RACK1 suppresses gastric tumorigenesis by stabilizing the β-catenin destruction complex.
ABSTRACT 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.
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.
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.
RACK1 negatively regulates Wnt signaling pathway by stabilizing the β-catenin destruction complex and act as a tumor suppressor in gastric cancer cells.
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ABSTRACT: Eph/ephrin signaling system plays a very important role in the tumorigenesis and the formation of blood vessel. However, the function of EphB4 and its ligand ephrin B2 in the carcinogenesis of esophageal squamous cell carcinoma (ESCC) is not fully understood. Here, it was found that the expression of EphB4 was up-regulated in ESCC tissues compared with the paired normal tissues, while ephrin B2 was down-regulated in ESCC samples. Phosphorylation of EphB4 induced by its ligand ephrin B2-Fc inhibited the growth, migration and colony formation of ESCC cells. Moreover, over-expression of EphB4 or EphB4 kinase dead mutant (EphB4 KD) in ESCC cells promoted cell growth and migration, suggesting EphB4 promoted cell growth and migration independent of its kinase activity. Furthermore, we found that EphB4 interacted with the adaptor protein RACK1 and RACK1 decreased the phosphorylation level of EphB4. Taken together, our study revealed the important function and regulation of EphB4 in the progression of ESCC and suggested EphB4 as a novel target for the treatment of ESCC.Tumor Biology 04/2014; · 2.84 Impact Factor
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ABSTRACT: This paper first identified differentially expressed miRNAs associated with early gastric cancer and then respectively constructed relevant connection networks among the identified differentially expressed miRNAs that corresponded to early gastric cancer and control tissues. Twenty-three differentially expressed miRNAs were identified, 18 of which were different with the related results on the same data, and they provide great discriminatory power between patients and controls. There are not only conserved unchangeable sub-networks but also different sub-networks between the two connection networks. From the consistency and differences between two connection networks, we disclosed several new biological features that promote early gastric cancer development. This study shows 23 miRNAs that are early gastric cancer-specific and are worthy to do further experimental studies. The revealed biological features for early gastric cancer will provide new insights into improved understanding of the molecular mechanisms of this disease.Gene 07/2014; · 2.08 Impact Factor
Article: RACK1, a versatile hub in cancer.[Show abstract] [Hide abstract]
ABSTRACT: RACK1 is a highly conserved intracellular adaptor protein with significant homology to Gβ and was originally identified as the anchoring protein for activated protein kinase C. In the past 20 years, the number of binding partners and validated cellular functions for RACK1 has increased, which facilitates clarification of its involvement in different biological events. In this review, we will focus on its role in cancer, summarizing its aberrant expression, pro- or anti-oncogenic effects and the underlying mechanisms in various cancers.Oncogene advance online publication, 2 June 2014; doi:10.1038/onc.2014.127.Oncogene 06/2014; · 8.56 Impact Factor