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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