近日,，國際胃腸病學(xué)雜志（Gastroenterology）在線發(fā)表了上海生科院營養(yǎng)科學(xué)研究所謝東研究組的最新研究成果,。博士后鄧躍臻等研究人員發(fā)現(xiàn),，接頭蛋白R(shí)ACK1（Receptor for Activated PKC kinase 1）通過抑制Wnt/beta-catenin信號(hào)通路從而抑制胃癌的發(fā)生發(fā)展,。
Wnt/beta-catenin信號(hào)通路廣泛參與個(gè)體發(fā)育和腫瘤發(fā)生等生物學(xué)過程,。在沒有Wnt配體刺激的情況下,，beta-catenin通過由APC,、Axin,、GSK3beta和CK1等蛋白組成的降解復(fù)合物而降解失活。當(dāng)有Wnt配體刺激時(shí),，降解復(fù)合物失活,，beta-catenin在細(xì)胞質(zhì)內(nèi)積累，進(jìn)而轉(zhuǎn)移到細(xì)胞核內(nèi),，激活下游基因的轉(zhuǎn)錄,。Wnt/beta-catenin信號(hào)通路在胃癌發(fā)生中起著重要的作用。在60％以上的胃癌臨床樣品中可以觀察到beta-catenin細(xì)胞核定位的現(xiàn)象。但是,，beta-catenin的活化突變以及APC缺失突變?cè)谖赴悠分胁⒉怀Ｒ?。這說明在胃癌發(fā)生中還存在其他活化Wnt/beta-catenin信號(hào)通路的機(jī)制。
RACK1在胃癌樣品中低表達(dá),，并且其表達(dá)水平與腫瘤分化程度和浸潤(rùn)深度顯著相關(guān),。 在分子機(jī)制的研究中，研究人員發(fā)現(xiàn)RACK1抑制Wnt/beta-catenin信號(hào)通路,。RACK1與Axin,、GSK3beta和beta-catenin等諸多降解復(fù)合物的組分形成復(fù)合物，對(duì)該復(fù)合物的穩(wěn)定起到積極作用,。當(dāng)有Wnt配體刺激時(shí),，RACK1抑制Dvl對(duì)Axin的招募。此外,，該研究還揭示了Wnt信號(hào)對(duì)RACK1的調(diào)控機(jī)制,。Wnt配體刺激誘導(dǎo)RACK1發(fā)生寡聚，而RACK1寡聚以后對(duì)Wnt/beta-catenin信號(hào)通路的抑制能力顯著削弱,。該研究發(fā)現(xiàn)了RACK1是beta-catenin降解復(fù)合物的新組分,，豐富了人們對(duì)Wnt/beta-catenin信號(hào)通路的認(rèn)識(shí)，也為胃癌的治療提供了潛在的新靶點(diǎn),。(生物谷Bioon.com)
doi:10.1053/j.gastro.2011.12.046
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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.
