Down-Regulation of PDCD4 Promotes Proliferation, Angiogenesis and Tumorigenesis in Glioma Cells.

Guo Pin,Yao Weicheng,Zhu Chengzhan,Li Zhaojian,Liu Wei,Li Shifang,Kong Xinjuan,Li Huanting,Feng Yugong,Yu Yanan,Qiu Yongming,Han Kun,Lin Yingying

doi:10.3389/fcell.2020.593685

Abstract

The programmed cell death 4 (PDCD4) tumor-suppressor gene regulates cell apoptosis, protein translation, signal transduction, and induction of mediators of inflammation. However, the mechanism by which PDCD4 is down-regulated and regulates tumor growth remains elusive. In this study, we showed that PDCD4 is down-regulated in glioma cells and acts as a tumor suppressor. Based on the TCGA data, we confirmed that AKT2, but not AKT1 or AKT3, interacts with PDCD4, thus leading to the suppression of PDCD4 in glioma cells. Moreover, the analysis suggested that PDCD4 regulates the expression of IL-5, CCL-5, VEGF, and CXCL10 via the NF-kB pathway. Additionally, depletion of levels of PDCD4 promoted angiogenic activity of glioma cells via the VEGF-STAT3 pathway. When tumor cells over-expressing PDCD4 were injected into nude mice, the increased expression of PDCD4 blocked tumorigenesis and prolonged overall survival. Our study indicates the need to develop drugs that can modulate the expression of PDCD4 and test their efficacy in clinical trials.

Highlights

Glioblastoma multiforme is the most aggressive tumor of the central nervous system, with an annual incidence rate of approximately 6 per 100,000 individuals (Hanif et al, 2017)
The analysis indicated programmed cell death 4 (PDCD4) to be significantly down-regulated in seven glioma cell lines than in normal astrocytes (Figures 1B,D), consistent with previous studies (Gaur et al, 2011; Liwak et al, 2013)
We found that the knockdown of PDCD4 suppressed colony formation in the monolayer culture, and anchorage-independent growth in soft agar assay (Figures 1E,F)

Summary

Introduction

Glioblastoma multiforme is the most aggressive tumor of the central nervous system, with an annual incidence rate of approximately 6 per 100,000 individuals (Hanif et al, 2017). The initiation and progression of glioma is regulated by various factors, including copy number variations, somatic mutations, epigenetic modifications, metabolic conversion, stem cell pathways, gene fusions and tumor microenvironment (Gladson et al, 2010). It is imperative to further explore efficient molecular-targeted therapies of glioma. The human programmed cell death 4 (PDCD4) was considered to encode a nuclear antigen and located on chromosome 10 (Azzoni et al, 1998). The expression of PDCD4 is regulated by interleukins IL-2, IL-12, and IL-15 (Ozpolat et al, 2007). The PDCD4 acts as a tumor-suppressor gene and performs essential functions in many biological events, including apoptosis, protein translation, signal transduction, and stimulation of inflammattion mediators (Zhang et al, 2014)

Methods

Results

Conclusion