumors. The selective requirement for YAP in oncogenic growth highlights the potential of YAP inhibitors as molecular targeted therapies against breast cancers.     

Hippo通路核心蛋白在小鼠出生后不同时间点脑皮质中的表达变化

目的 探究Hippo信号通路核心蛋白在小鼠出生后不同时间点皮质中的表达变化。方法 在C57BL/6小鼠出生后（postnatal,P）3 d、6 d、9 d、3周和8周,通过测量脑重及脑横径来检测小鼠脑组织生长发育情况;通过Western Blot检测小鼠皮质中MST1、LATS1的表达;通过酪酰胺信号放大技术检测小鼠皮质中小胶质细胞在小鼠出生后五个不同时间点的数目变化以及Yes-相关蛋白（Yes-associated protein,YAP）在小胶质细胞中的定位情况。 结果 小鼠出生后早期脑重、脑横径增速显著;MST1和LATS1从P9d开始极显著降低,P3周与P8周相比无统计学意义;皮质中IBA1阳性小胶质细胞数目占比随鼠龄上升,出生后早期增速显著,伴随小胶质细胞数目增多的是YAP从核外转向核内聚集。 结论 Hippo信号通路在出生后早期的小鼠皮质中被激活,可能参与出生后脑发育时体积调控。     

Notch信号通路在孤独症谱系障碍中的研究进展

正孤独症谱系障碍(Autism spectrum disorders,ASDs)是一组病因复杂、发病机制尚不明确的神经发育障碍性疾病。ASDs包括典型孤独症、阿斯伯格综合症、Rett综合征、童年瓦解性障碍及其它待分类的非特异性广泛发育障碍。其主要的行为表现有社交障碍、语言发育障碍以及重复刻板的兴趣或行为等。近年来,ASDs由于发病率在不同国家均有所上升,而成为研究的一大热点。ASDs发病机制尚不清楚,目前主要     

New role of Notch-mediated signaling pathway in myocardial ischemic preconditioning

Ischemic preconditioning (IPC) is the strongest endogenous myocardial protective mechanism, but up to now, its specific mechanisms have not been completely understood. The Notch network regulates multiple cellular processes, including cell fate determination, development, differentiation, proliferation, apoptosis, and regeneration. Recent loss-of-function studies have shown that the Notch1 receptor controls the response to injury in the adult heart by limiting myocyte hypertrophy, enhancing myocyte survival, promoting precursor proliferation and reducing interstitial fibrosis. Notch signaling also plays a regulatory role in adult cardiac injury and in protection of myocardial function after ischemia. The Notch pathway cross-talks with the PI3K/Akt and NF-κB signaling pathways, both of which are well-known factors involved in IPC-induced myocardial protection. We therefore hypothesize that Notch signaling may play a regulatory role in myocardial protection during ischemic preconditioning and hope to find new drug targets to attain the same beneficial effects of Notch signaling without ischemic insults.     

Dll4-Notch信号传递途径在血管发生中的作用

血管发生(angiogenesis)依赖多种促进血管发生因子和抑制血管发生因子之综合的交互作用所调控。血管内皮生长因子(VEGF)和Notch信号传递途径(Notch signaling pathway)参与此过程。之前研究已证明Notch信号传递途径在胚胎发育和肿瘤血管发生(tumour angiogenesis)中扮演重要的角色,而最近研究则发现在血管发育过程中Dll4-Notch信号传递途径扮演着前所未知的新角色,并阐明因Notch信号传递减少而引起血管缺陷之机制,从而揭示破坏肿瘤血管发生的新药物靶点。本文着重于介绍Notch信号传递途径的组成;Dll4-Notch在血管发生中的作用;以及Dll4-Notch对肿瘤治疗的意义。     

The interplay between centrosomes and the Hippo tumor suppressor pathway

Centrosome amplification is a common feature of both solid and hematological human malignancies. Extra centrosomes are not merely innocent bystanders in cancer cells, but rather promote tumor progression by disrupting normal cellular architecture and generating chromosome instability. Consequently, centrosome amplification correlates with advanced tumor grade and overall poor clinical prognosis. By contrast, extra centrosomes are adversely tolerated in non-transformed cells and hinder cell proliferation. This suggests that in addition to acquiring extra centrosomes, cancer cells must also adapt to overcome the deleterious consequences associated with them. Here, we review evidence that implicates core components of the Hippo tumor suppressor pathway as having key roles in both the direct and indirect regulation of centrosome number. Intriguingly, functional inactivation of the Hippo pathway, which is common across broad spectrum of human cancers, likely represents one key adaptation that enables cancer cells to tolerate extra centrosomes.     

Notch信号通路介导卵巢生理病理的作用

Notch信号通路参与卵子发生、卵巢激素分泌,调控卵巢生殖干细胞的增殖分化,此外它还参与卵巢癌的发生发展等病理过程。