Astrocyte elevated gene-1 promotes tumour growth and invasion by inducing EMT in oral squamous cell carcinoma

Abstract

Oral squamous cell carcinoma (OSCC) is a common human malignancy with a high incidence rate and poor prognosis. Although astrocyte elevated gene 1 (AEG-1) expression is up-regulated in various human cancers and plays an important role in carcinogenesis and tumour progression, the impact of AEG-1 on the development and progression of OSCC remains unclear. Accordingly, this study aims to clarify the biological significance of AEG-1 in OSCC. We found AEG-1 to be overexpressed in OSCC tissues compared to normal oral mucosa. Knockdown or overexpression of AEG-1 in OSCC cell lines showed that AEG-1 is important for tumour growth, apoptosis, drug tolerance, and maintaining epithelial-mesenchymal transition (EMT)-mediated cell migration and invasion in vitro. Moreover, in a xenograft-mouse model generated by AEG-1-overexpressing SCC15 cells, we found that higher expression of AEG-1 promoted tumour growth, angiogenesis, and EMT in vivo. These findings provide mechanistic insight into the role of AEG-1 in regulating OSCC tumour growth, apoptosis, drug tolerance, and invasion, as well as AEG-1-induced activation of p38 and NF-κB signalling, suggesting that AEG-1 is an important prognostic factor and therapeutic target for OSCC.Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Each year, 1.6 million new cases of HNSCC are diagnosed, with half localized in the oral cavity (oral squamous cell carcinoma, OSCC), and 33,3000 deaths 1 . Indeed, OSCC is an important component of the worldwide cancer burden; despite radical surgery combined with radiation, chemotherapy and targeted therapy, OSCC has a 5-year survival rate of only approximately 50% 2 . The pathogenesis of OSCC is complex, involving many genes and pathways, though the mechanism of OSCC development remains unclear.Metastasis is dependent on unique mechanisms by which cancer cells escape from the primary tissue and spread to surrounding tissues. As part of the epithelial-mesenchymal transition (EMT), molecular reprogramming is a crucial step in the metastasis of most carcinomas 3 . During metastatic progression, EMT causes primary epithelial-like tumour cells to acquire invasive potential, including increased motility and mesenchymal characteristics, which results in dissemination from the original tumour and intravasation into the tumour vessel. EMT-driven cells circulating in the blood then redifferentiate into a primary status via the mesenchymal-epithelial transition (MET) during colonisation of and growth at distant metastatic sites 4,5 . Because of the important roles of EMT in the metastatic process, controlling EMT progression in tumours is thought to be a promising strategy to inhibit metastasis and prolong patient survival.Astrocyte elevated gene-1 (AEG-1), also known as metadherin (MTDH) or LYsine-RIch CEACAM1 co-isolated (LYRIC), is a 582-amino acid, type II transmembrane protein without any known functional domains. Recently, numerous reports have demonstrated that AEG-1 might play a pivotal role in the pathogenesis, ...

MicroRNA‑655 suppresses cell proliferation and invasion in oral squamous cell carcinoma by directly targeting metadherin and regulating the PTEN/AKT pathway

“…Among these candidates, MTDH was predicted as a major target of miR-655 ( Fig. 3A), which has been previously reported to be involved in OSCC occurrence and development (26)(27)(28)(29). To confirm this hypothesis, luciferase reporter assays were performed to determine whether the 3'-UTR of MTDH was directly targeted by miR-655 in OSCC cells.…”

“…In addition, MTDH was previously confirmed as an independent prognostic factor for overall survival rates in OSCC patients (26,27). Highly expressed MTDH was reported to serve important roles in the onset and the progression of OSCC by affecting tumor cell growth, colony formation, migration and invasion (26,28,29). MTDH has previously been reported to be involved in the regulation of the PTEN/AKT signaling pathway (23,24).…”

Effect of Huaier on Melanoma Invasion, Metastasis, and Angiogenesis

“…AEG-1 has emerged as an essential oncogene in regulating multiple aspects of cancer development and progression, including metastasis. It is important for tumor growth and cell migration and invasion mediated by EMT [19]. Increasing evidence shows that the level of AEG-1 is elevated in MM and that silencing of AEG-1 significantly inhibits the proliferation and metastasis of melanoma cells [20].…”

miR‐30e‐5p represses angiogenesis and metastasis by directly targeting AEG‐1 in squamous cell carcinoma of the head and neck

“…Only Ma et al have reported that MiR‐30e‐5p regulates the process of EMT in vitro; however, we also provide more pervasive in vivo evidence to strengthen the links between miR‐30e‐5p and EMT. In addition, mounting evidence has indicated that AEG‐1, as an oncogene, has an important function in the process of EMT and metastasis in diverse human solid cancers . miR‐30e‐5p and AEG‐1 can form an miR‐30e‐5p/AEG‐1 axis pathway, which regulates the metastasis and EMT of SCCHN.…”