科学家们发现，激活Rho小蛋白能抑制肝脏恶性肿瘤

StephenW

Scientists find that activating family of small protein could suppress liver malignancies
Published on October 21, 2013 at 2:13 AM · No Comments

  

A team of scientists from the National University of Singapore (NUS) has found that activating a family of small protein, known as Rho, could suppress liver malignancies. This is the first time that a research group has provided evidence to show that the signaling crosstalk between different protein switches has an influence on the development of cancer tissues. The findings pave the way for the development and application of therapeutics targeted at liver cancer.

The team, led by Associate Professor Low Boon Chuan from the Department of Biological Sciences at the NUS Faculty of Science and the Mechanobiology Institute at NUS, first published the research in the journal Oncogene.

Importance of signalling crosstalk between proteins

The proteins Ras and Rho are among the key molecular switches that control cell dynamics, cell growth and tissue development through their distinct signalling pathways. Although much has been studied about their individual functions, the underlying molecular mechanism of signalling crosstalk between these two proteins in an in vivo context remains largely unknown, especially in the area of liver development and formation of liver tumours.

In order to identify the consequences of their signalling crosstalk, the research team generated different scenarios with different liver-specific proteins and genes that have the potential to cause cancer, using the zebrafish as an in vivo model.

Due to its ability to reverse and forward genetics and low incidence of spontaneous tumours, the zebrafish is fast becoming a popular model for studying human cancers.

Through the use of quantitative bioimaging and molecular markers, the team found that when the zebrafish is induced to produce an active state of Kras (a form of Ras), which is an oncogene, liver enlargement is observed, and liver cancer that resembles the human liver cancer was formed. Subsequently, in adult zebrafish, the hepatocellular carcinoma, a major form of liver cancer, was developed. However, when the same cells were made to turn on Rho, these abnormalities were abated.


The team also found that when an inactive form of Rho was introduced when Kras is kept active, the Kras-mediated liver overgrowth and tumour formation were elevated.

These findings provided evidence about the significance of the previously understudied signalling crosstalk between the proteins Kras and Rho in regulating liver overgrowth, transformation of liver tissue and cancer mortality. As Rho is a known inducer of mechanical force, the team's findings also implicate the possible role of mechanical and physical forces in regulating cancer development and other functions in the liver.  

The Next Step

The group is now investigating the exact chain of biochemical reactions that specify such unique signalling crosstalk. They are also investigating the aspects of cell metabolism and other major growth related pathways that are being affected to address the inherent inconsistency associated with cell-based studies. They hope to establish zebrafish as an alternative drug screening platform that is relatively cheap and convenient to identify novel targets for therapeutic intervention.

Source: National University of Singapore

StephenW

新加坡国立大学（ NUS ）的一组科学家发现，激活的小蛋白，被称为Rho的，一个家庭可能会抑制肝脏恶性肿瘤。这是第一次，一个研究小组提供的证据表明，不同的蛋白质开关​​信号之间的串扰癌组织的发展具有影响。这一发现为针对肝癌的治疗的发展和应用铺平了道路。

的团队，从科学与力学生物学研究所在新加坡国立大学新加坡国立大学生物科学系的副教授低恩赐川​​的带领下，首先在“致癌基因”杂志上发表的研究。

蛋白质之间的串扰信号的重要性

蛋白质的Ras和Rho控制细胞动力学，细胞生长和组织的发展，通过不同的信号转导通路中的关键分子开关。他们个人的功能，虽然已经研究了这两种蛋白质在体内上下文之间的信号串扰相关的分子机制仍是未知的，特别是在肝脏发育和肝肿瘤的形成。

为了查明其信号串扰的后果，研究小组产生不同的场景，不同的肝细胞特异性的蛋白质和基因，有可能会导致癌症，使用斑马鱼体内模型。

由于它能够反向和正向遗传学和自发性肿瘤的发病率较低，斑马鱼正迅速成为一个流行的模型，为研究人类癌症。

通过使用定量生物成像和分子标记，该研究小组发现，斑马鱼时，被诱导产生的KRAS （ RAS的一种形式），这是一种致癌基因的激活状态观察，肝脏肿大，类似于人类的肝癌肝癌形成。随后，在成年斑马鱼，肝癌，肝癌的一种主要形式，被开发了。然而，当打开Rho的相同的细胞，这些异常退。


小组还发现，当一个无效的形式引入，嘉仕保持活跃的Rho ，嘉仕介导的肝脏过度增生和肿瘤形成明显升高。

这些研究结果提供的证据充分研究的信令蛋白KRAS和Rho调节肝脏过度生长，肝组织的改造和癌症死亡率之间的串扰的意义。由于Rho是一个已知的机械力诱导剂，该小组的研究结果也牵连机械和物理力量可能发挥的作用，在肝脏癌症的发展和其他功能的调节。

下一步

该小组目前正在调查确切的连锁生化反应， ，指定这种独特的信号串扰。他们也正在调查细胞代谢和其他主要增长相关的途径都受到影响，解决的固有矛盾，伴有细胞为基础的研究方面。他们希望建立斑马鱼作为一种替代药物筛选平台是相对廉价和方便的治疗干预，以确定新的目标。

资料来源：新加坡国立大学