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Gastroenterology:谢东等发现RACK1是Wnt信号通路新的调控因子

来源:上海生科院营养所 2012-02-03 22:51

近日,国际胃肠病学杂志(Gastroenterology)在线发表了上海生科院营养科学研究所谢东研究组的最新研究成果。博士后邓跃臻等研究人员发现,接头蛋白RACK1(Receptor for Activated PKC kinase 1)通过抑制Wnt/beta-catenin信号通路从而抑制胃癌的发生发展。

Wnt/beta-catenin信号通路广泛参与个体发育和肿瘤发生等生物学过程。在没有Wnt配体刺激的情况下,beta-catenin通过由APC、Axin、GSK3beta和CK1等蛋白组成的降解复合物而降解失活。当有Wnt配体刺激时,降解复合物失活,beta-catenin在细胞质内积累,进而转移到细胞核内,激活下游基因的转录。Wnt/beta-catenin信号通路在胃癌发生中起着重要的作用。在60%以上的胃癌临床样品中可以观察到beta-catenin细胞核定位的现象。但是,beta-catenin的活化突变以及APC缺失突变在胃癌样品中并不常见。这说明在胃癌发生中还存在其他活化Wnt/beta-catenin信号通路的机制。

RACK1在胃癌样品中低表达,并且其表达水平与肿瘤分化程度和浸润深度显著相关。 在分子机制的研究中,研究人员发现RACK1抑制Wnt/beta-catenin信号通路。RACK1与Axin、GSK3beta和beta-catenin等诸多降解复合物的组分形成复合物,对该复合物的稳定起到积极作用。当有Wnt配体刺激时,RACK1抑制Dvl对Axin的招募。此外,该研究还揭示了Wnt信号对RACK1的调控机制。Wnt配体刺激诱导RACK1发生寡聚,而RACK1寡聚以后对Wnt/beta-catenin信号通路的抑制能力显著削弱。该研究发现了RACK1是beta-catenin降解复合物的新组分,丰富了人们对Wnt/beta-catenin信号通路的认识,也为胃癌的治疗提供了潜在的新靶点。(生物谷Bioon.com)

RACK1 Suppresses Gastric Tumorigenesis by Stabilizing the β-Catenin Destruction Complex

Yue-Zhen Deng1, Fan Yao1, Jing-Jing Li1, Zheng-Fa Mao4, Ping-Ting Hu1, Ling-Yun Long1, Guo Li1, Xiao-Dan Ji1, Shuo Shi1, Dong-Xian Guan1, Yuan-Yuan Feng1, Lei Cui4, Dang-Sheng Li5, Yong Liu1, Xiang Du3, Ming-Zhou Guo6, Li-Yan Xu2, En-Min Li2, Hong-Yang Wang7, Dong Xie1

Abstract
Background & Aims
Dysregualtion of Wnt signaling has been involved in Gastric tumorigenesis by mechanisms that are not fully understood. The receptor for activated protein kinase C (RACK1, GNB2L1) is involved in development of different tumor types, but its expression and function have not been investigated in gastric tumors.

Methods
We analyzed expression of RACK1 in gastric tumor samples and their matched normal tissues from 116 patients using immunohistochemistry. Effects of knockdown with small interfering (si)RNAs or overexpression of RACK1 in gastric cancer cell lines were evaluated in cell growth and tumor xenograft. RACK1 signaling pathways were investigated in cells and zebrafish embryos using immunoblot, immunoprecipitation, microinjection, and in situ hybridization assays.

Results
Expression of RACK1 was reduced in gastric tumor samples and correlated with depth of tumor infiltration and poor differentiation. Knockdown of RACK1 in gastric cancer cells accelerated their anchorage-independent proliferation in soft agar, while overexpression of RACK1 reduced their tumorigenecity in nude mice. RACK1 formed a complex with glycogen synthase kinase Gsk3β and Axin to promote the interaction between Gsk3β and β-catenin and thereby stabilized the β-catenin destruction complex. Upon stimulation of Wnt3a, RACK1 repressed Wnt signaling by inhibiting recruitment of Axin by Dishevelled 2 (Dvl2). Moreover, there was an inverse correlation between expression of RACK1 and localization of β-catenin to the cytoplasm/nucleus in human gastric tumor samples.

Conclusion
RACK1 negatively regulates Wnt signaling pathway by stablizing the β-catenin destruction complex and act as a tumor supressor in gastric cancer cells.

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