Abstract
Emerging studies show that dysregulation of the receptor of activated protein kinase C1 (RACK1) plays a crucial role in tumorigenesis and progression of various cancers. However, the biological function and underlying mechanism of RACK1 in glioma remains poorly defined. Here, we found that RACK1 was significantly up-regulated in glioma tissues compared with normal brain tissues, being closely related to clinical stage of glioma both in mRNA and protein levels. Moreover, Kaplan-Meier analysis demonstrated that patients with high RACK1 expression had a poor prognosis (p = 0.0062, HR = 1.898, 95% CI: 1.225–3.203). In vitro functional assays indicated that silencing of RACK1 could dramatically promote apoptosis and inhibit cell proliferation, migration, and invasion of glioma cells. More importantly, knockdown of RACK1 led to a vast accumulation of cells in G0/G1 phase and their reduced proportions at the S phase by suppressing the expression of G1/S transition key regulators Cyclin D1 and CDK6. Additionally, this forced down-regulation of RACK1 significantly suppressed migration and invasion via inhibiting the epithelial-mesenchymal transition (EMT) markers, such as MMP2, MMP9, ZEB1, N-Cadherin, and Integrin-β1. Collectively, our study revealed that RACK1 might act as a valuable prognostic biomarker and potential therapeutic target for glioma.
Highlights
Glioma, accounting for about 70% of malignant tumors in the central nervous system (CNS), is the most primary and lethal brain tumor [1,2,3]
The results demonstrated that knockdown of receptor of activated protein kinase C1 (RACK1) led to a reduced accumulation their proportions at theinG0/G1
The epithelial-mesenchymal transition (EMT) plays a crucial role in migration and invasion of various cancers, and the change of EMT protein levels was considered an Recently, an increasing number of researches demonstrated that aberrant expression of RACK1 was supposed to be prevalent in a wide spectrum of cancers, such as breast cancer [15,26], hepatocellular carcinoma [27], and gastric cancer [28], suggesting that abnormal expression of RACK1 might be correlated with cancer development and progression
Summary
Glioma, accounting for about 70% of malignant tumors in the central nervous system (CNS), is the most primary and lethal brain tumor [1,2,3]. Res. Public Health 2016, 13, 1021 generally no significantly improved clinical outcomes for glioma patients mainly due to their resistance to chemo-radiotherapy and insufficient understanding of the molecular mechanisms of glioma [5,6]. It is crucial to unravel the underlying molecular mechanisms and explore potential prognostic biomarkers, which contributes to the development of new effective therapeutic targets and strategies for glioma. RACK1 was composed of seven internal Trp-Asp 40 (WD40) repeats, which was similar to a bladed propeller structure [9]. This structure allowed RACK1 to interact with a variety of proteins and exert diverse functions. We examined the effect and underlying molecular mechanisms of RACK1 in the regulation of the cell cycle, apoptosis, migration, and invasion in glioma U87 and U251 cells
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