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Published on: June 17, 2014
RACK1 suppresses gastric tumorigenesis by stabilizing the β-catenin destruction complex
Yue-Zhen Deng1, Fan Yao, Jing-Jing Li
1Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Background & Aims:
Dysregulation 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 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, whereas overexpression of RACK1 reduced their tumorigenicity 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. On 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.
Conclusions:
RACK1 negatively regulates Wnt signaling pathway by stabilizing the β-catenin destruction complex and act as a tumor suppressor in gastric cancer cells.
Insights
Receptor for activated protein kinase C (RACK1) acts as a tumor suppressor in gastric cancer. Reduced RACK1 expression promotes tumor growth by stabilizing beta-catenin, a key Wnt signaling component.
Area of Science:
- Molecular Biology
- Oncology
- Cell Biology
Background:
- Wnt signaling pathway dysregulation is implicated in gastric cancer.
- The role of Receptor for Activated Protein Kinase C (RACK1) in gastric tumors is unknown.
Purpose of the Study:
- Investigate RACK1 expression and function in gastric cancer.
- Elucidate RACK1's role in Wnt signaling and gastric tumorigenesis.
Main Methods:
- Immunohistochemistry on 116 gastric tumor samples.
- RACK1 knockdown/overexpression in gastric cancer cells and xenografts.
- Analysis of RACK1 signaling pathways in cells and zebrafish.
Main Results:
- RACK1 expression is decreased in gastric tumors, correlating with infiltration depth and poor differentiation.
- RACK1 knockdown enhances cell proliferation; RACK1 overexpression reduces tumorigenicity.
- RACK1 stabilizes the beta-catenin destruction complex and negatively regulates Wnt signaling.
Conclusions:
- RACK1 functions as a tumor suppressor in gastric cancer.
- RACK1 negatively regulates the Wnt signaling pathway.
- RACK1 stabilizes the beta-catenin destruction complex, inhibiting Wnt signaling.
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