近日，《胃肠病学》杂志发表了中科院上海生科院营养科学研究所谢东研究组的最新成果。该成果揭示了在胃癌发生发展过程中，接头蛋白RACK1（Receptor for Activated PKC kinase 1）通过对促进肿瘤发生的Wnt/beta-catenin信号进行负调控，从而抑制胃癌发生发展的机制。
Wnt/beta-catenin信号通路参与了多种肿瘤的发生发展过程。通常情况下，该信号通路的核心分子beta-catenin被降解失活，整个信号处于关闭状态。在肿瘤细胞中，beta-catenin降解途径被阻断，Wnt/beta-catenin信号处于活化状态，激活下游许多癌基因的表达。Wnt/beta-catenin信号通路在胃癌发生中起着重要的作用，“但在胃癌发生中该信号通路的活化机制还有待阐明”。
博士后邓跃臻等在谢东指导下发现，RACK1在胃癌样品中表达下调，并且其表达水平与肿瘤分化程度和浸润深度显著相关。
在后续有关分子机制的研究中，研究人员发现RACK1等显著促进Wnt/beta-catenin信号通路的核心分子beta-catenin降解，抑制该信号通路的活化。
另一方面，Wnt/beta-catenin信号通路的活化又可以对RACK1蛋白进行修饰调控，使其对该信号通路的抑制能力显著削弱。
有关专家认为，该研究不仅丰富了人们对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。
RACK1 Suppresses Gastric Tumorigenesis by Stabilizing the β-Catenin Destruction Complex
Yue-Zhen Deng, Fan Yao, Jing-Jing Li, Zheng-Fa Mao, Ping-Ting Hu, Ling-Yun Long, Guo Li, Xiao-Dan Ji, Shuo Shi, Dong-Xian Guan, Yuan-Yuan Feng, Lei Cui, Dang-Sheng Li, Yong Liu, Xiang Du, Ming-Zhou Guo, Li-Yan Xu, En-Min Li, Hong-Yang Wang, Dong Xie
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.
文献链接：https://www.gastrojournal.org/article/S0016-5085(12)00014-5/abstract
